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WO2008150324A1 - Subanalgesic doses of drug combinations - Google Patents

Subanalgesic doses of drug combinations Download PDF

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Publication number
WO2008150324A1
WO2008150324A1 PCT/US2008/004059 US2008004059W WO2008150324A1 WO 2008150324 A1 WO2008150324 A1 WO 2008150324A1 US 2008004059 W US2008004059 W US 2008004059W WO 2008150324 A1 WO2008150324 A1 WO 2008150324A1
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WIPO (PCT)
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dose
compound
pain
administration
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PCT/US2008/004059
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French (fr)
Inventor
Najib Babul
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Theraquest Biosciences, Inc.
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Publication of WO2008150324A1 publication Critical patent/WO2008150324A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds

Definitions

  • the present invention is directed to parenteral pharmaceutical compositions involving combinations of two or more analgesics and the use thereof for treating and preventing pain, inflammation and fever, wherein each component of the combination, selected from a different pharmacologic class, is given parenterally at a subanalgesic dose and wherein the combination provides robust analgesia with improved safety.
  • the present invention is also directed to a method of parenteral administration of pharmaceutical compositions of two or more analgesics to provide effective analgesic, anti-inflammatory and antipyretic effects and the use thereof for treating and preventing pain, inflammation and fever.
  • Acute pain is usually a consequence of an identifiable insult, such as surgery or other trauma, or a consequence of a disease, e.g. , kidney stones, mechanical low back pain, etc.
  • an identifiable insult such as surgery or other trauma
  • a disease e.g. , kidney stones, mechanical low back pain, etc.
  • public health statistics several hundred million people worldwide undergo inpatient or outpatient surgery each year.
  • several hundred million visits are made annually to the emergency room. Of these emergency room visits, it is estimated by survey data that more than 20% require analgesic treatment.
  • Recent studies have shown that more than 60% of patients who undergo surgery experience moderate to severe pain despite analgesic treatment.
  • opioid analgesics e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine
  • acetaminophen nonsteroidal anti-inflammatory drugs (NSAIDs) e.g., ketoprofen, ibuprofen, naproxen, tiaprofenic acid, aceclofenac, diclofenac, piroxicam, loxaprofen, fenoprofen, flurbiprofen, tenoxicam, lornoxicam, acetylsalicylic acid, flufenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, diflunisal, etodolac, fenbufen, isoxi
  • opioid analgesics e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine
  • neuro-active steroids including beta adrenergic agonists, e.g., albuterol; selective prostanoid receptor antagonists; NMDA antagonists; neuronal nicotinic receptor agonists; calcium channel antagonists; serotonin 5-HT(lB/lD) receptor agonists sodium channel blockers; cannabinoid agonists; superoxide dismutase mimetics; p38 MAP kinase inhibitors; triptans, TRPVl agonists; ketamine; NKl receptor antagonists; gabapentinoids; and glycine receptor antagonists.
  • beta adrenergic agonists e.g., albuterol
  • NMDA antagonists e.g., NMDA antagonists
  • neuronal nicotinic receptor agonists e.g., calcium channel antagonists
  • serotonin 5-HT(lB/lD) receptor agonists sodium channel blockers
  • cannabinoid agonists superoxid
  • parenteral drug formulations have become a very important component in the arsenal of available drug delivery options, particularly for drugs having analgesic, anti- inflammatory or antipyretic effects.
  • Parenteral routes of administration including subcutaneous, intramuscular, intrathecal, epidural and intravenous injection, offer numerous benefits over oral delivery in particular situations, for a wide variety of drugs.
  • parenteral administration of a drug typically results in attainment of a therapeutically effective blood concentration of the drug in a shorter time than is achievable by oral administration. This is especially true of intravenous injection, whereby the drug is placed directly into the bloodstream.
  • Parenteral administration by the intramuscular or subcutaneous routes can also offer rapid onset of effect in setting where intravenous access is possible or practical, such is in the usual family primary care physician's office or in settings where self-administration (e.g., subcutaneous administration) is possible to treat unexpected pain (e.g., breakthrough pain, migraine, etc).
  • Parenteral administration can also result in more predictable blood serum concentrations of a drug, because drug loss in the gastrointestinal tract due to absorption, distribution, metabolism, binding to food and other causes are eliminated.
  • Parenteral administration is generally the preferred method of drug delivery in emergency situations, and is also useful in treating subjects who are uncooperative, unconscious, or otherwise unable or unwilling to accept oral medication.
  • Parenteral drugs are particularly useful for treating a condition such as pain, inflammation or fever when: 1) the condition is of severe intensity; 2) there is a need for rapid onset of effect; 3) there is a need for a robust effect; 4) there is a need for rapid or frequent dose titration to keep condition under control; 5) the patient is unable to receive oral medication e.g., due to nausea, vomiting, confusion, obtundation, loss of consciousness and bowel obstruction.; and/or 6) the patient already has venous access or is in a medical facility (e.g., hospital or clinic).
  • a medical facility e.g., hospital or clinic
  • the incidence and severity of side effects limits the use of morphine in some patients (Hagen and Babul, Cancer 1997;79: 1428-37).
  • morphine's principal metabolites morphine-3-glucuronide and morphine-6-glucuronide can accumulate. Morphine-3-glucuronide accumulation has been implicated in hyperalgesia, respiratory stimulation, and behavioral excitatory properties through nonopioid receptor mechanisms.
  • Morphine-6-glucuronide accumulation has been implicated in increasing levels of nausea and sedation in patients with renal impairment (Babul and Darke, Clin Pharm Ther, 1993;54:286-92).
  • the principal metabolite of hydromorphone, hydromorphone- 3-glucuronide can accumulate in patients with renal impairment and has been found to be more neurotoxic than morphine-3-glucuronide (Babul and Darke, Pain, 1992;51:260-61; Hagen et al., J Clin Pharmacol, 1995;35:38-45; Babul et al., J Pain Symptom Manage, - -
  • morphine-like opioids include alfentanil, carfentanil, diamorphine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, lofentanil, meperidine, oxycodone, oxymorphone, racemorphan, remifentanil and sufentanil.
  • opioid agonists such as morphine, hydromorphone, oxycodone, fentanyl, carfentanil, lofentanil, alfentanil and sufentanil do not have a "dose ceiling". In other words, their doses can be increased almost indefinitely, being limited only by the occurrence of side effects.
  • opioids are nausea, vomiting, constipation, sedation, fatigue, pruritus, blurred vision, urinary retention, respiratory depression, convulsions, mood changes and alterations of the endocrine and autonomic nervous systems. Many of these side effects are sufficiently bothersome as to require: i) use of additional medications to treat the iatrogenic symptoms; ii) more intensive patient management; iii) use of lower doses that leave patients in continued pain; or iv) in other cases, complete discontinuation of analgesic therapy. Opioids can also produce potentially fatal respiratory depression at high doses. (Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No.
  • Undertreatment of pain may also occur when higher doses of opioid analgesics are required to manage the patient's pain due to: 1) prescribing resistance by clinicians and 2) patient and family barriers to dose escalation. Physicians frequently have exaggerated fears about the risk of iatrogenic addiction, respiratory depression and the risk of adverse regulatory sanctions. Similarly, patients and family members have fears about drug addiction and in some cases, equating increased opioid requirement with terminal disease, death and dying. - -
  • Opioids exert effects on the neuroendocrine system, including hypothalamic inhibition of the release of gonadotropin releasing hormone and corticotropin-releasing factor, thereby decreasing circulating concentrations of luteinizing hormone, follicle stimulating hormone, adrenocorticotropin and ⁇ -endorphin.
  • hypothalamic inhibition of the release of gonadotropin releasing hormone and corticotropin-releasing factor thereby decreasing circulating concentrations of luteinizing hormone, follicle stimulating hormone, adrenocorticotropin and ⁇ -endorphin.
  • plasma concentrations of testosterone and Cortisol decline.
  • the administration of opioids increases plasma prolactin concentrations, most likely by reducing the dopaminergic inhibition of prolactin secretion.
  • Opioid side effects are managed in a variety of ways, including: i) adjusting the dose; ii) adding a non-analgesic drug to manage side effects (e.g., a laxative or antiemetic); iii) switching to another opioid; and iv) using analgesic doses of a non-opioid analgesic.
  • An alternative strategy to provide optimal analgesia without intolerable side effects has involved use of lower doses of an opioid analgesic in combination with analgesic doses of one or more non-opioid drugs, thereby reducing the side effects that might otherwise occur from higher opioid doses given alone.
  • U.S. Patent No. 5,512,578 which is directed to a method for selectively enhancing the analgesic potency (inhibitory effects) of a bimodally acting opioid agonist such as morphine and simultaneously attenuating the development of physical dependence, tolerance and other undesirable side effects caused by chronic administration thereof, comprising co-administration of a bimodally acting opioid agonist and an opioid receptor antagonist which selectively inactivates excitatory opioid receptor-mediated side effects.
  • NMDA antagonist a tramadol analgesia-enhancing, but essentially subanalgesic dose of the NMDA antagonist's dextromethorphan or dextrorphan.
  • U.S. Patent No. 6,007,841 discloses an analgesic composition
  • an analgesic composition comprising a narcotic agonist-antagonist analgesic selected from the group consisting of pentazocine, nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, nalorphine, cyclazocine and an NMDA receptor antagonist.
  • the first tier for mild to moderate pain, consists of NSAIDs and acetaminophen with or without adjuvant medications.
  • a weak opioid such as codeine or hydrocodone
  • treatment progresses to the third tier: substitution of the "weak” opioid for a "strong” opioid (i.e., one more readily titrated to doses with greater analgesic efficacy).
  • the latter category includes morphine, hydromorphone, methadone, fentanyl, and levorphanol, all full opioid agonists at the morphine or mu receptor.”
  • the AHRQ report further notes that "if pain relief is not achieved at the maximum recommended dose of a particular NSAID or opioid, it should be discontinued and another drug from the same class tried before abandoning that class. Case series indicate that on an individual basis, other drugs from the same class may prove more effective or be better tolerated.”
  • the Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on Acute Pain Management (Guideline No. 1, AHRQ Publication No. 92-0032, February 1992) supports a generally similar approach to acute pain management.
  • the NSAIDs are highly effective as analgesics. They are used to treat both acute and chronic pain, usually by the oral route of administration.
  • the main mechanism by which NSAIDs exert an analgesic effect is through the inhibition of the synthesis of certain prostaglandin, or prostanoids.
  • the synthesis of prostanoids utilizes two distinct COX enzymes: COX-I and COX-2.
  • Traditional NSAIDs inhibit both enzymes.
  • NSAIDs may also inhibit other lipogenic enzymes, such as 5-lipooxygenase.
  • NSAIDs are not addictive, they are not without significant toxic effects, such as gastrointestinal injury, hepatotoxicity and decrease clotting ability.
  • Ketorolac is presently the only NSAID available in parenteral form in the United
  • parenteral ketorolac has been withdrawn from the market by the local health authorities, due to its high propensity to cause serious and life threatening side effects. Injectable ketorolac must be given every 4 to 6 hours to provide continuous relief of pain. In some countries, other parenteral NSAIDs such as diclofenac and lornoxicam are also available, but in most countries, ketorolac still remains by far the most frequently used injectable NSAID.
  • Parecoxib a parenteral COX-2 selective NSAID, has been approved in Europe with restrictions on its use and has been twice denied approval by the United States Food and Drug Administration for the management of acute post-surgical pain.
  • parecoxib the injectable prodrug of the now withdrawn drug, valdecoxib
  • An important early adverse postsurgical safety signal came from a CABG study included in the original U.S. NDA. In the parecoxib and valdecoxib group, 19.0% had serious adverse events, versus 9.9% in the placebo group.
  • NSAIDs When administered by the IV route, many NSAIDs are associated with one or more drawbacks, including poor solubility, pain on injection, venous irritation, thrombophlebitis, intramuscular pain and irritation, and the need to inject in a large volume of physiologic fluid and/or as a slow IV infusion (instead of as a bolus) to minimize local irritation.
  • drawbacks including poor solubility, pain on injection, venous irritation, thrombophlebitis, intramuscular pain and irritation.
  • Kostamovaara et al. (Br. J. Anaesth.
  • a formulation of injectable diclofenac is approved as a 75 mg/3 mL solution for IM administration. It contains benzyl alcohol as a solubilizing agent. Benzyl alcohol has been associated with a fatal toxic syndrome in premature infants, and parenteral preparations containing the benzyl alcohol are not recommended in neonates. (See British National Formulary, No. 49, March 2005). The 3 mL volume for IM administration is more that the 2 mL maximum recommended volume and therefore it may be associated with increased frequency and intensity of injection site pain. Some regulatory health authorities have required the following dosing language for IM diclofenac acid (Voltarol Ampoules. U.K. Summary of Product Characteristics, March 2005):
  • Diclofenac must not be given as an intravenous bolus injection. Diclofenac must be diluted with 100-500 mL of either sodium chloride solution (0.9%) or glucose solution (5%). Both solutions should be buffered with sodium bicarbonate solution (0.5 mL 8.4% or 1 mL 4.2%). Only clear solutions should be used. Two alternative regimens are recommended: For the treatment of moderate to severe post-operative pain, 75 mg should be infused continuously over a period of 30 minutes to 2 hours. If necessary, treatment may be repeated after 4-6 hours, not exceeding 150 mg within any period of 24 hours. For the prevention of post-operative pain, a loading dose of 25 to 50 mg should be infused after surgery over 15 minutes to 1 hour, followed by a continuous infusion of approximately 5 mg per hour up to a maximum daily dosage of 150 mg.”
  • Pain as a consequence of administration of a drug intended to ameliorate other pains can lead to patient refusal to accept therapy and require diagnostic workup to rule out infiltration, extravasation and infection at the injection site. It can also lead to further medical complications, increased reliance on opioid analgesics for pain relief, delayed discharge from hospital and increased cost of therapy. Patients report the pain sensation as stinging, burning, soreness, tenderness, aching, throbbing, cramping, gripping and radiating. It may be localized to the injection site or it may radiate to the proximal area, e.g., the arm. It may or may not be accompanied by redness.
  • Phlebitis is an inflammation of the vein in which endothelial cells of the venous wall become irritated and cells roughen, allowing the adherence of platelets.
  • the site is tender to touch and can be very painful. Phlebitis can prolong hospitalization unless it is treated early.
  • the process of phlebitis formation involves increased capillary permeability, resulting in leakage of proteins and fluids into interstitial space.
  • the traumatized tissue continues to be irritated chemically. This in turn provokes an immune reaction, resulting in mobilization of leukocytes release of inflammatory mediators [Phillips, LD, Manual of LV. Therapeutics, 3 rd Edition (2001), p.
  • Intravenous administration of NSAIDs in racemic or enantiomeric form including aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, felbinac, fenbufen, fenoprofen, fiufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen, indobufen, indomethacin, isonixin, isoxicam, ketorolac, ketoprofen, lo
  • Phlebitis occurs when a vein becomes inflamed by irritation or vesicant solutions or drugs. Although the use of a 0.5 to 1.0 micron inline filter can remove particulate matter not visible to the naked eye, it cannot eliminate the precipitation that occurs when the drug comes in contact with blood. Precipitation is considered to be a major cause of injection site pain, venous irritation and phlebitis.
  • Solvents, acids and bases, and some drugs can damage living tissue.
  • some dissolved drugs can produce undesirable pharmacological effects by reacting with specific receptors on the vein walls.
  • the undesirable effects caused pharmacologically and chemically are worsened by direct cellular contact with the highly concentrated precipitate.
  • precipitation of the drug within the vein upon dilution significantly exacerbates the irritation and is a key factor in determining the duration and severity of the irritation.
  • One approach to reducing mechanical, chemical and idiopathic IV NSAID irritation is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
  • One approach to reducing pain, irritation and muscular or subcutaneous toxicity after IM or SC (SQ) administration is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
  • SQ IM or SC
  • One approach to reducing pain, irritation and muscular or subcutaneous toxicity after IM or SC (SQ) administration is to drastically reduce the volume of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
  • One approach to reducing and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic or anti-inflammatory effect.
  • NSAIDS, epidural and intrathecal administration are contraindicated.
  • the volume is commensurately reduced, thereby providing the option of epidural and intrathecal NSAID administration.
  • One approach to improving the tolerability of NSAIDS after parenteral administration is to drastically reduce the dose of NSAID administered to the patient, thereby reducing the need for irritating and otherwise toxic or disagreeable pharmaceutical excipients such as benzyl alcohol.
  • the parenteral route of NSAID administration is usually used in the post-surgical pain, post-traumatic pain or intensive or critical care setting, where the patient is particularly predisposed metabolic stress, gastrointestinal perforation, ulcers and bleeding, and bleeding from the site of surgery or trauma.
  • These adverse effects, along with the aforementioned injection site effects are particularly important with the use of parenteral NSAIDS. Most of the adverse effects of NSAIDS are dose related. Consequently the lowest possible dose of an NSAID associated therapeutic effectiveness is usually suggested.
  • NSAID side effects can occur in any patients, some patient groups are at particular risk.
  • Patients at particular risk include those who: (i) are elderly; (ii) are cachectic' (iii) are immunocompromised; (iv) have a malignancy; (iv) are receiving corticosteroids; (v) with a history of significant alcohol consumption; (vi) are smokers; (vii) are receiving long-term NSAID therapy; (viii) are receiving high doses of NSAID's; (ix) have prior history of peptic ulcer disease, perforations and GI bleeding; (x) have ischemic heart disease; (xi) are undergoing CABD surgery; (xii) have a history of stroke; (xiii) are anticoagulated; (xiv) have a history of renal impairment and renovascular - -
  • NSAIDs for parenteral administration (e.g., intravenous [IM], intramuscular [IM], subcutaneous [SC], intrathecal [IT], epidural], particularly IV administration, there is a need for new therapeutic methods and pharmaceutical compositions that have analgesic, anti-inflammatory and antipyretic activity.
  • parenteral administration e.g., intravenous [IM], intramuscular [IM], subcutaneous [SC], intrathecal [IT], epidural]
  • analgesic, anti-inflammatory and antipyretic methods and pharmaceutical compositions that are: (i) readily soluble; (ii) have a reduced injection volume; (iii) have a rapid onset of effect; (iv) have a robust peak effect; (v) have a long duration of action; (vi) have a reduced incidence and severity of injection site pain, venous irritation and phlebitis; (vii) have a reduced propensity for gastrointestinal side effects, including dyspepsia, ulceration, perforation and bleeding; (viii) have a reduced frequency and severity of bleeding from or near the site of surgery or trauma; (ix) have a reduced frequency and severity of cardiovascular side effects; (x) have a reduced frequency and severity of injection site pain and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration; and (xi) have a reduced frequency and severity of other NSAID side effects.
  • An ideal parenteral NSAID formulation should provide robust analgesic, antiinflammatory, and antipyretic effects (rapid onset and high efficacy), as well as good tolerability at and around the injection site. Further, an ideal parenteral NSAID formulation should be safe for administration by the IM, IV, SC, IT and epidural routes. Additionally, an ideal parenteral NSAID formulation should be safe for administration by the IM, IV, SC, IT and epidural routes by avoiding the use of large quantities of potentially toxic solubilizing agents, e.g., benzyl alcohol and by avoiding or minimizing the risk of precipitation following injection.
  • potentially toxic solubilizing agents e.g., benzyl alcohol
  • One approach of the invention to encourage clinicians to liberally utilize parenteral NSAIDs and optimize pain control, especially in the setting of acute pain is to reduce the frequency and severity of NSAID associated side effects while providing an effective therapeutic intervention.
  • acute pain e.g., acute postsurgical pain, trauma, renal colic, burn pain, etc
  • clinicians are forced either manage pain, inflammation and fever sub- optimally or provide adequate analgesia while risking patient safety.
  • One approach of the invention to reducing the various know toxicities of parenteral NSAID therapy while providing robust analgesic, anti-inflammatory and antipyretic is to utilize subanalgesic doses of parenteral NSAID's in combination with subanalgesic doses of other analgesics, said combinations providing robust analgesia without side effects that plague the use of analgesic doses of such drugs.
  • NSAIDS and other drugs e.g., acetaminophen
  • intermittently e.g., Q4H, Q6H, Q8H, Q12H PRN
  • each individual dose provides a shorter duration of action. This in turn requires a more frequent dosing and can adversely impacts on: (i) nursing, pharmacy and other institutional resources; (ii) the cost of drug and supplies (syringes, alcohol swabs, sterile solution, infusion devices, etc); (iii) sterility and the risk of infection.
  • One approach of the invention to mitigate against the adverse consequences of increased dosing frequency is to administer the subanalgesic doses of parenteral NSAIDS and other drugs (e.g., acetaminophen) using patient controlled analgesia (e.g, patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g, patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • PCA patient controlled intravenous analgesia
  • PCEA patient controlled epidural analgesia
  • Current standard of care does not recommend administration of NSAIDS and acetaminophen by patient controlled analgesia.
  • the present invention stems, in part from the surprising discovery that usual recommended doses of parenteral analgesics, with their associated adverse safety profile are not required to provide effective analgesic, anti-inflammatory and antipyretic effects. Such effects may be achieved with subanalgesic doses, which have a reduced propensity for side effects.
  • the present invention stems, in part from the surprising discovery that usual recommended doses of parenteral NSAIDS given by IV infusion (e.g., over 5, 10, 15, 20 or 30 minutes), with their associated adverse safety profile are not required to provide effective analgesic, anti-inflammatory and antipyretic effects. Said effects may be achieved with subanalgesic doses NSAIDS given by IV bolus in combination with other drugs, which have a reduced propensity for side effects.
  • subanalgesic doses of NSAIDS and other drugs e.g., acetaminophen
  • patient controlled analgesia e.g., acetaminophen
  • subanalgesic doses of NSAIDS and other drugs e.g., acetaminophen
  • NSAIDS and other drugs e.g., acetaminophen
  • the subanalgesic doses the combination analgesic is preceded by one or more loading doses of the non-opioid analgesic of the combination by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said non-opioid by said route.
  • the present invention involves the use of subanalgesic doses (hereinafter, "SAD") of selected combination analgesics to provide effective analgesia.
  • SAD subanalgesic doses
  • the present invention involves the use of SAD of selected combination analgesics to provide effective anti-inflammatory effects.
  • the present invention involves the use of SAD of selected combination analgesics to provide effective antipyretic effects.
  • the present invention involves the use of SAD of selected combination analgesics to provide effective analgesic, anti-inflammatory and/or antipyretic effects while reducing the frequency and intensity of side effects.
  • the present invention involves the use of SAD of selected combination analgesics given by bolus injection to provide effective analgesic, antiinflammatory and/or antipyretic effects while reducing the frequency and intensity of side effects.
  • the present invention involves the use of SAD of selected combination analgesics given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) to provide effective analgesic, anti-inflammatory and/or antipyretic effects while reducing the frequency and intensity of side effects.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • the present invention involves the use of subanalgesic doses (SAD) of selected combination analgesics to provide effective analgesic, anti-inflammatory and antipyretic effects while reducing the frequency and intensity of selected combination analgesics side effects
  • SAD subanalgesic doses
  • a first aspect of the present invention is directed to a method and pharmaceutical compositions for eliciting a rapid analgesic, anti-inflammatory and antipyretic response after parenteral administration of selected combination analgesics, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a second aspect of the present invention is directed to a method and pharmaceutical compositions for eliciting a robust peak analgesic, anti-inflammatory, and/or antipyretic response after parenteral administration of selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a third aspect of the present invention is directed to a method and pharmaceutical compositions for improving the IV tolerability of a selected combination analgesic, e.g., reduced venous irritation, injection site pain, and phlebitis after IV bolus injection, slow IV injections, short term infusions and continuous infusions, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a selected combination analgesic e.g., reduced venous irritation, injection site pain, and phlebitis after IV bolus injection, slow IV injections, short term infusions and continuous infusions
  • a fourth aspect of the present invention is directed to a novel method for improving the intramuscular tolerability of a selected combination analgesic, e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage after IM injection, e.g., into the gluteus, deltoid, vastus lateralis, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a selected combination analgesic e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage after IM injection, e.g., into the gluteus, deltoid, vastus lateralis
  • a fifth aspect of the present invention is directed to a novel method for improving the SC tolerability of a selected combination analgesic, e.g., reduced injection site pain, subcutaneous irritation, inflammation and abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a selected combination analgesic e.g., reduced injection site pain, subcutaneous irritation, inflammation and abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions
  • a sixth aspect of the present invention is directed to a method and pharmaceutical compositions for directly administering a selected combination analgesic by the intravenous route without the need for prior dilution and/or administration through automated or gravity feed volume control devices, e.g., volutrol, minibag, large volume parenteral bag, syringe driver, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • automated or gravity feed volume control devices e.g., volutrol, minibag, large volume parenteral bag, syringe driver
  • a seventh aspect of the present invention is directed to a method and pharmaceutical compositions for safely administering a selected combination analgesic into soft tissue at the site of, or in close proximity to the pain and inflammation, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • An eighth aspect of the present invention is directed to a method and pharmaceutical compositions for improving the tolerability and safety of intrathecal and epidural administration of a selected combination analgesic, e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas after epidural or intrathecal administration, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a selected combination analgesic e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas after epidural or intrathecal administration
  • a ninth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of injection site pain, venous irritation and phlebitis of a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a tenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of gastrointestinal side effects, including nausea, vomiting, retching, constipation, dyspepsia, ulceration, perforation, bleeding and biliary spasm from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • An eleventh aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of bleeding from or near the site of surgery from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twelfth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of cardiovascular, cerebrovascular and pulmonary side effects, (e.g., myocardial infarctions, hypertension, peripheral edema, cerebrovascular accidents and pulmonary embolism) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • cardiovascular, cerebrovascular and pulmonary side effects e.g., myocardial infarctions, hypertension, peripheral edema, cerebrovascular accidents and pulmonary embolism
  • a thirteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of postsurgical wound complications (e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • postsurgical wound complications e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling
  • a fourteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of postsurgical blood loss from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a fifteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and amount of blood transfusion from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a sixteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of renal and renovascular complications from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a fifteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of hepatic complications from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a sixteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of surgical complications from orthopedic surgery or bone manipulation (e.g., non-union, malunion, avascular necrosis) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics. - -
  • a seventeenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of other NSAID side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • An eighteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of drug-drug interactions, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a nineteenth aspect of the present invention is directed to pharmaceutical compositions comprising SAD of selected combination analgesics.
  • a twentieth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of CNS side effects (e.g., sedation, fatigue, convulsions, obtundation, coma, mood changes, physical dependence, addiction, hyperalgesia and respiratory depression) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • CNS side effects e.g., sedation, fatigue, convulsions, obtundation, coma, mood changes, physical dependence, addiction, hyperalgesia and respiratory depression
  • a twenty-first aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of other opioid side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-first aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of other acetaminophen and acetaminophen analog side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-second aspect of the present invention is directed to a method and pharmaceutical compositions for reducing the volume for parenteral administration (e.g., less than 1 mL, or less than 2 mL, or less than 5 mL, or less than 10 mL), said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a method and pharmaceutical compositions for reducing the volume for parenteral administration e.g., less than 1 mL, or less than 2 mL, or less than 5 mL, or less than 10 mL
  • a twenty-third aspect of the present invention is directed to a method and pharmaceutical compositions for allowing safe bolus parenteral administration, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-third aspect of the present invention is directed to a method and pharmaceutical compositions for allowing longer duration of therapeutic effect, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-fourth aspect of the present invention is directed to a method and pharmaceutical compositions for allowing longer duration of therapeutic effect, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-fifth aspect of the present invention is directed to a method and pharmaceutical compositions for allowing safe parenteral over a few minutes (e.g., less than 1 minute, or less than 2 minutes, or less than 5 minutes), said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-sixth aspect of the present invention is directed to a method and pharmaceutical compositions for providing comparable analgesia with reduced side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-seventh aspect of the present invention is directed to a method and pharmaceutical compositions for providing early patient ambulation and physiotherapy, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-eighth aspect of the present invention is directed to a method and pharmaceutical compositions for providing reduce the risk of deep vein thrombosis and pulmonary embolism, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a twenty-ninth aspect of the present invention is directed to a method and pharmaceutical compositions for providing faster restoration of normal bowel function - -
  • said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a thirtieth aspect of the present invention is directed to a method and pharmaceutical compositions for reducing the duration of hospitalization or medical facility stay, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a thirty-first aspect of the present invention is directed to a method and pharmaceutical compositions for reduced motor, psychomotor and cognitive impairment during the period of analgesic, anti-inflammatory and antipyretic administration (e.g., improved performance scores on driving simulation, reaction time, trail making, finger tapping, digit substitution and other tests known in the art), said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
  • a thirty second aspect of the present invention is directed to a method and pharmaceutical compositions for reducing pain, irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics, said combination analgesics administered in reduced injection volume of selected combination analgesics
  • a thirty third aspect of the present invention is directed to a method and pharmaceutical compositions for reducing pain, irritation, nerve damage, sterile abscess, and muscular or subcutaneous toxicity after IM or SC (SQ) administration, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics, said combination analgesics administered in reduced injection volume.
  • a thirty fourth aspect of the present invention is directed to a method and pharmaceutical compositions for improving the safety and tolerability of selected combination analgesics after parenteral administration, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics, said combination analgesics administered with a reduced need for irritating and otherwise toxic or disagreeable pharmaceutical excipients and solubilizing agents.
  • a thirty fifth aspect of the present invention is directed to a method and pharmaceutical compositions for improving the efficiency of pain management after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • a thirty sixth aspect of the present invention is directed to a method and pharmaceutical compositions for reducing pharmacy, nursing and/or institutional resources for pain management after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • a thirty seventh aspect of the present invention is directed to a method and pharmaceutical compositions for reducing drug and ancillary supply costs (e.g., sterile infusion containers, sterile swabs, syringes, etc) associated with parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • a thirty eighth aspect of the present invention is directed to a method and pharmaceutical compositions for reducing the risk of infection after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), preferably with a closed loop system.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • a thirty ninth aspect of the present invention is directed to a method and pharmaceutical compositions for providing effective pain relief after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said SAD of selected combination analgesics having an improved safety profile compared with usual doses of selected combination analgesics.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • PCA patient controlled intravenous analgesia
  • PCEA patient controlled epidural analgesia
  • a fortieth aspect of the present invention is directed to a method and pharmaceutical compositions for providing pain relief with reduced side effects after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics given by bolus injection.
  • a forty first eighth aspect of the present invention is directed to a method and pharmaceutical compositions for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral administration of selected combination analgesics, said method comprising administering one or more loading dose(s) of at least the non-opioid from the selected combination analgesics, followed by a therapeutically effective amount of SAD of selected combination analgesics given by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said non-opioid by the specified route of administration.
  • a forty second aspect of the present invention is directed to a method and pharmaceutical compositions for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics complexed to or in conjunction with ethylenediamine and/or piperazine.
  • a forty third aspect of the present invention is directed to a method and pharmaceutical compositions for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics in conjunction with glycine.
  • FIG. 1 illustrates a simulated plasma NSAID concentration after administration of drug as a rapid IV injection (IV bolus or IV push), as a slow IV infusion over 30 to 120 minutes, and after IM administration.
  • FIG. 2 illustrates the dynamic in vitro apparatus used for predicting mechanical phlebitis.
  • a Harvard Apparatus Precision Syringe Pump 22 was used to direct ISPB (which is used as a blood surrogate in this experiment), at pH 7.4 and 25 C, through a 40- cm length of flexible Tygon ® plastic tubing (type R-3603, inner diameter of 3mm), then through a Hellma QS quartz flow-through cell with a 1-cm path length at a 5 mL/min flow rate. This flow rate is comparable to that of human blood flow in readily accessible arm veins.
  • ISPB at pH 7.4 was chosen over plasma because it has a buffer capacity of 0.03.
  • a Beckman DU 640 ultraviolet spectrophotometer holding the flow-cell was used to read occlusion of light.
  • the 22-gauge Becton Dickinson Precision Glide sterile stainless steel needle of a 20-mL latex-free Becton Dickinson plastic syringe containing each formulation to be tested was introduced into the flexible tubing at 10 cm upstream from the flow cell. If a formulation precipitates upon injection, it produces opacity in the tubing, which passes through the flow cell and is interpreted by the spectrophotometer as reduced transmittance or increased absorbance.
  • FIG. 3 illustrates a UV wavelength-scan for ketoprofen-ethylenediamine (50 mg/mL) demonstrating absence of absorbance at 540 nm.
  • FIG. 4 illustrates dynamic dilution test profile for ketoprofen-ethylenediamine (50 mg/mL) formulation at 540 nm.
  • FIG. 5 illustrates a UV wavelength-scan for ketoprofen-piperazine (50 mg/mL) demonstrating absence of absorbance at 540 nm.
  • FIG. 6 illustrates dynamic dilution test profile for ketoprofen-piperazine (50 mg/mL) formulation at 540 nm.
  • FIG. 7 illustrates a UV wavelength-scan for ketoprofen-piperazine (50 mg/mL) demonstrating absence of absorbance in a 1:1 ratio at 540 nm.
  • FIG. 8 illustrates dynamic dilution test profile for ketoprofen-piperazine (50 mg/mL) formulation in a 1 :1 ratio at 540 nm
  • FIG 9 illustrates a UV wavelength-scan for phenytoin sodium (50 mg/mL), a drug with high phlebitis potential, demonstrating absence of absorbance at 540 nm.
  • FIG 10 illustrates dynamic dilution test profile for phenytoin sodium (50 mg/mL).
  • the Y axis is 10 times higher for phenytoin sodium compared to all other formulations.
  • FIG. 11 illustrates dynamic dilution test profile for unsalif ⁇ ed ketoprofen suspension (50 mg/mL) adjusted to pH 6.50 and filtered through a 0.45 micron filter before injection at 540 nm, showing approximately 80 and 440-fold greater propensity for precipitation relative to ketoprofen ethylenediamine and ketoprofen piperazine without pH adjustment, respectively.
  • FIG 12 shows pain relief over time on a five point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg ( ⁇ ); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg (• star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • FIG 13 shows total pain relief or TOTPAR over 0-2, 0-4, 0-6 and 0-8 hours derived from a five point categorical pain relief scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg ( ⁇ star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • FIG 14 shows pain intensity difference or change in pain intensity from baseline over time on a four point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg (• star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • FIG 15 shows the sum of pain intensity difference (SPID) over time derived using a four point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg (* star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • SPID pain intensity difference
  • FIG 16 shows pain intensity difference or change in pain intensity from baseline over time on 0-100 mm visual analog scale (VAS) in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg ( * star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • VAS visual analog scale
  • FIG 17 shows the sum of pain intensity difference derived using a 0-100 mm visual analog scale (VAS) in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg (• star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • VAS visual analog scale
  • FIG 18 shows the sum of pain intensity and pain relief (SPRID) derived using the four point categorical pain intensity and the five point categorical pain relief scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg ( * star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • SPRID pain intensity and pain relief
  • FIG 19 shows the patient's global evaluation of treatment in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg; 50% of the minimum approved dose of ketoprofen, 50 mg; 150% of the maximum approved dose of tramadol, 150 mg; maximum approved dose of tramadol, 100 mg); and maximum recommended bolus dose of morphine, 4 mg; represented as percent of patients and collected using the following descriptors, from left to right: Poor, Fair, Good, Very Good and Excellent. Patients with Good, Very Good and Excellent are considered to have a positive or favorable treatment outcome. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a method of treating or preventing pain, inflammation or fever comprising administering to a subject in need of such treatment or prevention subanalgesic doses (SAD) of selected combination analgesics, in racemic, enantiomeric excess or enantiomeric form.
  • SAD subanalgesic doses
  • one or more selected analgesic refers to administering a pharmaceutical composition comprising at least one compound each selected from at least two of the three groups below (a, b, c): a.
  • NSAIDS cyclooxygenases (COX-2 and/or COX-I inhibitors) including aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, celecoxib, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, flufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen, indobufen, indom
  • COX-2 and/or COX-I inhibitors
  • opioid receptor agonists i.e., mu ( ⁇ ), delta ( ⁇ ), kappa (K) and /or nociceptin/orphanin FQ (N/OFQ) opioid receptors
  • opioid receptor agonists i.e., mu ( ⁇ ), delta ( ⁇ ), kappa (K) and /or nociceptin/orphanin FQ (N/OFQ) opioid receptors
  • their subtypes and splice variants including alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, brifentanil, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, - -
  • opioid receptor agonists i.e., mu ( ⁇
  • dihydrocodeine dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromo ⁇ hone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmo ⁇ hine, metopon, mirfentanil, morphine, morphine-6- glucuronide (M6G), myrophine, nalbuphine, narceine, nicomorphine, norlevo ⁇ hano
  • acetaminophen analogs including acetaminophen, propacetamol, prodrugs of acetaminophen, nitroparacetamol and nitric-oxide donating acetaminophen analogs in racemic, enatiomeric or enantiomeric excess, pharmaceutically acceptable salts thereof of mixture thereof.
  • a pharmaceutical composition comprising at least one compound each selected from at least two of the three groups below (a, b, c): a. one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and
  • SAD refers to "subanalgesic dose”, “subanalgesic doses” and “subanalgesic dosage”, wherein the subanalgesic compound is chosen from the group of compounds defined herein as selected combination analgesics.
  • Subanalgesic doses are doses of selected combination analgesics given by a specified route of administration which are lower than the minimum approved or recommended unit dose, individual dose, and/or daily dose of the selected combination analgesics, where said "approved” or “recommended” is approval or recommendation with respect to a parenteral selected combination analgesics dose by a supranational, national, federal, regional, state, provincial, governmental and/or territorial health authority or drug regulatory authority, a major pharmacopeia (e.g., US Pharmacopeia, British Pharmacopeia, European Pharmacopeia, Japanese Pharmacopeia and the like), Physician's Desk Reference (PDR), Thomson Publications; Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker, eds, 11th ed., McGraw Hill (2005); or Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); or Martindale: The Complete Drug Reference
  • approved or “recommended” refers to a recommended or suggested parenteral dose of selected combination analgesics by a specified route of administration in a peer review journal cited in MEDLINETM or EMBASETM, or in its absence, the approved or recommended oral doses of the selected combination analgesics.
  • the minimum approved or recommended dose is the approved or recommended dose, as defined, as of the priority date of this patent application.
  • the SAD of a specified combination analgesic refers to not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration.
  • the SAD of a specified combination analgesic refers to a dose of said analgesic given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
  • the SAD of a specified combination analgesic refers to a dose of said analgesic given by bolus injection, said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration.
  • the SAD of a specified combination analgesic refers to a dose of said analgesic given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or - -
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65,
  • the SAD of a specified combination analgesic refers to a dose of said analgesic which is not more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration, wherein said SAD of non-opioid analgesic is preceded by one or more loading dose of said non-opioid by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said non-opioid by the specified route of administration.
  • Nonsteroidal anti-inflammatory drugs typically have analgesic, anti-inflammatory, and antipyretic properties. Their mode of action appears to involve inhibition of cyclooxygenases (COX-I and COX-2), leukotriene biosynthesis, and antibradykinin activity.
  • NSAIDs may be non-selective (inhibit COX-I and COX-2 isozymes) or COX-2 selective (preferentially inhibit the COX-2 isozymes). NSAIDs can produce a wide variety of adverse effects.
  • analgesic For each selected combination analgesic, standard of care, randomized clinical trials, evidence based medicine, anecdotal evidence, medical practice, tradition guide the selection of the range of doses utilized for the analgesic, anti- inflammatory and antipyretic effects in order to provide analgesia with the fewest possible side effects.
  • Most NSAID analgesic use is by the oral route and for a majority of NSAIDs there are no data on efficacy or safety on their use by the parenteral route of administration. Although the exact mechanisms of adverse effects have not been clearly established, at least some appear related to COX-I inhibition, while at least some of the cardiovascular complications appear to be related to COX-2 inhibition.
  • NSAIDs In addition to their gastrointestinal adverse effects, NSAIDs produce dose related inhibition of platelet aggregation, prolongation of bleeding time, renal impairment, and hepatotoxicity. Parenteral administration can produce injection site burning and pain.
  • Ketoprofen ( ⁇ )-2-(3-benzoylphenyl)propionic acid) or ( ⁇ ,5>2-(3-benzoylphenyl) propionic acid), is a NSAID with analgesic, anti-inflammatory and antipyretic properties. These properties of ketoprofen have been demonstrated in classical animal models and in vitro test systems. Its mode of action appears to be similar to that of other NSAIDs and includes inhibition of prostaglandin (COX-I and COX-2 inhibition) and leukotriene biosynthesis, antibradykinin activity, and lysosome membrane-stabilizing activity. Chemically, ketoprofen belongs to the group of substituted 2-phenylpropionic acids.
  • ketoprofen (3-benzoylphenyl)propionic acid (dexketoprofen), is marketed in a number of countries in a variety of forms, including oral solids, suppositories, and a topical gel.
  • Ketoprofen is soluble in benzene, ethanol, chloroform, acetone, ether, and alkaline solutions, but it is practically insoluble in water.
  • Ketoprofen is marketed as an IM 100 mg/2 mL formulation (Profenid ® , France, Aventis, Oruvail ® , Hawgreen, UK) and as a lyophilized powder for intravenous use.
  • the maximum daily dose by this route is 300 mg.
  • the IM formulation containing benzyl alcohol
  • This formulation is approved for deep intramuscular injection into the gluteal muscle, 50- 100 mg every 4 hours (max. 200 mg in 24 hours) for up to 3 days.
  • IM intramuscular
  • IM solution containing arginine, benzyl alcohol, citric acid, and water for injection
  • IM administration does not provide a very rapid onset of effect, and it is painful, especially with repeated administration or with a large injection volume.
  • Most clinicians and hospitals discourage the repeated IM administration of drugs and the use of - -
  • IM injection volumes greater than 1 mL are generally strongly discouraged or prohibited from routine use. Furthermore, IM administration is not appropriate in many patients due to an absence of adequate muscle mass and the possibility of bleeding and hematoma formation, especially if anticoagulated with drugs like heparin or warfarin. IM administration of the acid formulation of NSAIDs has also been associated with sever nerve damage, muscle tissue necrosis, and even death.
  • a separate IV formulation of racemic ketoprofen is available in a few countries as a lyophilized powder containing sodium hydroxide, glycine, and citric acid. It is recommended by the manufacturer that IV ketoprofen be diluted in 100 to 150 mL of 5% dextrose in water or 0.9% saline and administered over approximately 20 minutes.
  • IV ketoprofen be diluted in 100 to 150 mL of 5% dextrose in water or 0.9% saline and administered over approximately 20 minutes.
  • an infusion of ketoprofen over 20 minutes means that the onset of analgesia is delayed and the peak pain relief is lower, owing to lower maximal blood concentrations.
  • ketoprofen can cause significant side effects, including venous irritation.
  • venous irritation See, e.g., Castagnera, L., et al., Sem Hop Paris 64(32):2179- 2182 (1988); Semaine des hospitaux (Paris) 32:2179-88 (1988)).
  • ketoprofen by the intravenous route has been limited by the poor solubility of the drug, the need to administer it in a large volume of solution (100 to 150 mL), the need to infuse the dose over 15 to 20 minutes and the need to use solubilizers that can be toxic and that can result in drug precipitation upon injection.
  • PCT Patent application number PCT/US2006/016078 discloses novel formulations of ketoprofen, dexketoprofen, piroxicam and tenoxicam, with ethylenediamine and/or piperazine.
  • Piroxicam is an N-heterocyclic carboxamide of 1,2 benzothiazine 1,1 dioxide with analgesic and anti-inflammatory activity. It has an extended half-life of about 40 hours and is suitable for once daily administration. It is primarily biotransformed in the liver to inactive metabolites; less than 10% of a dose appears unchanged in the urine. Evidence from clinical trials indicates that piroxicam 20 mg per day is comparable to daily doses of aspirin 3 to 6 g, indomethacin 75 to 150 mg, naproxen 500 mg, ibuprofen 1200 to 2400 mg, diclofenac 75 mg and fenbufen 600 mg.
  • Piroxicam has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, acute gouty arthritis, ankylosing spondylitis, acute musculoskeletal disorders, dysmenorrhea, renal colic and acute postsurgical pain.
  • the usual adult dose of oral piroxicam is 20 to 40 mg given once a day.
  • Tenoxicam an NSAID with an oxicam structure (4-Hydroxy-2-methyl-N-2- pyridinyl-2H-thieno(2,3-e)-l,2-thiazine-3-carboxamide 1,1 -dioxide), is entirely ionized at physiological pH, has minimal lipophilic properties, high plasma protein binding, does not accumulate in fatty tissue and skin and thus has a small volume of distribution. It is completely absorbed via the oral route and is about 99% protein bound in human plasma. Food consumption delays its rate of absorption without affecting its bioavailability. An elimination half-life of 50 to 80 hours has been estimated. Tenoxicam demonstrates linear pharmacokinetics over the 10 to 100 mg dose range.
  • tenoxicam is poorly distributed into body tissues. Tenoxicam is primarily biotransformed in the liver. Its two major metabolites, the 5'-hydroxy and 6-O-glucuronidated products are inactive and are excreted in urine and bile, respectively. Tenoxicam demonstrates linear pharmacokinetics during multiple- dosing. As a result of its long half-life, tenoxicam can be administered once daily. Clinical trials in patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout suggest that tenoxicam 20 mg daily is an effective anti-inflammatory and analgesic agent. Gastrointestinal symptoms are the most frequently reported side effects. Compared with many other NSAIDs, tenoxicam offers certain advantages in that it is conveniently administered once daily and dosage adjustment is not required in the elderly or in patients with renal or hepatic.
  • Ketorolac ( ⁇ )-5-Benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid
  • the absorption of ketorolac is rapid, with peak plasma concentrations occurring between 20 to 60 minutes post-dose.
  • the oral bioavailability of ketorolac is estimated to range from 80 to 100%.
  • the drug is extensively bound to plasma - -
  • Ketorolac is extensively metabolized through glucuronidation and oxidation and very little is excreted unchanged. Most of the dose of ketorolac is recovered in the urine as conjugate. Ketorolac is the only nonsteroidal anti- inflammatory drug (NSAID) in widespread clinical use that is available in an injectable form. Ketorolac is presently the only NSAID available in parenteral form in the United States.
  • NSAID nonsteroidal anti- inflammatory drug
  • ketorolac provides efficacy comparable to that standard doses of opioid analgesics.
  • parenteral ketorolac has demonstrated efficacy in patients with renal colic, migraine headache and musculoskeletal pain.
  • the utility of ketorolac in acute pain is somewhat limited due to a prolonged time to onset of analgesia.
  • the clinical utility of parenteral ketorolac is limited due to its adverse effect profile and a restriction on duration of use. In a number of countries, including France, Germany, The Netherlands, Portugal, and Greece, injectable ketorolac has been withdrawn from the market by the local health authorities, due to its high propensity to cause serious and life threatening side effects.
  • Diclofenac (2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid) is an effective analgesic, antipyretic, and anti-inflammatory. It is rapidly absorbed after oral administration, undergoes extensive protein binding and has a short half-life. It undergoes significant first-pass metabolism, with approximately 50% of the dose biotransformed upon first pass through the liver. Diclofenac is metabolized in the liver by CYP2C to 4-hydroxydiclofenac, its primary metabolite, and to other hydroxylated forms. Following glucuronidation and sulfation the metabolites are excreted in the urine and bile.
  • Diclofenac is approved in the United States for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Diclofenac has also been extensively studied in the short-term treatment of acute musculoskeletal pain, postsurgical pain and dysmenorrhea. The major adverse events with diclofenac are gastrointestinal (approximately 20%). Elevations in hepatic transaminases occur in a significant number of patients. In some patients, transaminase levels may increase more than 3-fold. Other - -
  • diclofenac side effects of diclofenac include rashes, allergic reactions, fluid retention and edema.
  • diclofenac appears to have the greatest risk of adverse cardiovascular outcomes.
  • Ibuprofen ( ⁇ -Methyl-4-(isobutyl)phenylacetic acid), the most commonly used
  • NSAID in the United States was the first member of the propionic acid class of NSAIDs to become commercially available.
  • Naproxen, flurbiprofen, fenoprofen, ketoprofen, and oxaprozin are other drugs in the propionic acid class of NSAIDs that have been widely commercialized.
  • Naproxen has a longer half-life than ibuprofen.
  • Oxaprozin also has a long half-life and may be given once daily.
  • Propionic acid derivatives are approved for use in the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain (e.g., postsurgical pain, musculoskeletal pain, primary dysmenorrhea).
  • the pharmacodynamics of the propionic acid derivatives do not differ greatly.
  • Ibuprofen has a half-life of approximately 2 hours. It is rapidly absorbed and undergoes significant hepatic biotransformation, followed by renal excretion of metabolites. Gastrointestinal adverse events are common with ibuprofen. Other side effects include rashes, headache, dizziness, fluid retention, and edema.
  • Ibuprofen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain.
  • Naproxen (( 1 S)-(+)-2-(6-Methoxy-2-naphthyl)propionic acid) is almost completely absorbed upon oral administration. Food delays the rate of absorption. Peak naproxen concentrations in plasma occur within 2 to 4 hours. Naproxen is about 99% protein bound. The half-life of naproxen in plasma is about 14 hours in the young, with a 2-fold increase observed in elderly patients. Approximately one-third of the dose of naproxen undergoes 6-demethylation. This metabolite, along with naproxen is excreted as conjugated products. Gastrointestinal side effects are common. Other side effects include drowsiness, headache, dizziness and fatigue. Naproxen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain.
  • Flurbiprofen (2-Fluoro- ⁇ -methyl-4-biphenylacetic acid ) is a chiral NSAID of the
  • Flurbiprofen is rapidly and almost completely absorbed when given orally.
  • the area under the plasma concentration-time curve of flurbiprofen is proportional to the dose administered to patients. Flurbiprofen binds extensively to plasma albumin and substantial concentrations of the drug are attained in synovial fluid. It is eliminated following extensive glucuronidation. Metabolites are primarily excreted in urine and approximately 20% of flurbiprofen is eliminated unchanged. Flurbiprofen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain. Side effects include hypertension, congestive heart failure, gastrointestinal ulceration, bleeding and perforation, renal and hepatic impairment.
  • Lornoxicam (6-Choloro-4-Hydroxy-2-methyl-N-2-pyridinyl-2H-thieno(2,3-e)- l,2-thiazine-3-carboxamide 1,1 -dioxide or chlorotenoxicam) is a nonsteroidal antiinflammatory drug of the oxicam class. Unlike other oxicams, lornoxicam has a relatively short plasma half-life (of approximately 3 to 5 hours. Lornoxicam is eliminated through hepatic metabolism to 5'-hydroxylornoxicam. Lornoxicam's metabolites are excreted in urine and feces. Lornoxicam and its major metabolites bind extensively to plasma proteins. Lornoxicam has been shown to be effective in the treatment of acute and chronic pain, including postsurgical pain and osteoarthritis. Lornoxicam's side effects are consistent with its NSAJD pharmacology.
  • NSAID associated toxicity including intravenous tolerability (e.g., venous irritation, injection site pain and reduced phlebitis), intramuscular tolerability, (e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage), subcutaneous tolerability (e.g., injection site pain, subcutaneous irritation and abscesses), intrathecal and epidural tolerability (e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas), cardiovascular side effects (e.g., hypertension, peripheral edema, fluid retention, congestive heart failure and myocardial infarction), renal and hepatic complications, complications from orthopedic surgery or bone manipulation (e.g., nonunion, malunion, avascular necrosis), gastrointestinal side effects (e.g., including dyspepsia, ulceration, perforation and bleeding), postsurgical wound complications
  • the rate of absorption of celecoxib is moderate when given orally, with a Cmax of approximately 2 to 4 hours.
  • Celecoxib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455 ⁇ 166 L.
  • the extent of absorption of celecoxib increases in proportion to increasing oral doses between 100 and 800 mg. It is eliminated following biotransformation to carboxylic acid and glucuronic acid metabolites that are excreted in urine and feces.
  • Celecoxib has an elimination half-life of approximately 11 hours in healthy individuals. In randomized clinical trials, celecoxib is superior to placebo and similar in efficacy as conventional NSAIDS for osteoarthritis and rheumatoid arthritis.
  • celecoxib 100 and 200 mg and naproxen 500 mg twice daily provide similarly efficacy.
  • celecoxib 200 mg twice daily shows efficacy comparable to twice daily slow-release diclofenac 75 mg over a 24-week period.
  • Parecoxib a prodrug of valdecoxib is the only parenterally administered cyclooxygenase-2-selective inhibitor available. The recommended dose is 40 mg administered IV or IM, followed every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. Clinical trials of parecoxib demonstrate comparable efficacy with ketorolac in a variety of postsurgical pain states. However, parecoxib has significant adverse cardiovascular risk (Babul et al, Anesthesia and Analgesia 2006;102:644-56; Babul et al., Anesthesiology 2006; 104:375).
  • Lumiracoxib is a selective COX-2 inhibitor with an oral bioavailability of 74%. It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. It has a short elimination half-life from plasma of approximately 4 hours and demonstrates dose-proportional plasma pharmacokinetics. Lumiracoxib is extensively metabolized prior to excretion, with only a small amount - -
  • lumiracoxib is excreted unchanged in urine or feces. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen.
  • lumiracoxib 100 to 200 mg per day has been shown to be superior to placebo in patients with osteoarthritis, with clinical efficacy comparable to diclofenac 150 mg/day, celecoxib 200 mg/day and rofecoxib 25 mg/day.
  • lumiracoxib 400 mg/day is as effective as standard doses of NSAIDs and other coxibs. Liver function test abnormalities were more frequent with lumiracoxib than with the comparator NSAIDS. There are no data on the efficacy of parenterally administered lumiracoxib. Lumiracoxib has been withdrawn from the market in a number of countries due to serious hepatic adverse effects.
  • Etoricoxib is a selective inhibitor of COX-2. Extensive clinical trials have confirmed its analgesic and anti-inflammatory efficacy to be comparable to nonselective NSAIDS. Like other COX-2 selective NSAIDS, etoricoxib displays improved gastrointestinal safety compared with nonselective NSAIDS. It is rapidly and completely absorbed following oral administration providing a rapid onset of action. Its long plasma half-life allows for once-daily dosing. Etoricoxib is currently approved in a number of countries for various indications including the treatment of acute pain, acute gouty arthritis, chronic back pain, dysmenorrhea, osteoarthritis and rheumatoid arthritis.
  • etoricoxib is 30 mg once daily (maximum daily dose, 60 mg) for OA, 90 mg once daily for RA (maximum daily dose, 90 mg) and 120 mg once daily for acute gouty arthritis (maximum daily dose, 120 mg for up to 8 days).
  • NSAID side effects including: (i) intravenous injection site pain, venous irritation and phlebitis; (ii) the propensity for gastrointestinal side effects, including dyspepsia, ulceration, perforation and bleeding; (iii) bleeding from or near the site of surgery; (iv) bleeding from nonsurgical sites; (v) cardiovascular, cerebrovascular and pulmonary side effects, including myocardial infarctions, hypertension, peripheral edema, cerebrovascular accidents and pulmonary; (vi) the injection site pain and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration; (vii) intramuscular injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage; (viii) bleeding and bleeding risk in anticoagulated patients; (ix) renal and renovascular impairment; (x) hepatic impairment; and (xi) subcutaneous injection site pain, subcutaneous irritation, inflammation
  • Acetaminophen is administered intravenously as a prodrug (propacetamol) and more recently as the unsalified product.
  • Propacetamol and acetaminophen can produce venous irritation and have only modest analgesia, comparable to approximately 30 to 50% that provided by analgesic doses of NSAIDs even when the dose of intravenous acetaminophen is doubled to 2 g, its efficacy is significantly inferior to analgesic doses of NSAIDs.
  • 1 gram intravenous acetaminophen in postsurgical pain demonstrates a duration of action of less than three hours.
  • acetaminophen Since the maximum permissible daily dose of acetaminophen is 4 grams per day, 24-hour analgesic coverage is not achievable with intravenous acetaminophen. In addition to its suboptimal efficacy, acetaminophen does not possess an anti-inflammatory effects which have now been deemed. Acetaminophen is devoid of meaningful anti-inflammatory effects which are now believed to be important for the optimal control of post-surgical pain. There are also safety significant concerns about the use of acetaminophen in the setting of both acute and chronic pain, including untoward renal and hepatic effects. Intravenous acetaminophen and propacetamol require dilution in a large volume of infusate and is then given over 10 to 20 minutes. There is therefore a need for alternative strategies that optimize the analgesic and antipyretic effects of acetaminophen and that also provide anti-inflammatory effects.
  • Levorphanol (7-3-Hydroxy-N-methylmorphinan) tartrate dihydrate is a potent narcotic analgesic with a molecular formula of Ci 7 H 23 NO . C 4 H 6 O 6 . 2H 2 O and molecular weight 443.5. Each mg of levorphanol tartrate dihydrate is equivalent to 0.58 mg levorphanol base. Following IV administration, levorphanol undergoes rapid ( ⁇ 1 hr) distribution and redistribution and has a steady-state volume of distribution of from 10-13 L/kg. The clearance of levorphanol is very high. In one study, the clearance of levorphanol was reported as 0.75-1.0 L/kg/hr. Levorphanol clearance has been reported to be approximately one half of the hepatic blood flow. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins.
  • Levorphanol is well absorbed after PO administration with peak blood levels occurring 1 hour after dosing.
  • the extent of first-pass metabolism of levorphanol is not well defined, but is likely to lie within the range of 30-70% based on a comparison of blood levels after oral and parenteral administration.
  • the relative bioavailability of levorphanol tablets compared to IM or IV administration is not known.
  • the parenteral to oral potency of levorphanol is 2:1.
  • the half-life of levorphanol has been evaluated in two subjects after oral administration and found to be 16 hours and 30 hours. This is significantly longer than the half-life of other opioids such as morphine, hydromorphone and oxycodone.
  • the usual recommended starting dose for oral immediate release levorphanol tartrate is 2 mg.
  • the approved prescribing information for Levorphanol indicates that immediate release levorphanol should be dosed "3-6 hours as needed”.
  • the effective daily dosage range depending on the severity of the pain, is 8-16 mg in 24 hours in the non-tolerant (opioid naive) patient. Total daily doses of more than 16 mg are generally not recommended as starting doses in opioid-naive patients.
  • the mean daily dose of PRN levorphanol was 8.9 mg (approx. 90% CL: 3-15 mg).
  • Levorphanol is an alternative to morphine and other strong opioid agonists in patients with moderate to severe acute and chronic pain. At equipotent or equianalgesic doses, levorphanol is believed to produce analgesia comparable to morphine, oxycodone, - -
  • hydromorphone, fentanyl and other strong opioids (Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005; Clinical Practice Guidelines for Cancer Pain Management, Agency for Health Care Policy and Research Guideline No. 9, AHCPR Publication No. 94-0592, March 1994).
  • Oxycodone (4, 5-epoxy-14-hydroxy- 3-methoxy-17-methylmorphinan-6-one) is a semisynthetic opioid analgesic that has been in clinical use since 1917. When given orally, oxycodone has a higher oral bioavailability (approximately 60% to 85%) and is approximately twice as potent than morphine. Like all full (or pure) opioid agonists, there is no ceiling effect to analgesia, such as is seen with partial agonists or non-opioid analgesics. Oxycodone is extensively metabolized to noroxycodone, oxymorphone, and their respective glucuronides.
  • the major circulating metabolite is noroxycodone which is reportedly a considerably weaker analgesic than oxycodone.
  • Oxymorphone concentrations following oral oxycodone administration are low and are unlikely to contribute significantly to oxycodone analgesia.
  • Biotransformation of oxycodone to oxymorphone, but not noroxycodone, is mediated by CYP2D6 and as such its formation can be affected by inhibitors of CYP2D6.
  • the analgesic activity of oxycodone is primarily due to the parent drug oxycodone.
  • oxycodone has demonstrated efficacy in acute postsurgical pain, osteoarthritis, low back pain, cancer pain and neuropathic pain (Watson and Babul, Neurology 1998;50:1837-41; Hagen and Babul, Cancer 1997; Matsumoto, Babul and Ahdieh, Pain Medicine 2005;6:357-66; Sunshine et al., J Clin Pharmacol.
  • Methadone (6-dimethylamino-4,4-diphenylheptan-3-one) is a synthetic opioid that has been available for approximately 50 years. Methadone a schedule II under the United States Controlled Substances Act. It was initially used solely for detoxification treatment and maintenance treatment ("methadone maintenance") within licensed opioid addiction - -
  • methadone is now prescribed by physicians in the USA for the treatment of pain. It is widely used by the oral route for the treatment of cancer pain, chronic non-cancer pain and neuropathic pain. In addition to its effects at the mu opioid receptor, methadone is also an agonist at the delta opioid receptor and an NMDA antagonist.
  • methadone differs from morphine in that methadone has a higher bioavailability, a much longer half-life, and is hepatically metabolized by cytochrome P450 enzymes.
  • the pharmacokinetics of methadone are quite variable. An understanding of the factors that impact the onset, magnitude, and duration of analgesia is paramount to optimize treatment outcomes. Caution is advised when switching to methadone, from other opioids, due to a variable equianalgesic dose ratio and the potential for late-onset toxicity due to its accumulation kinetics.
  • Methadone is approved for oral and intramuscular use, although it is also used rectally, intravenously, subcutaneously, epidurally, and intrathecally.
  • Oral methadone has a bioavailability of approximately 80 percent compared with approximately 30 to 35% for morphine. Methadone is metabolized in the liver and unlike morphine, it has no known active metabolites. The elimination half-life of methadone is highly variable (mean half-life approximately 22 hours). Unlike morphine, it usually is not necessary to adjust the dosage of methadone in patients with renal insufficiency. The duration of analgesia is approximately 4 to 6 hours, although upon repeated dosing, methadone has been administered every 8 to 12 hours in some instances. Due to its long half-life, it may take up to 7 to 10 days to reach steady state plasma concentrations. Methadone continues to be used for detoxification treatment and opioid maintenance treatment and increasingly for the treatment of cancer pain, chronic non-cancer pain and neuropathic pain.
  • Tramadol hydrochloride [( ⁇ ) ⁇ s-2-[(dimethylamino)methyl]-l-(3-methoxyphenyl) cyclohexanol hydrochloride] is a widely available synthetic, centrally acting aminocyclohexanol opioid analgesic which was first marketed in Germany in 1977 and approved for sale in the United States in 1995.
  • tramadol is presently available as an oral immediate release single-entity tablet from a number of manufacturers "for the management of moderate to moderately severe pain" and as a fixed-dose combination with acetaminophen.
  • Oral tramadol is also available in the United States as a once-a-day extended release formulation for the "management of - -
  • Tramadol exerts its analgesic effects through a binding of parent and Ml metabolite to ⁇ -opioid receptors and inhibition of re-uptake of norepinephrine and serotonin.
  • Hydromorphone [4,5 ⁇ -epoxy-3-hydroxy-17 methylmorphinan-6-one] is a semisynthetic congener of morphine differing structurally from morphine by the substitution of an oxygen for the 6-hydroxyl group and the hydrogenation of the 7-8 double bond. It was introduced into clinical medicine in 1926. Hydromorphone is metabolized primarily to hydromorphone-3-glucuronide (H3G) in a reaction catalyzed by UDP-glucuronyl transferase and to a much lesser extent to dihydromorphine and dihydroisomorphine via NADPH dihydromorphinone ketone reductase. H3G accumulates significantly in patients with renal impairment.
  • H3G hydromorphone-3-glucuronide
  • hydromorphone has been established in postsurgical pain, post-traumatic pain, cancer pain and chronic non-cancer pain when administered intravenously, epidurally, intramuscularly, subcutaneously and orally.
  • Hydromorphone is approximately five times as potent as morphine on a milligram per milligram basis and has efficacy comparable to morphine and oxycodone Hagen and Babul, Cancer 1997;79: 1428-37; Babul and Darke, Journal of Pain and Symptom Management 1995;10:184-86; Babul and Darke, Pain 1992;51:260-61; Hays et al., Cancer 1994;74:1808-16; Hagen et al., Journal of Clinical Pharmacology 1995;35:38- 45).
  • tramadol has been established following oral, rectal, intravenously and intramuscularly administration to adults or children in randomized, placebo and positive controlled clinical trials.
  • Tramadol has been evaluated in acute pain following single-dose and short-term, repeated-dose administration to patients following third molar extraction, post-orthopedic surgery pain and post-Cesarean section pain.
  • tramadol has been established in numerous studies in chronic pain states, including cancer pain, neuropathic pain, fibromyalgia, low back pain and osteoarthritis (Lee et al., 1993; U.S., Ultram Package Insert, 2003; Rodrigues & Rodrigues, 1989; Grond et al., 1992; Osipova et al., 1991; Wilder-Smith et al., 1994; Roth, 1998; Harati et al., 1998; Biasi et al., 1998; Raber et al., 1999b; Schnitzer et al., 1999; Harati et al., 2000; Schnitzer et al., 2000; Sindrup et al., 1999; Mullican and Lacy, 2001; Wilder-Smith et al, 2001; Adler et al., 2002; Peloso et al., 2002; Silverfield et al., 2002; Babul et
  • Oxymorphone is (4, 5 ⁇ -epoxy-3, 14-dihydroxy-17-methylmorphinan-6-one or
  • 14-hydroxydihydromorphinone is a semisynthetic opioid agonist derived from thebaine whose principal therapeutic action is analgesia. It is structurally related to morphine, differing in a ketone group substitution at the C-6 position of morphine and saturation of the 7-8 double-bond. The ketone group substitution makes the molecule more lipid soluble, conferring greater potency and more rapid onset of action than the hydroxylated parent compound morphine. Oxymorphone was first approved by for use by the US FDA in 1959. In addition to analgesia, other pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression.
  • oxymorphone Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses.
  • the absolute oral bioavailability of oxymorphone is approximately 10%. Oxymorphone is not extensively bound to human plasma proteins; binding is in the range of 10% to 12%. Oxymorphone is highly metabolized principally in the liver and undergoes reduction or conjugation with glucuronic acid to form both active and inactive metabolites. The major metabolite of oxymorphone is oxymorphone-3-glucuronide.
  • the mean plasma AUC for oxymorphone-3-glucuronide is approximately 90-fold higher than the parent compound.
  • 6-OH-oxymorphone has been shown in animal studies. Less than ⁇ 1% of the administered dose is excreted unchanged in the urine. Approximately 30 to 40% of the administered dose is excreted in the urine as oxymorphone-3-glucuronide and 0.25% to 0.62% excreted as 6-OH-oxymorphone in subjects with normal renal and hepatic function. The bioavailability of oxymorphone is increased in patients with renal and hepatic impairment.
  • M6G is not metabolized; rather is excreted through the kidneys. M6G exhibits a delay in its analgesic effect (blood-effect site equilibration half-life 4-8 h), which is in part related to slow transfer of drug across the blood-brain barrier and subsequent distribution within the brain. In humans, M6G's potency is just approximately one-half that of morphine. In clinical trials, M6G is well tolerated and produces adequate and long lasting postsurgical pain relief. According to Kilpatrick and Smith (Med Res Rev 2005;25:521-44), "The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor.
  • Morphine has a slightly higher affinity for the ⁇ -opioid receptor than M6G
  • M6G shows a slightly higher efficacy at the ⁇ -opioid receptor
  • M6G has a lower affinity for the ⁇ -opioid receptor than morphine
  • ADME absorption, distribution, metabolism, and excretion
  • Racemorphan ⁇ d,l 3-hydroxy-N-methylmorphinan is a potent opioid analgesic with a molecular formula of Ci 7 H 23 NO, developed approximately 60 years ago. It is an alternative to morphine, hydromorphone, oxycodone, oxymorphone and other strong opioid agonists in patients with moderate to severe acute and chronic pain. At equipotent or equianalgesic doses, racemorphan produces analgesia comparable to morphine, oxycodone, hydromorphone, fentanyl and other strong opioids.
  • opioid side effects there is a need for optimized strategies to provide robust analgesic and additionally, anti-inflammatory and antipyretic effects, without the frequency and severity of side effects seen at usual doses of opioids.
  • Opioid associated side effects are well documented in the scientific and medical literature.
  • such strategies can reduce opioid side effects including nausea, vomiting, constipation, sedation, fatigue, pruritus, rash, hives, blurred vision, urinary retention, respiratory depression, convulsions, obtundation, coma, mood changes, alterations of the endocrine and autonomic nervous systems, physical -5 -
  • analgesic, anti-inflammatory and antipyretic methods and pharmaceutical compositions administered as selected combination analgesics that: (i) have reduced intravenous injection site pain, venous irritation and phlebitis; (ii) have reduced epidural and intrathecal injection site pain, irritation, hematoma, abscess, inflammatory lesions and granulomas; (iii) have reduced intramuscular injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage; (iv) have reduced subcutaneous injection site pain, subcutaneous irritation, inflammation and abscesses; (v) have reduced bleeding and bleeding risk in anticoagulated patients; (vi) have reduced bleeding from or near the site of surgery; (vii) have reduced bleeding from non-surgical sites; (viii) have reduced renal, renovascular and hepatic impairment; (ix) have a reduced gastrointestinal side effects, including nausea, vomiting, retching, constipation, dyspepsia, ulceration, perforation, bleeding and
  • the pharmaceutical composition is administered IV,
  • the pharmaceutical composition of the selected analgesic when given by the intravenous route, may be administered by rapid IV injection, e.g., IV bolus, IV push, or slow 2 minute IV injection for rapid onset of effect and a more robust peak effect, or alternatively by longer duration infusions.
  • the pharmaceutical composition when administered by intravenous route, the pharmaceutical composition produces little to substantially no precipitation of in the subject's vein.
  • the pharmaceutical composition when given by the intravenous route, may be administered by slow IV infusion.
  • the pharmaceutical composition can be administered directly into epidurally or into the intrathecal space.
  • the SAD of selected combination analgesics is less than about 1% of the usual dose of the said analgesic by the specified parenteral route of administration. In other embodiments, the SAD of the said analgesic is less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose of the said analgesic by the same parenteral route of administration.
  • the doses of the specified SAD combination analgesic by the parenteral route are for the treatment of pain of mild intensity. In other said doses are for the treatment of pain of moderate intensity, moderately severe intensity or severe intensity.
  • the specified SAD combination analgesic by the parenteral route is for the treatment of pain in children, in which case the adult dose may - -
  • the dose for the child for the said embodiments is 2.5 mg
  • the SAD of the selected combination analgesic is less than about 1% of the usual dose of the selected combination analgesic by the specified parenteral route of administration, said dose administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration.
  • the SAD of the selected combination analgesic is less than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose of the same combination analgesic by the same parenteral route of administration.
  • the SAD of the selected combination analgesic is administered by the specified parenteral route of administration in a volume that is less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% the minimum approved or recommended dose by the same route of administration.
  • the SAD of the selected combination analgesic is administered at a rate that is at least about 10, 20, 30, 40, 50, 60, 70, 80, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 1000% faster than the minimum approved or recommended rate of administration for the minimum approved or recommended dose by the same route of administration.
  • the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, individual dose, demand dose or daily dose is administered or solely administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration.
  • the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose comprises the demand dose to be administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration.
  • the patient controlled analgesia is by the intravenous route (PCA).
  • said demand dose is preceded by one or more loading doses, preferably one loading dose, with the same drug by the same route of administration, said loading dose at least equal to the minimum recommended or approved dose for the intended route of administration or for oral administration.
  • the demand dose must be preceded by one or more loading doses, preferably one loading dose, with the same drug by the same route of administration, said loading dose at least equal to the minimum recommended or approved dose for the intended route of administration or for oral administration.
  • the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose comprises the demand dose, said demand dose administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration, said demand dose to be administered at a frequency not to exceed a prespecified dosing frequency (the lockout period), said lockout period determined by a qualified clinician or medical practitioner.
  • the lockout period for patient controlled analgesia is programmed or preprogrammed into the patient controlled analgesia device or pump.
  • the demand dose by patient controlled analgesia must be associated with a lockout period.
  • the lockout period for administration of a demand dose by patient controlled analgesia is at least about 5, 6, 7, 8, 10, 12, 15, 18, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 240, 270, 300, 330 or 360 minutes.
  • the lockout period is not more than about 15, 30, 45, 60, 90, or 120 minutes.
  • the lockout period for administration of a demand dose by patient controlled analgesia is not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended dosing frequency of the unit dose or individual dose of the combination analgesic by the same route of administration or by the oral route of administration.
  • the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose is: (1) preceded by a loading dose; (ii) given as a demand dose by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration, preferably by the intravenous route (PCA); (iii) administered not more frequently then the lockout period; (iv) administered at a cumulative daily or 24 hour dose not to exceed 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70 of the minimum approved or recommended daily dose of the said combination analgesic by the same route of administration or by the oral route of administration.
  • the SAD of the selected combination analgesic may be adjusted upwards or downwards based on the patients efficacy and safety response, tolerability of therapy, desired outcome and speed of outcome, provided that the each individual, unit or demand dose does not exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended dose by the same route of administration or by the oral route of administration.
  • the SAD of the selected combination analgesic may be adjusted upwards or downwards based on the patients efficacy and safety response, tolerability of therapy, desired outcome and speed of outcome, provided that the daily or 24 hour dose does not exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended daily or 24 hour dose by the same route of administration or by the oral route of administration.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less gastrointestinal side effects (e.g., nausea, vomiting, retching, constipation, dyspepsia, heartburn, ulceration, perforation, bleeding and biliary spasm) compared to administration of usual doses of the selected analgesics.
  • gastrointestinal side effects e.g., nausea, vomiting, retching, constipation, dyspepsia, heartburn, ulceration, perforation, bleeding and biliary spasm
  • the method of the invention comprising administration of SAD of selected combination analgesics comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less venous irritation, injection site pain or phlebitis after IV bolus injection, slow IV injections, short term infusions and continuous infusions, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more intramuscular tolerability, e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation or nerve damage after IM injection, e.g., into the gluteus, deltoid, vastus lateralis, compared to administration of usual doses of the selected analgesics.
  • intramuscular tolerability e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation or nerve damage after IM injection, e.g., into the gluteus,
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more intra-articular safety and tolerability, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more subcutaneous tolerability, e.g., reduced injection site pain, subcutaneous irritation, subcutaneous inflammation, injection site redness, or sterile or nonsterile abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions, compared to administration of usual doses of the selected analgesics.
  • subcutaneous tolerability e.g., reduced injection site pain, subcutaneous irritation, subcutaneous inflammation, injection site redness, or sterile or nonsterile abscesses after subcutaneous injection
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more intrathecal and epidural tolerability, e.g., reduced injection site pain and irritation, reduced epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions or intrathecal granulomas after epidural or intrathecal administration, compared to administration of usual doses of the selected analgesics.
  • intrathecal and epidural tolerability e.g., reduced injection site pain and irritation, reduced epidural hematoma and abscess,
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less bleeding from or near the site of surgery, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less postsurgical wound complications (e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling), compared to administration of usual doses of the selected analgesics.
  • postsurgical wound complications e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less surgical complications from orthopedic surgery or surgery involving bony manipulation (e.g., non-union, malunion, avascular necrosis), compared to administration of usual doses of the selected analgesics.
  • bony manipulation e.g., non-union, malunion, avascular necrosis
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less postsurgical blood loss, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% lower requirement for blood transfusions, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% improved tolerability upon infiltration into soft tissue, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less elevation of liver function tests (e.g., AST, ALT, ALP, GGT, bilirubin and albumin), compared to administration of usual doses of the selected analgesics.
  • liver function tests e.g., AST, ALT, ALP, GGT, bilirubin and albumin
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less elevation of renal function tests (e.g., BUN and creatinine), compared to administration of usual doses of the selected analgesics.
  • renal function tests e.g., BUN and creatinine
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, - - -
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less elevation in systolic or diastolic blood pressure, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less myocardial infarction, particularly in patients at high risk (e.g. patients with significant ischemic heart disease, angina, coronary occlusion and stenosis, angioplasty candidates, or CABG surgery candidates), compared to administration of usual doses of the selected analgesics.
  • patients at high risk e.g. patients with significant ischemic heart disease, angina, coronary occlusion and stenosis, angioplasty candidates, or CABG surgery candidates
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less congestive heart failure, particularly in patients at high risk, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less pulmonary side effects (e.g., pulmonary embolism), particularly in patients at high risk, compared to administration of usual doses of the selected analgesics.
  • pulmonary side effects e.g., pulmonary embolism
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, - -
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less aggregate cardiovascular adverse events, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less CNS side effects (e.g., sedation, fatigue, convulsions, obtundation, coma, mood changes, physical dependence, addiction, hyperalgesia and respiratory depression), compared to administration of usual doses of the selected analgesics.
  • CNS side effects e.g., sedation, fatigue, convulsions, obtundation, coma, mood changes, physical dependence, addiction, hyperalgesia and respiratory depression
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% greater postsurgical, post-bum and posttraumatic wound healing, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% greater postsurgical and posttraumatic bone repair and bone growth, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less NSAID-associated side effects, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less opioid-associated side effects, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less acetaminophen, propacetamol, nitroparacetamol or acetaminophen analog-associated side effects, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less NSAID-associated side effects, or opioid- associated side effects or acetaminophen-associated side effects in the aggregate, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less NSAID and opioid-associated side effects, or acetaminophen and opioid-associated side effects or NSAID and acetaminophen- associated side effects in the aggregate, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less drug-drug interactions, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% reduced risk of bleeding during concurrent anticoagulation therapy (e.g., warfarin, heparin, etc), compared to administration of usual doses of the selected analgesics.
  • concurrent anticoagulation therapy e.g., warfarin, heparin, etc
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% reduced pruritus, rash, hives, blurred vision or urinary retention, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700%, 1000%, 1300%, 1600%, 2000%, 3000%, 4000%, 5000%, 6000%, 7000%, 8000%, 9000%, 10,000%, 12,000%, 14,000%, 16,000%, 18,000%, 20,000% reduced volume for parenteral administration, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700%, 1000%, 1300%, 1600%, 2000%, 3000%, 4000%, - -
  • parenteral administration time e.g., IV injection time, IV infusion time, SC infusion time, epidural infusion time, intrathecal infusion time
  • parenteral administration time e.g., IV injection time, IV infusion time, SC infusion time, epidural infusion time, intrathecal infusion time
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% earlier patient ambulation and physiotherapy, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% reduced risk of deep vein thrombosis and pulmonary embolism, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% shorter time to oral fluid and food intake, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% shorter duration of hospitalization or stay in a supervised medical facility, compared to administration of usual doses of the selected analgesics.
  • the method of the invention comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% faster restoration of normal bowel function after anesthesia (particularly prolonged general anesthesia), after major surgery and after gastrointestinal and abdominal manipulation, including time to normal bowel sounds, time to first flatus, time to fluid intake, compared to administration of usual doses of the selected analgesics.
  • the SAD of selected combination analgesics is less than about 1% of the usual dose of the selected combination analgesics by the specified parenteral route of administration.
  • the subanalgesic doses (SAD) of selected combination analgesics is less than about 1.5%, or less than about 2%, or less than about 2.5%, or less than about 3%, or less than about 3.5%, or less than about 4%, or less than about 4.5%, or less than about 5%, or less than about 5.5%, or less than about 6%, or less than about 6.5%, les than about 7%, or less than about 7.5%, or less than about 8%, or less than about 8.5%, or less than about 9%, or less than about 9.5%, or less than about 10%, or less than about 10.5%, or less than about 11%, or less than about 12%, or less than about 13%, or less than about 14%, or less than about 15%, or less than about 16%, or less than about 17%,
  • the SAD of selected combination analgesics obtain total pain relief (TOTPAR), sum of pain intensity difference (SPID) or sum of pain relief intensity difference (SPRID) at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • TOTPAR total pain relief
  • SPID sum of pain intensity difference
  • SPRID sum of pain relief intensity difference
  • the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax
  • this dose obtains a TOTPAR of Ay
  • the dose of the SAD selected combination analgesic is 2x
  • this dose obtains a TOTPAR of not less than 3y.
  • the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a TOTPAR, SPID or SPRID at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
  • the SAD of selected combination analgesics obtain pain intensity difference (PID) and pain relief (PR) at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • PID pain intensity difference
  • PR pain relief
  • the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a PID and PR at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
  • the SAD of selected combination analgesics obtain peak pain relief (PPR) or peak pain intensity difference (PPID) for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • PPR peak pain relief
  • PPID peak pain intensity difference
  • the SAD of the selected combination analgesic obtains a PPR or PPID for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
  • the SAD of selected combination analgesics obtain a "number of patients with pain who need to be treated to obtain > 50% pain relief in one patient" (NNT, i.e., number needed to treat or NNT) at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • NNT number of patients with pain who need to be treated to obtain > 50% pain relief in one patient
  • the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax
  • this dose obtains an NNT of Ay
  • the dose of the SAD selected combination analgesic is 2x
  • this dose obtains an NNT of not less than 3y.
  • the SAD of the selected combination analgesic obtains an NNT for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than - -
  • the SAD of selected combination analgesics obtain a percentage of patients who have a 30% postbaseline reduction in pain (Responder30%) at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax
  • this dose obtains a Responder 3 o% of Ay
  • the dose of the SAD selected combination analgesic is 2x
  • this dose obtains an NNT of not less than 3y.
  • the SAD of the selected combination analgesic obtains a Responder 30 o /o for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
  • the SAD of selected combination analgesics obtain a time to confirmed perceptible pain relief using a double stopwatch method after first administration for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax
  • this dose obtains a time to confirmed perceptible pain relief using a double stopwatch method of 40 minutes
  • the dose of the SAD selected combination analgesic is 2x
  • this dose obtains a time to confirmed perceptible pain relief of not less than 30 minutes.
  • the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a time to confirmed perceptible pain relief using a double stopwatch method for the selected combination analgesic which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected combination analgesic.
  • the SAD of selected combination analgesics obtain a time to meaningful pain relief using a double stopwatch method for the selected combination analgesic after first administration by the specified parenteral route of administration which is not less than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax
  • this dose obtains a time to meaningful pain relief using a double stopwatch method of 80 minutes
  • the dose of the SAD selected combination analgesic is 2x
  • this dose obtains a time to meaningful pain relief of not less than 60 minutes.
  • the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a time to meaningful pain relief using a double stopwatch method for the selected combination analgesic which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected combination analgesic.
  • the SAD of selected combination analgesics obtain a median time to rescue analgesic use for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic.
  • the usual analgesic dose of the selected combination analgesic by the intravenous route is 4x, and this dose obtains a median time to rescue analgesic use of 100 minutes, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains a median time to rescue analgesic use of not less than 75 minutes.
  • the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a median time to rescue analgesic use for the selected combination analgesic which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected combination analgesic.
  • Analgesic efficacy measures including PID, PR, PPID, PPR, SPID, SPRID,
  • TOTPAR time to confirmed perceptible pain relief, time to meaningful pain relief, NNT and Responder 3 o % can be measured using known methods.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain.
  • the SAD of the selected combination analgesic is for the treatment of acute pain.
  • the SAD of the selected combination analgesic is for the treatment of chronic pain.
  • the SAD of the selected combination analgesic is for the treatment of acute exacerbations of chronic pain.
  • the SAD of the selected combination analgesic is for the treatment of breakthrough pain.
  • the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain.
  • the SAD of the selected combination analgesic is for the treatment of renal colic. In other embodiments, the SAD of the selected combination analgesic is for the treatment of signs and symptoms of migraine, including pain, phonophobia, photophobia and nausea. In other embodiments, the SAD of the selected combination analgesic is for the treatment of cancer pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of chronic non-cancer pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of acute exacerbations of chronic pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of neuropathic pain.
  • the SAD of the selected combination analgesic is for the treatment of burn pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of burn dressing change pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of posttraumatic pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of acute musculoskeletal pain. In certain preferred embodiments, the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain. In certain preferred embodiments, the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain following major surgery.
  • the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in the inpatient setting (i.e., a medically supervised setting where the patient has been admitted into the hospital, clinic or medical facility, usually involving an overnight stay).
  • the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain for use in the day surgery or outpatient surgery setting (i.e., a medically supervised setting where the patient is expected to be rapidly discharged, usually not involving an overnight stay).
  • the SAD of the selected combination analgesic is for the treatment of acute headache (e.g., migraine) or acute renal colic, or acute posttraumatic pain in the emergency room.
  • the SAD of the selected combination analgesic is for the treatment of pain for conditions under which the standard of care or the usual standard of care involves the presence of or insertion of an indwelling sterile catheter for subcutaneous, venous, epidural or intrathecal access.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of mild pain.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain of at least moderate severity (i.e., moderate intensity).
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain of moderately severe intensity.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain of that is of severe intensity.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends parenteral analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends intravenous analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain only by intermittent analgesia, short term infusions or prolonged infusions but excluding all administration by patient controlled (intravenous) analgesia (PCA).
  • PCA patient controlled (intravenous) analgesia
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain but excluding all administration by patient controlled epidural analgesia (PCEA).
  • PCEA patient controlled epidural analgesia
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain but excluding all administration by the subcutaneous route.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain but excluding all administration by the intramuscular route.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends subcutaneous analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends intramuscular analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends epidural or intrathecal analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain of dysmenorrhea.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain of headache (e.g., migraine or tension headache).
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding dental pain.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding pain following third-molar extractions.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain associated with metatarsophalangeal surgery (e.g., bunionectomy, hammer toe repair).
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention for infiltration analgesia.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention by patient controlled analgesia, also know as patient controlled intravenous analgesia or PCA.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention by patient controlled epidural analgesia or PCEA.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention by the intra-articular route.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain associated with podiatric surgery.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain associated with sore throat or mucositis.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by administration by the infiltration route in proximity to the field of surgical incision.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by administration by the infiltration route in proximity to source of pain.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding renal colic.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by intraarticular administration.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding mild pain (i.e., pain of mild intensity).
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding moderate pain (i.e., pain of moderate intensity).
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding pain treated by intravenous infusions of the SAD selected combination analgesic (i.e., intravenous administration lasting longer than about 5 minutes).
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding chronic pain.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding neuropathic pain.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding cancer pain.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain in patients receiving concomitant opioid analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding concomitant use with opioid analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic pharmaceutical composition for the treatment of pain said composition devoid of opioid analgesics.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by the parenteral route, said parenteral route excluding intra-articular administration.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by the parenteral route, said parenteral route excluding administration by local tissue infiltration.
  • both the dose and the total daily dose of the selected combination analgesic given as SAD selected combination analgesic is significantly lower than the usual dose and daily dose of selected combination analgesic; said lower dose of the selected combination analgesic given as a SAD of the selected combination analgesic resulting in a shorter duration of analgesia for each administered dose compared with the usual dose of the selected combination analgesic; said lower dose of the SAD selected combination analgesic providing about the same overall or total analgesic or pain relieving effect by virtue of being given more frequently than the usual dose of the selected combination analgesic given at its usual dosing frequency; said invention still providing a significantly lower total daily dose despite about the same analgesic or pain relieving effect as the usual dose of the selected combination analgesic.
  • the dose of the selected combination analgesic given as SAD selected combination analgesic is not significantly lower than the usual dose; however, the daily dose of selected combination analgesic given as SAD selected combination analgesic is significantly lower than the usual daily dose of selected combination analgesic; said composition still providing some or all of the benefits of the present invention.
  • the invention requires that the subanalgesic dose (SAD) of the selected combination analgesics comprising a pharmaceutical composition of at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors
  • the parenteral dose of the invention will vary depending on the method of administration.
  • the intravenous dose of an analgesic administered by PCA is usually much smaller than intravenous dose administered by intermittent injection. This is because the IV PCA analgesic "demand dose" is self-administered and can be re-administered by the patient as required, only subject to a lock-out period programmed into the PCA device.
  • the adult IV PCA demand dose of morphine is usually 0.5 to 2.5 mg and the usual starting dose is 1 mg (after an initial loading dose)
  • the adult PCA demand dose of hydromorphone is usually 0.05 to 0.4 mg and the usual starting dose is 0.2 mg (after an initial loading dose).
  • the usual IV PCA lockout period for the aforementioned morphine and hydromorphone demand doses ranges from 5 to 10 minutes (usual starting lockout period is 8 minutes).
  • the usual intermittently administered dose of morphine and hydromorphone is 10 mg and 1.5 mg, respectively, given every 2 to 4 hours.
  • the IV PCA dose is approximately one-fifth to one-tenth the intermittent IV dose.
  • the at one or more compounds of the selected combination analgesic is chosen from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketoprofen adult dose of the invention (i.e., the adult SAD dose of the ketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 30 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20.5 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or - -
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketoprofen adult dose of the invention (i.e., the adult SAD dose of the ketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.65 mg/kg, or less than about 0.6 mg/kg, or less than about 0.55 mg/kg, or less than about 0.5 mg/kg, or less than about 0.45 mg/kg, or less than about 0.4 mg/kg, or less than about 0.38 mg/kg, or less than about 0.36 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.32 mg/kg, or less than about 0.30 mg/kg, or less than about 0.29 mg/kg or less
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexketoprofen adult dose of the invention (i.e., the adult SAD dose of the dexketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 25 mg, or less than about 22.5 mg, or less than about 20 mg, or less than about 17.5 mg, or less than about 15 mg, or less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 25 mg, or less than about 22.5 mg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexketoprofen dose of the invention (i.e., the SAD dose of the dexketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.357 mg/kg, or less than about 0.35 mg/kg, or less than about 0.325 mg/kg, or less than about 0.3 mg/kg, or less than about - -
  • 0.275 mg/kg or less than about 0.25 mg/kg, or less than about 0.225 mg/kg, or less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural diclofenac adult dose of the invention (i.e., the adult dose of the SAD diclofenac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 20 mg, or less than about 18 mg, or less than about 16 mg or less than about 15 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural diclofenac dose of the invention (i.e., the SAD dose of the diclofenac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.3 mg/kg, or less than about 0.29 mg/kg, or less than about 0.28 mg/kg, or less than about 0.25 mg/kg, or less than about 0.22 mg/kg, or less than about 0.20 mg/kg, or less than about 0.18 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural piroxicam adult dose of the invention (i.e., the adult SAD dose of the piroxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 10 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural piroxicam dose of the invention (i.e., the SAD dose of the piroxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1.42 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.0714 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.067 mg/kg, or less than about 0.066 mg/kg, or less than about 0.065 mg/kg, or less than about 0.064 mg
  • the invention for the treatment of pain, inflammation and/or fever is less than about 180 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 85 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 67.5 mg, or less than about 65 mg, or less than about 62.5 mg, less than about 60 mg, or less than about 57.5 mg, or less than about 55 mg, or less than about 52.5 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 44 mg, or less than about 42 mg, or less than
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ibuprofen dose of the invention (i.e., the SAD dose of the ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 2.58 mg/kg, or less than about 2.57 mg/kg, or less than about 2.5 mg/kg, or less than about 2.4 mg/kg, or less than about 2.3 mg/kg, or less than about 2.2 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg
  • mg/kg or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(+)-ibuprofen (dexibuprofen) adult dose of the invention i.e., the adult SAD dose of the S(+)-ibuprofen - -
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 90 mg, or less than about 85 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, less than about 55 mg or less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 30 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20.5 mg, or less than about 20 mg, less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(+)-ibuprofen (dexibuprofen) dose of the invention i.e., the SAD dose of the S(+)-ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the SAD dose of the S(+)-ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route is less than about 01.29 mg/kg, or less than about 1.28 mg/kg, or about 1.2 mg/kg, or about 1.1 mg/kg, or less than about 1 mg/kg, less than about 0.9 mg/kg or less than about 0.8 mg/kg or less than about 0.7 mg/kg or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.357 mg/kg
  • about 0.06 mg/kg or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0025, or less than about 0.001.
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketorolac adult dose of the invention (i.e., the adult SAD dose of the ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 9 mg, or less than about 8.75 mg, or less than about 8.5 mg, or less than about 8.25 mg,.or less than about 8 mg, or less than about 7.75 mg, or less than about 7.5 mg, or less than about 7.25 mg, or less than about 7 mg, or less than about 6.75 mg, or less than about 6.5 mg, or less than about 6.25 mg, or less than about 6 mg, or less than about 5.9 mg, or less than about 5.8 mg, or less than about 5.7 mg, or less than about 5.6 mg, or less than about 5.5 mg, or less than about 5.4 mg, or less
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketorolac dose of the invention (i.e., the SAD dose of the ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain is less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.067 mg/kg, or less than about 0.066 mg/kg, or less than about 0.065 mg/kg, or less than about 0.064 mg/kg, or less than about 0.063 mg/kg, or less than about 0.062 mg/kg, or
  • 0.005 mg/kg or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg or less than about 0.00025 mg/kg.
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(-)-ketorolac adult dose of the invention (i.e., the adult SAD dose of the S(-)-ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 5 mg, less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, less than about 2.45 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(-)-ketorolac dose of the invention (i.e., the SAD dose of the S(-)-ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.07 mg/kg, or less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural naproxen adult dose of the invention is or less than about 245 mg, or less than about 240 mg, or less than about 230 mg, or less than about 220 mg, or less than about 210 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 125 mg, or less than about 120 mg, or less than about 115 mg, or less than about 110 mg, or less than about 105 mg, or less than about 100 mg, or less than about 98 mg, or less than about 96 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural naproxen dose of the invention (i.e., the SAD dose of the naproxen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 2.9 mg/kg, or less than about 2.8 mg/kg, or less than about 2.7 mg/kg, or less than about 2.6 mg/kg, or less than about 2.5 mg/kg, less than about 2.4 mg/kg, or less than about 2.3 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.428 mg/kg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tenoxicam adult dose of the invention (i.e., the adult SAD dose of the tenoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15.5 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12.5 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tenoxicam dose of the invention (i.e., the SAD dose of the tenoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2857mg/kg, or less than about 0.28 mg/kg, or less than about 0.27 mg/kg, or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.21 mg/kg, or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, less than about 0.2857mg/kg, or less than
  • the adult SAD dose of the flurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route for the treatment of pain, inflammation and/or fever is less than about 100 mg, or less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural flurbiprofen dose of the invention (i.e., the SAD dose of the flurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg or less than about 0.6 mg/kg or less than about 0.5 mg/kg or less than about 0.4 mg/kg, or less than about 0.3571 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.33 mg/kg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexflurbiprofen (S(+)- flurbiprofen)adult dose of the invention i.e., the adult SAD dose of the dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the adult SAD dose of the dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route is less than about 100 mg, or less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexflurbiprofen dose of the invention (i.e., the SAD dose of the dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg or less than about 0.6 mg/kg or less than about 0.5 mg/kg or less than about 0.4 mg/kg, or less than about 0.3571 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.33
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lornoxicam adult dose of the invention i.e., the adult SAD dose of the lornoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the adult SAD dose of the lornoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route for -9 -
  • the treatment of pain, inflammation and/or fever is less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lornoxicam dose of the invention (i.e., the SAD dose of the lornoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural celecoxib dose of the invention for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg or less than about 30 mg, or less than about 28 mg, or less than about 25 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural celecoxib dose of the invention (i.e., the SAD dose of the celecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lumiracoxib dose of the invention for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg or less than about 30 mg, or less than about 28 mg, or less than about 25 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lumiracoxib dose of the invention (i.e., the SAD dose of the lumiracoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural parecoxib dose of the invention (i.e., the adult SAD dose of the parecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural parecoxib dose of the invention i.e., the SAD dose of the parecoxib by the intravenous, intramuscular, - -
  • subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.00
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural etoricoxib dose of the invention (i.e., the adult SAD dose of the etoricoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural etoricoxib dose of the invention (i.e., the SAD dose of the etoricoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about - -
  • 0.16 mg/kg or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg.
  • the intrathecal dose of the SAD selected combination analgesic invention i.e., the intrathecal dose of the selected combination analgesic, preferably chosen from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen) dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam by the intrathecal route) for the treatment of pain is less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.09 mg, or less than
  • the intrathecal dose of the SAD selected combination analgesic invention i.e., the intrathecal dose of the selected combination analgesic, preferably chosen from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen) dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lomoxicam by the intrathecal route) for the treatment of pain is less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg
  • mg/kg or less than about 0.0000005 mg/kg, or less than about 0.0000004 mg/kg, or less than about 0.0000003 mg/kg, or less than about 0.0000002 mg/kg, or less than about 0.0000001 mg/kg, or less than about 0.00000009 mg/kg.
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen adult dose of the invention (i.e., the adult SAD dose of the acetaminophen by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1000 mg, or less than about 900 mg, or less than about 800 mg, or less than about 750 mg, or less than about 650 mg, or less than about 645 mg, or less than about 600 mg, or less than about 645 mg, or less than about 600 mg, or less than about 550 mg, or less than about 500 mg, or less than about or less than about 475 mg, or less than about 450 mg, or less than about 425 mg, or less than about 400 mg, or less than about 375 mg, or less than about 350 mg, or less than about 325 mg, or less than about 300 mg, or less than about 275 mg, or
  • the intravenous [excluding
  • PCA intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen adult dose of the invention (i.e., the adult SAD dose of the acetaminophen by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less _
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen dose of the invention for the treatment of pain, inflammation and/or fever is less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about 9.28 mg/kg, or less than about 9 mg/kg, or less than about 7.14 mg/kg, or less than about 7 mg/kg, or less than about 6.5 mg/kg, or less than about 6 mg/kg, or less than about 5.5 mg/kg, or less than about 5 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.5 mg/kg, or less than about 3 mg/kg, or less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen dose of the invention (i.e., the SAD dose of the acetaminophen by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 4.7 mg/kg, or less than about 4.6 mg/kg, or less than about 4.5 mg/kg, or less than about 4.4 mg/kg or less than about 4.3 mg/kg, or less than about 4.2 mg/kg, or less than about 4.1 mg/kg or less than about 4 mg/kg, or less than about 3.9 mg/kg, or less than about 3.8 mg/kg or less than about 3.7 mg/kg, or less than about 3.6 mg/kg, or less than about 3.5 mg/kg, or less than about 3.4 mg/kg or less than about 3.3 mg/kg, or less than about 3.2 mg/kg, or less than about 3.1
  • the PCA i.e., intravenous
  • PCA acetaminophen adult dose of the invention (i.e., the adult SAD dose of the acetaminophen by the PCA [i.e., intravenous PCA route]) is less than about less than - -
  • the PCA i.e., intravenous
  • PCA] acetaminophen dose of the invention is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about
  • the intrathecal acetaminophen adult dose of the invention is less than about less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about
  • the intrathecal acetaminophen dose of the invention is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol adult dose of the invention (i.e., the adult SAD dose of the propacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1000 mg, or less than about 900 mg, or less than about 800 mg, or less than about 750 mg, or less than about 650 mg, or less than about 645 mg, or less than about 600 mg, or less than about 645 mg, or less than about 600 mg, or less than about 550 mg, or less than about 500 mg, or less than about or less than about 475 mg, or less than about 450 mg, or less than about 425 mg, or less than about 400 mg, or less than about 375 mg, or less than about 350 mg, or less than about 325 mg, or less than about 300 mg, or less than about 275 mg, or less than about 250
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol adult dose of the invention (i.e., the adult SAD dose of the propacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 88 mg, or less than about 86 mg, or less than about 84 mg, or less than about 82 mg,
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol dose of the invention for the treatment of pain, inflammation and/or fever is less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about 9.28 mg/kg, or less than about 9 mg/kg, or less than about 7.14 mg/kg, or less than about 7 mg/kg, or less than about 6.5 mg/kg, or less than about 6 mg/kg, or less than about 5.5 mg/kg, or less than about 5 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.5 mg/kg, or less than about 3 mg/kg, or less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about 9.28
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol dose of the invention (i.e., the SAD dose of the propacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 4.7 mg/kg, or less than about 4.6 mg/kg, or less than about 4.5 mg/kg, or less than about 4.4 mg/kg or less than about 4.3 mg/kg, or less than about 4.2 mg/kg, or less than about 4.1 mg/kg or less than about 4 mg/kg, or less than about 3.9 mg/kg, or less than about 3.8 mg/kg or less than about 3.7 mg/kg, or less than about 3.6 mg/kg, or less than about 3.5 mg/kg, or less than about 3.4 mg/kg or less than about 3.3 mg/kg, or less than about 3.2 mg/kg, or less than about 3.1 mg/kg or
  • PCA propacetamol adult dose of the invention (i.e., the adult SAD dose of the propacetamol by the PCA [i.e., intravenous PCA route]) is less than about less than about 400 mg, or less than about 350 mg, or less than about 300 mg, or less than about 250 mg, or less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32
  • the PCA i.e., intravenous
  • PCA] propacetamol dose of the invention is less than about 5.7 mg/kg, or less than about 5.5 mg/kg, or less than about 5.25 mg/kg, or less than about 5 mg/kg, or less than about 4.75 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.75 mg/kg, or less than about 3.5 mg/kg, or less than about 3.25 mg/kg, or less than about 3 mg/kg, or less than about 2.9 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 5.7 mg/kg, or less than about 5.5 mg/kg, or less than about 5.25 mg/kg, or less than about 5 mg
  • the intrathecal propacetamol adult dose of the invention is less than about less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or
  • the intrathecal propacetamol dose of the invention is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than
  • PCA intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural nitroparacetamol (nitroxyparacetamol or NO-acetaminophen) adult dose of the invention (i.e., the adult SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1000 mg, or less than about 900 mg, or less than about 800 mg, or less than about 750 mg, or less than about 650 mg, or less than about 645 mg, or less than about 600 mg, or less than about 645 mg, or less than about 600 mg, or less than about 550 mg, or less than about 500 mg, or less than about or less than about 475 mg, or less than about 450 mg, or less than about 425 mg, or less than about 400 mg, or less than about 375 mg, or less than about 350 mg, or less than about 325 mg,
  • the intravenous [excluding
  • PCA intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural nitroparacetamol adult dose of the invention (i.e., the adult SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra- articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 88 mg, or less than about 86 mg, or less than about 84 mg, or less than about
  • the intravenous [excluding
  • PCA intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural - -
  • nitroparacetamol dose of the invention (i.e., the SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about 9.28 mg/kg, or less than about 9 mg/kg, or less than about 7.14 mg/kg, or less than about 7 mg/kg, or less than about 6.5 mg/kg, or less than about 6 mg/kg, or less than about 5.5 mg/kg, or less than about 5 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.5 mg/kg, or less than about 3 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural nitroparacetamol dose of the invention (i.e., the SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 4.7 mg/kg, or less than about 4.6 mg/kg, or less than about 4.5 mg/kg, or less than about 4.4 mg/kg or less than about 4.3 mg/kg, or less than about 4.2 mg/kg, or less than about 4.1 mg/kg or less than about 4 mg/kg, or less than about 3.9 mg/kg, or less than about 3.8 mg/kg or less than about 3.7 mg/kg, or less than about 3.6 mg/kg, or less than about 3.5 mg/kg, or less than about 3.4 mg/kg or less than about 3.3 mg/kg, or less than about 3.2 mg/kg, or less than about 3.1 mg//
  • about 1.7 mg/kg or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or les than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg.
  • the PCA i.e., intravenous
  • nitroparacetamol adult dose of the invention is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30
  • the PCA i.e., intravenous
  • nitroparacetamol dose of the invention is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less - -
  • the intrathecal nitroparacetamol adult dose of the invention is less than about less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg
  • the intrathecal nitroparacetamol dose of the invention is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G adult dose of the invention for the treatment of pain, inflammation and/or fever is less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G adult dose of the invention i.e., the adult SAD dose of the M6G by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about 2 mg, or less than about 1.75 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.75 mg, or less than about 0.5 mg, or less than about 0.25 mg.
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G dose of the invention for the treatment of pain, inflammation and/or fever is less than about 0.42 mg/kg, or less than about 0.40 mg/kg, or less than about 0.38 mg/kg, or less than about 0.36 mg/kg, or less than about 0.34 mg/kg, or less than about 0.32 mg/kg, or less than about 0.3 mg/kg, or less than about 0.28 mg/kg, or less than about 0.26 mg/kg, or less than about 0.24 mg/kg, or less than about 0.22 mg/kg, or less than about 0.210 mg/kg, or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G dose of the invention (i.e., the SAD dose of the M6G by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.07 mg/kg, or less than about 0.0675 mg/kg, or less than about 0.065 mg/kg, or less than about 0.0625 mg/kg or less than about 0.06 mg/kg, or less than about 0.0575 mg/kg, or less than about 0.055 mg/kg or less than about 0.0525 mg/kg, or less than about 0.05 mg/kg, or less than about 0.0475 mg/kg or less than about 0.045 mg/kg, or less than about 0.0425 mg/kg, or less than about 0.04 mg/kg or less than about 0.0375 mg/kg, or less than about 0.035 mg/kg, or less than about 0.0325 mg/kg or less
  • M6G adult dose of the invention is less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about less than about 2 mg, or less than about 1.75 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than 0.75, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg,
  • the PCA i.e., intravenous
  • PCA] M6G dose of the invention is less than about 0.072 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.066 mg/kg, or less than about 0.064 mg/kg, or less than about 0.062 mg/kg, or less than about 0.060 mg/kg, or less than about 0.058 mg/kg, or less than about 0.056 mg/kg, or less than about 0.069 mg/kg, or less than about 0.054 mg/kg, or less than about 0.052 mg/kg, or less than about 0.050 mg/kg, or less than about 0.048 mg/kg, or less than about 0.046 mg/kg, or less than about 0.044 mg/kg, or less than about 0.042 mg/kg, or less than about 0.040 mg/kg, or less than about 0.072 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about
  • the intrathecal M6G adult dose of the invention i.e., the adult SAD dose of the M6G by the intrathecal route
  • the intrathecal M6G adult dose of the invention is less than - -
  • the intrathecal M6G dose of the invention is less than about 0.001425 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone adult dose of the invention for the treatment of pain, inflammation and/or fever is less than about 0.5 mg, or less than about 0.475 mg, or less than about 0.45 mg, or less than about 0.425 mg, or less than about 0.4 mg, or less than about 0.375, or less than about 0.35 mg, or less than about 0.325 mg, or less than about 0.3 mg, or less than about 0.275 mg, or less than about 0.25 mg, or less than about 0.225 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.125 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg,
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone adult dose of the invention is less than about 0.125 mg, or less than about 0.12 mg, or less than about 0.115 mg, or less than about 0.11 mg, or less than about 0.105 mg, or less than about 0.1 mg, or less than about 0.095 mg, or less than about 0.09 mg, or less than about 0.085 mg, or less than about 0.08 mg, or less than about 0.075 mg, or less than about 0.07 mg, or less than about 0.065 mg, or less than about 0.06 mg, or less than about 0.055 mg, or less than about 0.05 mg, or less than about 0.045 mg, or less than about 0.04 mg, or less than about 0.035 mg, or less than about 0.03
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone dose of the invention is less than about 0.00714 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone dose of the invention is less than about 0.00178 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.000
  • the PCA i.e., intravenous
  • PCA] oxymorphone adult dose of the invention is less than about less than about 0.3 mg, or less than about 0.275 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.125 mg, or less than about 0.1 mg, or less than about 0.075 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg.
  • the PCA i.e., intravenous
  • PCA] oxymorphone dose of the invention is less than about 0.00428 mg/kg, or less than about - -
  • 0.0042 or less than about 0.004 mg/kg, or less than about 0.0038 mg/kg, or less than about 0.0036 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or
  • the intrathecal oxymorphone adult dose of the invention is less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.15 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than
  • the intrathecal oxymorphone dose of the invention i.e., the SAD dose of the oxymorphone by the intrathecal route
  • the intrathecal oxymorphone dose of the invention is - -
  • less than about 0.00714 mg/kg or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001425 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol adult dose of the invention i.e., the adult SAD dose of the levorphanol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol adult dose of the invention i.e., the adult SAD dose of the levorphanol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol dose of the invention for the treatment of pain, inflammation and/or fever is less than about 0.0142 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol dose of the invention is less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg or less than about 0.0008 mg/kg, or less than about
  • the PCA i.e., intravenous
  • PCA levorphanol adult dose of the invention is less than about less than about 0.3 mg, or less than about 0.29 mg, or less than about 0.28 mg, or less than about 0.27 mg, or less than about 0.26 mg, or less than about 0.25 mg, or less than about 0.24 mg, or less than about 0.23 mg, or less than about 0.22 mg, or less than about 0.21 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than
  • the PCA i.e., intravenous
  • PCA levorphanol dose of the invention is less than about 0.00428 mg/kg, or less than about 0.0042, or less than about 0.004 mg/kg, or less than about 0.0038 mg/kg, or less than about 0.0036 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about
  • the intrathecal levorphanol adult dose of the invention is less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg
  • the intrathecal levorphanol dose of the invention is less than about 0.0029 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0027 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.0021 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.00 0.00
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan adult dose of the invention for the treatment of pain, inflammation and/or fever is less than about 5 mg, is less than about 4 mg, or is less than about 3 mg, or is less than about 2 mg, or less than about 1.95 mg, or less than about 1.9 mg, or less than about 1.85 mg, or less than about 1.8 mg, or less than about 1.75 mg, or less than about 1.7 mg, or less than about 1.65 mg, or less than about 1.6 mg, or less than about 1.55 mg, or less than about 1.5 mg, or less than about 1.45 mg, or less than about 1.4 mg, or less than about 1.35 mg, or less than about 1.3 mg, or less than about 1.25 mg, or less than about 1.2 mg, or less than about 1.15 mg,
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan adult dose of the invention is less than about 0.83 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or is less than about 0.34 mg, or less than 0.33 mg, or less than 0.32 mg, or less than about 0.31 mg, or less than 0.3 mg, or less than 0.29 mg, or less than about 0.28 mg, or less than 0.27 mg, or less than 0.26 mg, or less than about 0.27 mg, or less than 0.26 mg, or less than 0.25 mg, or less than about 0.24 mg, or less than 0.23 mg, or less than 0.22 mg, or less than about 0.21 mg,
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan dose of the invention for the treatment of pain, inflammation and/or fever is less than about 0.071 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.035 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan dose of the invention is or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about
  • the PCA i.e., intravenous
  • the PCA i.e., intravenous
  • PCA [i.e., intravenous PCA route]) is less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than 0.0045 mg/kg, or less than about 0.00428 mg/kg, or less than about 0.0042, or less than about 0.004 mg/kg, or less than about 0.0038 mg/kg, or less than about 0.0036 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026, or less than about 0.00
  • the intrathecal racemorphan adult dose of the invention is less than about 0.4 mg, or less than about 0.38 mg, or less than about 0.4 mg, or less than about 0.38 mg, or less than about 0.36 mg, or less than about 0.34 mg, or less than about 0.32 mg, or less than about 0.3 mg, or less than about 0.28 mg, or less than about 0.26 mg, or less than about 0.24 mg, or less than about 0.22 mg, or less than about 0.21 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08,
  • the intrathecal racemorphan dose of the invention is less than about 0.0057 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0057 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0029 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0027 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.0021 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg,
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone adult dose of the invention i.e., the adult SAD dose of the oxycodone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone adult dose of the invention i.e., the adult SAD dose of the oxycodone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intravenous
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone dose of the invention for the treatment of pain, inflammation and/or fever is less than about 0.142 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.086 mg/kg, or less than about 0.085 mg/kg, or less than about 0.08 mg/kg, or less than about 0.0775 mg/kg, or less than about 0.075 mg/kg, or less than about 0.0725 mg/kg, or less than about 0.07 mg/kg, or less than about 0.0675 mg/kg, or less than about 0.065
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone dose of the invention is less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg or
  • the PCA i.e., intravenous
  • PCA] oxycodone adult dose of the invention is less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 4 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1.1 mg, or less than about less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg,
  • 0.009 mg or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg.
  • the PCA i.e., intravenous
  • PCA] oxycodone dose of the invention is less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg,
  • the intrathecal oxycodone adult dose of the invention is less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.4 mg, or less than about 0.35 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than
  • the intrathecal oxycodone dose of the invention is less than about 0.0072 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0033 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.00
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone adult dose of the invention i.e., the adult SAD dose of the methadone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route for the treatment of pain, inflammation and/or fever is less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5.75 mg, or less than about 5.5 mg, or less than about 5.25 mg, or less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone adult dose of the invention i.e., the adult SAD dose of the methadone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less - -
  • 1.8 mg or less than about 1.7 mg, or less than about 1.6 mg, less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone dose of the invention for the treatment of pain, inflammation and/or fever is less than about 0.142 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.086 mg/kg, or less than about 0.085 mg/kg, or less than about 0.08 mg/kg, or less than about 0.0775 mg/kg, or less than about 0.075 mg/kg, or less than about 0.0725 mg/kg, or less than about 0.07 mg/kg, or less than about 0.0675 mg/kg, or less than about 0.065 mg/kg,
  • 0.006 mg/kg or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg.
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone dose of the invention is less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/
  • the PCA i.e., intravenous
  • 0.4 mg or less than 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg.
  • the PCA i.e., intravenous
  • PCA] methadone dose of the invention is less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about
  • the intrathecal methadone adult dose of the invention is less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.4 mg, or less than about 0.35 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg
  • the intrathecal methadone dose of the invention is less than about 0.0072 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0033 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg,
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol adult dose of the invention (i.e., the adult SAD dose of the tramadol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol adult dose of the invention i.e., the adult SAD dose of the tramadol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol dose of the invention for the treatment of pain, inflammation and/or fever is less than about 0.42 mg/kg, or less than about 0.40 mg/kg, or less than about 0.38 mg/kg, or less than about 0.36 mg/kg, or less than about 0.34 mg/kg, or less than about 0.32 mg/kg, or less than about 0.3 mg/kg, or less than about 0.28 mg/kg, or less than about 0.26 mg/kg, or less than about 0.24 mg/kg, or less than about 0.22 mg/kg, or less than about 0.210 mg/kg, or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than
  • the intravenous [excluding
  • intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol dose of the invention i.e., the SAD dose of the tramadol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • intravenous [excluding PCA] intravenous
  • intravenous [excluding PCA] intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • about 0.02 mg/kg or less than about 0.0175 mg/kg, or less than about 0.015 mg/kg, or less than about 0.0125 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg or less than about 0.001 mg/kg, or less than about 0.0005 mg/kg.
  • the PCA i.e., intravenous
  • the PCA i.e., intravenous
  • PCA] tramadol dose of the invention is less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.10 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.072 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.066 mg/kg, or less than about 0.064 mg/kg, or less than about 0.062 mg/kg, or less than about 0.060 mg/kg, or less than about 0.058 mg/kg, or less than about 0.056 mg/kg, or less than about 0.069 mg/kg, or less than about 0.054 mg
  • the intrathecal tramadol adult dose of the invention is less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or
  • the intrathecal tramadol dose of the invention is less than about 0.072 mg/kg, or less than about 0.071 mg/kg, or less than about 0.07 mg/kg, or less than about 0.065 mg/kg, or less than about 0.06 mg/kg, or less than about 0.055 mg/kg, or - -
  • the pharmaceutical composition can be administered in varying amounts, volumes and doses, depending on the method of administration, route of administration and patient characteristics (for example, IV bolus; IV slow injection; IV brief infusion; IV prolonged infusion; IV continuous infusion; subcutaneous [SC]) injection; SC infusion; continuous SC infusion; PCA administration; PCEA administration; intrathecal and epidural injections; intrathecal and epidural infusions; IM injection; cerebrospinal fluid [CSF] volume; age, weight, and fluid status of patient; body mass; general health and nutrition; cachexia; pharmacokinetics; pharmacodynamics; nature and severity of pain, fever and/or inflammation; nature of surgical procedure; use of concomitant medications, including other analgesics; co-morbidities; availability of venous access; availability of skilled medical personnel; availability of sterile conditions, etc).
  • IV bolus for example, IV slow injection; IV brief infusion; IV prolonged infusion; IV continuous infusion; subcutaneous [SC]
  • SC infusion continuous SC
  • SAD of the selected combination analgesic compatible with acceptable medical practice are contemplated by the invention.
  • the bolus IV injection volume of a single therapeutic injection dose does not exceed about 100 mL, or about 75 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the aforementioned volume does not exceed about 10 mL, or about 5 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the slow IV injection, brief or continuous IV infusions hourly volume does not exceed about 1000 mL, or about 500 mL, or about 250 mL, or about 200 mL, or about 150 mL, or about 100 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL.
  • the SC injection volume of a single therapeutic injection dose does not exceed about 5 mL or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the SC injection volume of a single therapeutic injection dose does not exceed about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the aforementioned volume does not exceed about 100 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the brief or continuous SC infusion hourly volume does not exceed about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the IM injection volume of a single therapeutic dose does not exceed about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the aforementioned volume does not exceed about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the intrathecal volume (excluding intrathecal infusions) of a single therapeutic dose does not exceed about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
  • the aforementioned volume does not exceed about 0 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
  • the hourly intrathecal infusion volume does not exceed about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.4 mL, or about 0.3 mL, or about 0.2 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
  • the aforementioned volume does not exceed about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.4 mL, or about 0.3 mL, or about 0.2 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
  • the epidural volume (excluding epidural infusions) of a single therapeutic dose does not exceed about 100 mL, or about 80 mL, or about 60 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
  • the aforementioned volume does not exceed about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
  • the hourly epidural infusion volume does not exceed about 30 mL, or about 20 mL, or about 15 mL, or about 12 mL, or about 10 mL, or about 8 mL, or about 6 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
  • the aforementioned volume does not exceed about 15 mL, or about 12 mL, or about 10 mL, or about 8 mL, or about 6 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
  • the combination analgesic of the invention when the combination analgesic of the invention includes ethylenediamine and/or piperazine, the invention specifically excludes one of more NSAIDS selected from the group of compounds comprising ketoprofen, dexketoprofen, piroxicam and tenoxicam. - -
  • the invention specifically excludes one of more
  • NSAIDS selected from the group of compounds comprising dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with hydroxypropyl-beta-cylcodextrin.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with beta-cylcodextrin.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with cylcodextrins.
  • the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with hydroxypropyl-beta- cylcodextrin.
  • the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with beta-cylcodextrin.
  • the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with cylcodextrins.
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with hydroxypropyl- beta-cylcodextrin.
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with beta- cylcodextrin.
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with cylcodextrins.
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said SAD of the combination analgesics is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said SAD of combination analgesics is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) and preceded by a loading dose of the one or more combination analgesics by the same route of administration, said loading dose administered using at least the minimum approved or recommended dose of said combination analgesics by said route.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said combination analgesics is not given by bolus injection.
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the combination analgesics dosage form is devoid of ethylenediamine.
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, - -
  • the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the combination analgesics dosage form is devoid of glycine.
  • the invention specifically excludes NSAIDS and acetaminophen or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said NSAIDS or acetaminophen is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • the invention specifically excludes NSAIDS and acetaminophen or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said NSAIDS or acetaminophen is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) and preceded by a loading dose of the said NSAID or acetaminophen by the same route of administration, said loading dose administered using at least the minimum approved or recommended dose of said combination analgesics by said route.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • the invention specifically excludes NSAIDS and acetaminophen or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said NSAIDS and acetaminophen is not given by bolus injection.
  • the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAID dosage form is devoid of ethylenediamine.
  • the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAIDS dosage form is devoid of piperazine. - -
  • the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAIDS dosage form is devoid of glycine.
  • NSAIDS selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof are applicable or also applicable to other NSAIDS (ie., COX-2 and/or COX-I inhibitors), including, without limitation, compounds selected from the group comprising ace
  • opioids selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof, in - -
  • opioids including, without limitation, compounds selected from the group comprising opioid receptor agonists (i.e., mu ( ⁇ ), delta ( ⁇ ), kappa (K) and /or nociceptin/orphanin FQ (N/OFQ) opioid receptors), their subtypes and splice variants, including alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, brifentanil, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenox
  • opioid receptor agonists i.e., mu ( ⁇ ), delta ( ⁇ ), kappa (K) and /or nociceptin/orphanin FQ (
  • subanalgesic dose of the selected combination analgesics comprising at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group
  • some or all of the specifications and claims of the invention are achieved after first administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved after multiple dose administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved after intravenous, IV PCA, intramuscular, subcutaneous, intra-articular, local tissue infiltration, epidural or intrathecal administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of moderate intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of at least moderate intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of moderately severe intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of severe intensity. In certain preferred embodiments, some or all of - -
  • the specifications and claims of the invention are achieved in patients with acute pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with breakthrough pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with acute exacerbations of chronic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with cancer pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with chronic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with neuropathic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with fever. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with inflammation.
  • the selected combination analgesic given as a SAD of the selected combination analgesic is administered only by patient controlled (intravenous) analgesia (PCA) or patient controlled epidural analgesia (PCEA).
  • PCA patient controlled
  • PCEA patient controlled epidural analgesia
  • the methods and compositions described herein are useful for treating a wide range of specific types of pain including acute pain, subacute pain, chronic pain, cancer pain, breakthrough pain, neuropathic pain, nociceptive pain, visceral pain, idiopathic pain, inflammatory pain, non-inflammatory pain.
  • Nonlimiting examples of acute pain include peri-operative pain, postsurgical pain, headache, acute low back pain, fractures, strains and sprains, ligament pain, cystitis, post-traumatic pain, burn pain, procedure related pain, and renal colic.
  • Nonlimiting examples of chronic pain include cancer pain, osteoarthritis, fibromyalgia, low back pain, idiopathic pain, rheumatoid arthritis, bursitis, myofascial pain and the like.
  • Nonlimiting examples of neuropathic pain include postherpetic neuralgia, trigeminal neuralgia, painful diabetic neuropathy, pain HIV associated neuropathy, painful polyneuropathy, phantom limb pain, stump pain, spinal cord injury pain, post-stroke pain, central pain and the like.
  • the SAD of the selected combination analgesic chosen is for the treatment of fever, acute pain (e.g., - -
  • the SAD of the selected combination analgesic chosen is for use in patients who are generally expected to have an established venous access through a catheter.
  • the SAD of the selected combination analgesic chosen is for use in the treatment of pain, inflammation and fever in patients for whom standard of care generally requires hospitalization or retention in a medically supervised facility during the period of treatment with the pharmaceutical composition and methods of the invention.
  • analgesic effectiveness is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, along with a tolerable level of side effects, as determined by the human patient.
  • therapeutic effectiveness is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, fever and/or inflammation, along with a tolerable level of side effects, as determined by the human patient.
  • the term "effectiveness" is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, fever and/or inflammation, along with a tolerable level of side effects, as determined by the human patient.
  • the pharmaceutical composition can be administered in varying amounts and volumes.
  • the method of the invention may comprise administering, to a subject in need of an analgesic, anti-inflammatory or anti-pyretic treatment, a subanalgesic dose (SAD) of the selected combination analgesic comprising: (i) a pharmaceutical composition of at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac,
  • SAD subanal
  • mo ⁇ hine-6-glucuronide oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof;
  • Administration of the two or more SAD of the composition can be via different parenteral routes.
  • the two or more SAD of the composition may be administered as a single pharmaceutical composition. That is, the two or more SAD of the composition may be formulated together so that both active agents are contained in one pharmaceutical compositions.
  • the two or more SAD of the composition may be formulated into a single vial, ampoule or prefilled syringe, mixed together into a parenteral delivery system (e.g., a cassette, cartridge, volume control set, minibag, large volume parenteral, bottle, etc) or into a unit dosage form.
  • a parenteral delivery system e.g., a cassette, cartridge, volume control set, minibag, large volume parenteral, bottle, etc
  • the two or more SAD of the composition may be administered separately (for example through the same vein but separate containers, or through different veins or through different parenteral routes of administration.
  • the two or more SAD of the composition may be administered sequentially, simultaneously, contemporaneously, or using a different dosing frequency and dosing schedule for each, provided that are the two or more SAD of the composition are present in systemic circulation at quantifiable levels for at least part of the dosing period or treatment period.
  • the subanalgesic dose (SAD) of the two or more compounds of the invention are able to independently exert analgesia, despite their subanalgesic doses.
  • one , or more or all of the embodiments and specifications of the invention referring to SAD are applicable to analgesic doses.
  • the two or more SAD of the selected analgesics are administered by the same route of administration. It is further understood that the various embodiments of the method of the present invention may utilize each of the various composition embodiments described herein. - -
  • Administration of the present invention can be via any parenteral route of administration.
  • suitable parenteral routes of administration are described in general terms as follows. Each of the following routes of administration can be used in the present invention, in particular in each of the specific embodiments described.
  • IM Administration Once a popular method of drug administration, the intramuscular (IM) route is used considerably less frequently today due to improved availability of oral drugs and due to the ease of intravenous administration. This method of drug administration involves injecting drug directly into muscle mass, from where drug will gradually be absorbed systemically. For drugs that are not irritating when given by the IM route which require only a single injection, the IM route is still a viable route of administration, particularly in the outpatient setting or where strict aseptic conditions cannot be assured. When repeated administration is required or a rapid and reliable onset is desired, the intravenous route is preferred as repeated IM administration can be painful and inconvenient. Commonly the deltoid, gluteus maximus and vastus lateralis are sites for IM injection.
  • IM administration is partly a function of the dose and the injection volume, both of which are reduced by SAD selected combination analgesics of the invention. Additionally, IM administration is particularly attractive in the ambulatory care/out-patient setting, where venous access is lacking or impractical, and in settings where sterility cannot be absolutely assured.
  • the reduced dose and volume of the SAD of the invention particularly facilitate deltoid injections which are more convenient, more socially acceptable and provide more reliable pharmacokinetics and clinical effects that injection into the gluteus maximus.
  • Subcutaneous Administration involves injection into the subcutaneous fatty tissue under the skin. It can be used for the intermittent administration and self-administration of insulin and other medicines. In a small number of patients, particularly outpatients, this route is also used for the continuous or intermittent administration of drugs, usually with a programmable subcutaneous infusion device.
  • Epidural and intrathecal infusions can provide effective analgesia, but require skilled personnel (usually an anesthetist) to put the systems in place.
  • Catheters can be placed at any level of the spinal cord, although - -
  • epidural and intrathecal routes of administration are advantageous for difficult abdominal or pelvic pain.
  • epidural catheters can be placed percutaneously, and fixed either by secure taping or subcutaneous tunnelling.
  • the drugs can then be delivered through a small pump or a syringe driver.
  • Subjects can be ambulant and managed at home with these systems.
  • the treatment team must have the necessary training, knowledge and support.
  • intrathecal systems which can be fully implantable, have many advantages. These offer great freedom to the patient, as there is no external equipment and the pump only needs to be refilled every few weeks.
  • epidural and especially intrathecal doses of selected combination analgesics can be lower than intravenous doses.
  • Epidural and intrathecal administration of selected combination analgesics can be also be used in conjunction with intravenous selected combination analgesics to provide additive or synergistic analgesia.
  • Patient-controlled epidural analgesia is abbreviated "PCEA”.
  • Intraarticular Administration This method of administration can be used to provide analgesic and anti-inflammatory drugs directly into affected joints to relieve pain and inflammation, usually due to surgery, osteoarthritis or joint trauma.
  • Surgical site or open wound This method of administration can be used when localized attenuation of pain or inflammation is deemed desirable and is achieved by topical, dermal administration or infiltration of a dose to a surgical site or open wound.
  • the term "infiltration”, “local infiltration”, “tissue infiltration” and “local tissue infiltration” shall mean administration into a discrete surgical site, open wound or at the location of pain in a human or animal.
  • IV Drug Administration The mode of IV drug administration depends on the particular selected combination analgesics used, the patient's condition, and the desired clinical effects of the selected combination analgesics.
  • the four primary modes of IV drug administration are continuous infusion, intermittent infusion, direct injection, and patient-controlled analgesia. - -
  • Continuous infusion typically refers to the admixture of a drug in a large volume of solution that is infused continuously over several hours to several days.
  • the solution container is connected to an administration set, and the solubilized drug is infused through the venous access.
  • the infusion may be administered by gravity feed or by use of electronic infusion control pump to deliver the drug accurately.
  • continuous infusions can be used when the drug is highly diluted and constant plasma drug concentration should be maintained.
  • continuous infusion can be used where large volumes of fluids and electrolytes need to be replenished along with the administration of the selected combination analgesics.
  • Among the disadvantages with continuous infusion are possible fluid overload and potential incompatibilities between the infusion and other IV drugs administered through the same venous access device. Patient comfort may be compromised and patient mobility restricted.
  • Intermittent infusion refers to the administration of the drug as a small volume of fluid, typically 25 to 250 mL, and infused over, for example, 15 to 120 minutes at periodic intervals.
  • advantages of the intermittent method are the ability of the drug to produce higher peak blood concentrations at periodic intervals (compared with a continuous infusion), decreased risk of fluid overload, and greater convenience for the patient.
  • Intermittent infusions may be given in a number of ways, including "piggyback" infusions through the established pathway of a primary infusion solution. Although the primary infusion is interrupted during the piggyback infusion, the drug from the intermittent infusion container mixes with the primary solution below the piggyback injection level. Thus, if this method is used, the drug and the primary solution must be compatible.
  • a second method to administer intermittent infusions is as a simultaneous infusion, where the drug is administered as a secondary infusion concurrently with the primary infusion. Instead of connecting the intermittent infusion at the piggyback port, it is attached to a lower secondary port.
  • One potential disadvantage of this method is the tendency for blood to back up into the tubing once the secondary infusion has been completed, potentially occluding the venous access device. This generally does not occur with the piggyback method because the hydrostatic pressure closes the back check valve once the intermittent infusion is completed.
  • a third method is the use of a volume control set. Although it was originally designed to control the fluid volume delivered to the patient, a drug may be added to a small amount of solution in the volume control set and infused at the desired rate. It is still used in some pediatric settings because it limits the amount of fluid the child receives.
  • a fourth method for administering intermittent infusions is directly into the venous access device.
  • the device is generally intended for intermittent administration, such as a peripheral heparin lock.
  • the drug is added to a minibag or minibottle and infused intermittently. Between doses, the drug container and tubing are discarded.
  • Direct injection also known as IV push, IV bolus, or slow IV injection
  • IV push is the administration of a drug directly into the venous access device or through the proximal port of a continuous infusion set.
  • a purpose is to achieve rapid plasma concentrations while avoiding costly and time consuming use of infusion devices.
  • a direct injection requires only the time it takes to push the syringe plunger. Since the drug may be incompatible with the infusing solution or heparin may be present in the intermittent device, the vascular access device can be flushed with normal saline before and after injecting the drug.
  • Direct injections may require that the drug be drawn into a syringe before administration or that the drug be available in a prefilled syringe.
  • a needle 1 inch or shorter should be used to administer the medication because longer needles may puncture the IV tubing or the vascular access device.
  • Another alternative is a needleless system, which also prevents inadvertent puncture of the tubing or device.
  • Patient-controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • PCA patient controlled intravenous analgesia
  • PCEA patient controlled epidural analgesia
  • patient controlled analgesia using the intrathecal or subcutaneous route of administration is the fourth method of administration of drug administration which promotes patient comfort through the self- administration of analgesic agents.
  • an automated pump is programmed to administer a small bolus of the drug when activated by the patient.
  • the bolus amount (demand dose) and the time between doses (lock-out interval) are predetermined and programmed into the pump.
  • PCA pump refers to intravenous, epidural, intrathecal or subcutaneous administration of an analgesic via a pumping device with the patient having some ability to control the timing and quantity of drug delivery. See, for example, U.S. Patent No. 6,010,483.
  • Pumps currently used for patient controlled analgesia generally give the clinician two to four parameters to set when prescribing a given drug for a patient.
  • a demand dose or bolus amount of drug administered whenever the patient presses a button includes (1) a demand dose or bolus amount of drug administered whenever the patient presses a button; (2) a lockout interval which determines how soon after a bolus is administered a second bolus will be delivered if the patient pushes the button again; and optionally (3) a daily or 24 hour maximum dose or a daily or 24 hour maximum number of demand doses; and (4) override doses, said override doses administered by or under the supervision of a qualified care giver or health care worker . If a patient presses the button before the lockout interval has elapsed, the pump simply ignores the request.
  • the dose and lockout are generally programmed into the pump for an individual patient and drug combination.
  • the dose is prescribed based on the clinician's assessment of the patient's opioid requirement (depending on weight, habituation, or other factors).
  • the lockout interval is generally set depending on the time to onset of clinical effect of a given drug.
  • the lockout interval is used to prevent a patient from giving himself or herself another bolus before the previous bolus has had a chance to take effect.
  • PCA refers to patient controlled analgesia by the intravenous route
  • PCEA refers patient controlled analgesia by the epidural route.
  • a co-administered drug may include other NSAIDs, NO-NSAIDs, COX-2 selective inhibitors, acetaminophen, nitroparacentamol, tramadol, local anesthetics, antidepressants, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, cannabinoid agonists, opioid receptor agonists, NO-opioids, NMDA receptor antagonists, gabapentin, pregabalin, gabapentinoids, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers, serotonin 5-HT(lB/lD) receptor agonists superoxide dismutase mimetics, p38 MAP kinase inhibitors, triptans, TRPVl agonists, dextromethorphan, dextrorphan, ketamine, glycine receptor antagonists,
  • Other therapeutically active agents from various therapeutic classes may also be used in combination with the present invention. They include, but are not limited to decongestants, analgesics, analgesic adjuvants, antidepressants, antipsychotics, anxiolytics, hypnotics, sedatives, drugs to treat urinary incontinence, antihistamines, expectorants, antitussives, diuretics, anti-inflammatory agents, antipyretics, antirheumatics, antioxidants, laxatives, local anesthetics, proton pump inhibitors, motility modifying agents, vasodilators, inotropes, beta blockers, beta adrenergic agonists, drugs to treat asthma and COPD, antiinfectives, anti-migraine agents, antihypertensives, antianginal agents, gastric acid reducing agents, anti-ulcer agents, anticoagulants, lipid and cholesterol lowering drugs, anti-diabetic drugs, anti-epileptic
  • Some preferred combination therapies comprise the use of a composition of the present invention in combination with a therapeutic and effective dose of one or more compounds selected from the group consisting of acemetacin, ⁇ -acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, iS-adenosyhnethionine, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), alvimopan, amfenac, amino chlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4- picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, anileridine, antrafenine, apazone, balsalazide, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benz
  • phenylbutazone phenyl salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone, pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamnide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, salverine, simetride, sodium salicylate, sufentanil, sulfasalazine, superoxide dismutase, suprofen, suxibuzone, tapentadol, tenoxicam, talniflumate, tapent
  • Particularly preferred combination therapies comprise the use of a composition of the present invention in combination with drugs that possess analgesic, anti-inflammatory, antipyretic and antimicrobial properties.
  • the drug being used in combination therapy with the present invention can be administered by any route, including parenterally, orally, topically, transdermally, inhalationally, and the like.
  • Another aspect of the present invention is directed to a composition
  • a composition comprising a subanalgesic dose (SAD) of the selected combination analgesics with at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof
  • composition comprising:
  • subanalgesic dose of the selected combination analgesics with at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group compris
  • the concentration of the selected combination analgesic may vary as needed, e.g., from about 0.000001 to about 1000 mg/mL, preferably from about 0.0001 to about 200 mg/mL, based on weight or potency of the NSAID.
  • Other suitable values include about 0.001, 0.01, 0.1, 1, 5, 10, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 500, 550, 600, 650, 700, 800, 900 or 1000 mg/mL.
  • the selected combination analgesic can be a parenteral drug formulation prepared, e.g., as a solid, liquid, semi-solid, or emulsion.
  • the most common forms include solid, - -
  • compositions can be reconstituted with a liquid vehicle just prior to administration. However, in many situations, it is particularly advantageous to provide a liquid formulation, more especially a ready-to-use or dilutable formulation.
  • the formulation may optionally contain one or more additives, adjuvants, excipients, auxiliary agents or enabling agents, such as buffers, stabilizing agents, tonicity agents, antioxidant, anesthetics or bulking agent.
  • the dosage form of the invention is devoid of one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds know in the art.
  • a surfactant benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol
  • the dosage form of the invention contains one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds known in the art.
  • a surfactant benzyl alcohol
  • a polyethylene glycol a N-methylglucamine or derivative thereof
  • arginine or a derivative thereof lysine or a derivative thereof
  • an adjuvant citric acid or derivative thereof
  • glycine or a derivative thereof glycerol or a
  • the pharmaceutical composition is devoid of one or more salts or complexes such as any of the inorganic cation salts (e.g., sodium, potassium, lithium, magnesium, calcium, cesium, ammonia, ferrous, zinc, manganous, aluminum, ferric, and manganic), organic salts (e.g., tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, tris-(hydroxymethyl)aminomethane, N- methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins).
  • the inorganic cation salts e.g., sodium, potassium, lithium, magnesium, calcium,
  • the pharmaceutical composition is devoid of one or more salts or complexes such as inorganic cation salts, organic salts such primary, secondary, tertiary and quaternary amines include substituted amines.
  • the pharmaceutical composition is devoid of one or more salts or complexes of aminoalcohols chosen from the group consisting of ethanolamine, 3-amino-l-propanol, (R)-I -amino-2-propanol, (S)-I -amino-2- propanol, 2-amino-l,3-propandiol, N-(2-hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, and N-methylglucosamine
  • the pharmaceutical composition is devoid of one or more salts or complexes of alkali and alkaline earth metals and salts of an organic nature, such as the salts of basic amino acids.
  • the pharmaceutical composition is devoid of one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds know in the art.
  • the invention contemplates all possible pharmaceutically acceptable salts and complexes of the SAD of the selected combination analgesic.
  • the pharmaceutical composition contains the SAD of the selected combination analgesic may be in unsalified form or as a salt or complex.
  • Nonlimiting examples of salts is provided below.
  • the pharmaceutical composition contains the
  • organic salts such primary, secondary, tertiary and quaternary amines include substituted amines
  • suitable pharmaceutically acceptable salts of selected combination analgesics include any of the inorganic cation salts such as sodium, - -
  • primary, secondary, tertiary and quaternary amines include substituted amines including but not limited to naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and mixtures thereof.
  • suitable amines include but are not limited to tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2- diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N- ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, tris- (hydroxymethyl)aminomethane, ⁇ -methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins and the like, and mixtures thereof.
  • the pharmaceutical composition contains the
  • SAD of the selected combination analgesic as a salt or complex of aminoalcohols chosen from the group consisting of ethanolamine, 3-amino-l-propanol, (K)-I -amino-2- propanol, (S)-I -amino-2-propanol, 2-amino-l,3-propandiol, N-(2- hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, and N- methylglucosamine.
  • the pharmaceutical composition contains the
  • SAD of the selected combination analgesic as a salt or complex of alkali and alkaline earth metals and salts of an organic nature, such as the salts of basic amino acids.
  • the pharmaceutical composition contains the
  • suitable pharmaceutically acceptable salts of selected combination analgesics include hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, citrates, tartrates, bitartrates, phosphates, malates, maleates, napsylates, fumarates, succinates, acetates, terephlhalates, pamoates and pectinates.
  • the pharmaceutical composition contains, in addition to the SAD of the selected combination analgesic, one or more cyclodextrins (e.g., beta-hydroxypropyl- cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether cyclodextrin, gamma-cyclodextrin).
  • one or more cyclodextrins e.g., beta-hydroxypropyl- cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether cyclodextrin, gamma-cyclodextrin.
  • the pharmaceutical composition contains, in addition to the SAD of the selected combination analgesic, ethanol, benzyl alcohol, - -
  • propylene glycol polyethylene glycol (PEG)-600, PEG-400, PEG-200, propylene glycol, glycerol, hydrotropes, sodium benzoate, sodium hydroxybenzoate and methyl-p- hydroxybenzoate sodium, sodium metabisulfite, EDTA.
  • the pharmaceutical composition contains, in addition to the SAD of the selected combination analgesic is micronized or prepared as a nanoparticulate composition.
  • the pharmaceutical composition contains the
  • SAD of the selected combination analgesic is free of preservatives.
  • the pharmaceutical composition contains the
  • SAD of the selected combination analgesic is free of pharmaceutical excipients.
  • Liquid carriers and excipients are known in the art. See, e.g., Remington's.
  • Suitable liquid carriers and excipients include, but are not limited to, water, saline, ethanol, benzyl alcohol, etc., and mixtures thereof.
  • a preferred carrier is water, in particular water for injection
  • the pharmaceutical composition may contain a buffer.
  • buffer refers to a pharmaceutically acceptable excipient that helps to maintain the pH of the solution within a particular range specific to the buffering system.
  • the buffer is present for example at a concentration in the range from about 0.03% to about 5.0% w/v, or about 0.1% to about 2.0% w/v.
  • Non-limiting illustrative examples of pharmaceutically acceptable buffering agents include phosphates, 2-amino-2-(hydroxymethyl)-l,3- - o -
  • Tris propanediol
  • ascorbate acetates
  • citrates tartrates
  • lactates succinates
  • amino acids and maleates and the like propanediol
  • Buffers are known in the art. See, e.g., Remington's.
  • the pH of a liquid formulation of the present invention in preferred embodiments is generally from about 5 to about 9, preferably from about 6 to about 8. In other embodiments, the pH of the liquid formulation is about 5, 6, 7, 8, or 9. Alternatively, the pH of the liquid formulation is about 7.5. Alternatively, the pH of the liquid formulation may be selected from the following ranges: 6.0 to 6.9; 6.5 to 6.9; 7 to 7.5; 7.6 to 8.0; 7.6 to 8.5; and 7.6 to 9.0.
  • the concentration and dosage of the selected combination analgesic in the liquid parenteral formulation can vary as needed.
  • the SAD of the selected combination analgesic can be in an amount of about from about 0.000001 to about 1000 mg/mL, alternatively from about 0.001 mg/mL to about 200 mg/mL, based for example on the mass of the selected combination analgesic, its solubility, the route of administration, the choice of dose, patient characteristics and the purpose of drug administration.
  • the liquid formulation may be packaged in any suitable container, for example, a vial, ampoule, bag, bottle, prefilled syringe, and the like.
  • the liquid formulation comprises a physiologically compatible fluid, such as sterile, buffered saline.
  • the liquid carrier used in preferred embodiments is preferably injection-quality water, by itself or preferably with the addition of conventional, physiologically tolerated solvents and/or solubilizing agents, e.g., propylene glycol, polyols such as glycerol, polyoxyalkylenes, e.g., poly(oxyethylene)-poly(oxypropylene) polymers, glycerol-formal, benzyl alcohol, or butanediol.
  • solubilizing agents produces a composition which is stable at low temperatures and minimizes or prevents partial crystallization of the selected combination analgesic, in spite of the high concentration NSAID that may be present.
  • the liquid pharmaceutical formulation may be characterized in terms of its osmolality.
  • the osmolality of the pharmaceutical formulation is from about 50 to about 1000 mOsm/L, preferably about 100 to about 500 mOsm/L.
  • the pharmaceutical compositions of the present invention are prepared such that the osmolality is about 200 to about 300 mOsm/L, about 250 to about 350 mOsm/L, about 270 to about 330 mOsm/L, about 270 to about 290 mOsm/L, or about 280 to about 300 mOsm/L, or is 270, 280, 290, 300, or 310 mOsm/L.
  • Alternative preferred embodiments include compositions which have a lower osmolality than physiological osmolality.
  • the injection preparations according to the invention can be sterilized by conventional methods or filled under sterile conditions.
  • the concentration of the selected combination analgesic in the liquid pharmaceutical composition can vary and may depend on the intended use.
  • the injection solutions according to the invention contain from about 0.0001 to about 90% of the selected combination analgesic.
  • liquid formulations of invention may employ one or more stabilizing agents.
  • a stabilizing agent may slow, delay, reduce, or prevent the precipitation of one or more analgesics. It will be understood that the effectiveness of such means for stabilizing the analgesic salt, illustrative examples of which are individually described in further detail below, depend on, inter alia, composition of the particular solvent liquid, selection and amount of analgesic salt, and desired final presentation of the composition.
  • One class of suitable salt stabilizing means is a means for limiting effective exposure of the composition to oxygen.
  • limiting effective exposure of the composition to oxygen includes placing the composition in contact with an oxygen-limited microatmosphere and/or including in the composition one or more excipients or agents that mitigate potential deleterious effects of oxygen. Limiting the effective exposure of the composition to oxygen can be accomplished by one or more of the illustrative, nonlimiting means described more fully immediately below.
  • One means for limiting effective exposure of the composition to oxygen is to place the composition in contact with an oxygen-limited microatmosphere in a sealed container.
  • a container can have a substantial internal headspace occupied by a microatmosphere having low oxygen pressure.
  • the container can have very little or no headspace, in which case effective exposure of the composition to oxygen is limited largely by the barrier effect provided by the sealed container itself.
  • Any suitable pharmaceutical container can be used to prepare an article of manufacture according to this embodiment.
  • the container can be a multi-dose container, enclosing an - oZ-
  • the container encloses an amount of the composition corresponding to a single unit dose.
  • Such a single-dose article of manufacture has the further advantage of eliminating a measuring step before administration of the composition. Since compositions of the invention are desirable for parenteral administration, the container preferably is sufficient to maintain sterility of a composition contained therein. The container can also be used to facilitate direct administration (without need for transfer to another vessel or container) of a composition of the invention, e.g., a syringe.
  • Non-limiting examples of suitable containers for an article of manufacture of this invention include vials of any shape and/or size, ampoules, syringes, packets, pouches, auto-injectors, etc.
  • the container further comprises means to protect the composition from exposure to light, e.g., amber glass walls.
  • a composition of the invention can be sealed in a container in any suitable manner including but not limited to frictionally- and/or hermetically-induced seals.
  • a seal can illustratively be provided by a stopper made of rubber or other polymeric material.
  • a preferred seal comprises an inert coating, for example a coating of a fluoropolymer such as polytetrafluoroethylene, e.g., Teflon , to prevent chemical interaction between the composition and the seal.
  • the seal can illustratively be secured by a metal over-cap and/or an external cover, e.g., plastic, until use.
  • the seal can comprise at least one septum or thinner area of sealing material through which a needle can be inserted to extract the composition without cracking or breaking any glass or plastic portion of container wall. Regardless of what form of seal is used, such a seal should substantially inhibit movement of gas into or out of the container until the seal is penetrated for use of the composition present in the container.
  • compositions are enclosed in a sealed container with an oxygen limited micro atmosphere
  • effective exposure of the composition to oxygen can be further limited by one or more of the following means: 1) a container size and/or shape that substantially maximizes fill volume and/or substantially minimizes headspace volume; 2) low oxygen pressure in the headspace; 3) use in the solvent liquid of water which has been purged of molecular oxygen; and 4) use of a grade of PEG having a low peroxide content, for example not greater than about 1.5 meq/kg and preferably not greater than about 1.0 meq/kg.
  • headspace or "headspace volume” with respect to an article of manufacture of the invention refers to any interior volume of the container that is not occupied by, but is in contact with, the composition. Generally, the headspace volume is occupied by a gaseous medium.
  • fill volume with respect to an article of manufacture of the invention refers to any interior volume of the container that is occupied by the composition.
  • total volume refers to the entire interior volume of the container and may also be referred to elsewhere as overflow volume; total volume generally equals the sum of the fill and headspace volumes.
  • Yet another suitable means for limiting effective exposure of a composition, particularly a PEG-containing composition, of the invention to oxygen, and thereby providing said analgesic salt stabilizing means comprises one or more pharmaceutically acceptable antioxidants, preferably free-radical scavenging antioxidants, as a component of the solvent liquid.
  • Non-limiting illustrative examples of suitable antioxidants include ⁇ -tocopherol (vitamin E), ascorbic acid (vitamin C) and salts thereof including sodium ascorbate and ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cystein, cysteinate HCl, dithionite sodium, ethylenediamine tetraacetic acid, fumaric acid, gentisic acid and salts thereof, hypophosphorous acid, malic acid, methionine, monothioglycerol, N-acetyl-cysteine, alkyl gallates, for example propyl gallate, octyl gallate and lauryl gallate, sodium sulfite, sodium bisulfite, sodium and potassium metabisulfite, thioglycolate sodium, ethanolamine, glutamate monosodium, formaldehyde, sulfoxylate sodium and monothioglycerol.
  • Preferred free radical-scavenging antioxidants are alkyl gallates, vitamin E, BHA, BHT, ascorbate and methionine, more especially BHA, ascorbate and methionine.
  • an antioxidant is selected that is substantially soluble in the particular solvent liquid employed and does not result in changes to the composition which are detectable by unaided sensory organs (e.g., color or odor changes).
  • BHA is an illustrative preferred antioxidant for use in a composition of the invention. If included, one or more antioxidants are preferably present in a composition of the invention in a - -
  • total antioxidant amount of about 0.001% to about 5%, preferably about 0.001% to about 2.5%, and still more preferably about 0.001% to about 1%, by weight.
  • the formulations may optionally contain a bulking agent.
  • a bulking agent refers to a pharmaceutically acceptable excipient that adds bulk to a formulation which results in a well-formed cake upon freeze drying.
  • the bulking agent is for example present in a formulation at a concentration in the range from about 1% to about 60% w/v, or about 3% to about 50% w/v.
  • suitable bulking agents include mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin.
  • the solid composition also may include a tonicity agent.
  • Suitable tonicity agents include, but are not limited to, glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, and sorbitol.
  • Non-limiting examples of suitable nonaqueous solubilizers that can be present in the solvent liquid include polyethylene glycol (PEG), ethanol, dimethylacetamide (DMAC), propylene glycol, and mixtures thereof. It is preferred that the solvent liquid comprise at least one of PEG, DMAC, and ethanol.
  • Yet another means for stabilizing the formulation in a PEG-containing composition is a metal sequestering agent or chelating agent.
  • suitable sequestering agents include ethylenediamine tetraacetic acid (EDTA), potassium polyphosphate, sodium polyphosphate, potassium metaphosphate, sodium metaphosphate, dimethylglyoxirne, 8-hydroxyquinoline, nitrilotriacetic acid, dihydroxyethylglycine, gluconic acid, citric acid and tartaric acid.
  • composition of the present invention can optionally contain a surfactant.
  • Non-limiting examples of suitable surfactants include cetrimide, docusate sodium, glyceryl monooleate, sodium lauryl sulfate, or sorbitan esters.
  • the surfactant may optionally be a polyoxyethylenesorbitan fatty acid ester.
  • Polyoxyethylenesorbitan fatty acid esters are also referred to as polysorbates, e.g., polysorbate 80 (polyoxyethylene sorbitan monooleate, Tween 80), polysorbate 40 and polysorbate 20.
  • composition of the present invention can optionally be manufactured in glass- lined or a "greater than or equal to 316 temper-grade" steel tank.
  • Oxygen pressure in a container headspace of an article of manufacture of the invention can be limited in any suitable manner, illustratively by placing nitrogen and/or a — —
  • the headspace volume preferably comprises one or more inert gases selected from the group consisting of nitrogen, helium, neon and argon.
  • inert gases selected from the group consisting of nitrogen, helium, neon and argon.
  • An inert gas atmosphere can illustratively be provided using a zero oxygen tunnel commercially available from Modified Atmosphere Packaging Systems of Des Plaines, 111., or by using a nitrogen or noble gas atmosphere glove bag.
  • polymorphs of this invention may be prepared by crystallization under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray data or such other techniques.
  • solvates of the invention may be prepared by conventional methods such as dissolving the compounds in solvents such as water, methanol, ethanol etc., and recrystallizing by using different crystallization techniques.
  • composition of the present invention comprises:
  • subanalgesic dose of the selected combination analgesics comprising a pharmaceutical composition of at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof;
  • nitric oxide donors thereof and mixtures thereof nitric oxide donors thereof and mixtures thereof;
  • sterile water optionally one or more pharmaceutically acceptable buffers;
  • optionally one or more pharmaceutically acceptable antioxidants optionally one or more pharmaceutically acceptable tonicity adjusters;
  • the composition is contained in a sealed glass vial or a prefilled syringe.
  • the present invention is directed to a composition comprising the SAD of selected combination analgesics with ethylenediamine and/or piperazine having an aqueous solubility of greater than about 50 mg/mL, greater than about 100 mg/mL, greater than about 200 mg/mL, greater than about 350 mg/mL, greater than about 400 mg/mL, greater than about 450 mg/mL, or greater than about 500 mg/mL.
  • the present invention is directed to sealed syringe comprising a sterile solution comprising one of more selected combination analgesic subanalgesic doses (SAD) comprising at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-
  • SAD selected combination analges
  • a solution comprising water, e.g., purified by reverse osmosis, piperazine, and one of more selected combination analgesic and optionally sorbitol, and adjusted to a pH from about 6.5 to about 8.5 is added to presterilized syringes under nitrogen atmosphere and aseptic conditions.
  • the solution is optionally first filtered through a filter, e.g., a 0.45 micron filter, and deoxygenated with nitrogen or deoxygenated and finally passed through 0.22 micron membrane filter into presterilized syringes under nitrogen atmosphere and aseptic conditions.
  • the syringes are sealed under an inert atmosphere, e.g., nitrogen.
  • the sealed syringe containing the selected combination analgesic can be used in accordance with the methods described herein.
  • the solutions in the sealed syringe show no visible signs of crystallization or significant deviation in pH and osmolality and contain 100% ⁇ 15% original NSAID content when stored for 12 weeks at 5 0 C, 25°C/60% RH, 30°C/60% RH, 40°C/75% RH as determined by HPLC. - -
  • the osmolality of the solution in the sealed syringe may be from about 200 to about 400, preferably from about 280 to about 300 mOsm/L.
  • compositions of the present invention can be prepared by direct salification or complexation between the selected combination analgesic in unsalified form and a pharmaceutically acceptable salt, complexing agent or solubility enabling agent.
  • parenteral pharmaceutical composition is well known in the art - see Niazi, S. Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products, (Volume 6), CRC Press, 2004; Remington: The Science of Pharmacy Practice, 21 st Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, MD; Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRC Press, 2001; Pharmaceutical Dosage Forms: Parenteral Medications, Volume I.
  • the selected combination analgesics are in the form of a solid, semisolid, suspension emulsion or solution within a single container (e.g., ampoule, vial, pref ⁇ lled-syringe, or minibag).
  • the one or more of the analgesics that form the selected combination analgesics of the invention may be in separate containers. This may be preferred in some embodiments when there is physical or chemical incompatible with between the selected combination analgesics.
  • the selected combination analgesics are mixed just prior to parenteral administration.
  • the one or more of the analgesics that form the selected combination analgesics of the invention may be in separate containers. To practice the invention, it is not necessary to administer all of the selected combination analgesics at the same time. In some embodiments, the one or more of the analgesics that form the selected combination analgesics may be administered separately (e.g., sequentially, consecutively, contemporaneously or temporally related, e.g., seconds, minutes or hours apart).
  • Kits for use in treating or preventing pain comprising: (i) a dosage form of the invention in an ampoule, vial, prefilled syringe, minibag, autoinjector or sterile container; (ii) a container or packaging for the dosage form; and optionally, any of (iii) to (ix): (iii) syringe; (iv) alcohol swab; (v) sterile absorbent gauze; (vi) sterile occlusive dressing to cover the injection site which is optionally adhesive (e.g., bandage, adhesive bandage, clear bandage, Liquid BandageTM, Band AidTM, ElastoplastTM, TegadermTM, etc); (vii) educational instructions in any media about various medical conditions, their etiology, pathophysiology, consequences and treatment, including information on the proper use and disposal of the medication; (viii) containers or bags for the safe disposal of any used or remaining unused dosage form and needles, preferably child proof,
  • adhesive e
  • compositions of the present invention can be evaluated in one or more of the tests described below:
  • the tail-flick test is considered to be very robust in that weak analgesic agents are not detected by this test. In contrast, it is considered highly selective. There is a high degree of correlation between drugs that are identified as antinociceptive in the tail-flick test and clinically active analgesic agents. It is especially predictive of rank-order of potency of opioid-type analgesic agents, and the clinically effective dose of a novel opioid may be predicted by the relative potency of the drug to a known substance, such as morphine, based on this assay. Importantly, agents that are sedating and may produce a positive response in the writhing test or hot plate test do not show antinociceptive activity in the tail-flick test. It is even possible to perform the tail-flick test in lightly anesthetized animals. [00565] Data obtained from the rat tail-flick test conform to a graded dose-response curve.
  • the raw tail withdrawal latencies are converted to a %MPE (% maximal possible effect) by the formula:
  • % MPE 100 x (test latency - basal latency)/(cut-off - basal latency).
  • This formula constrains the data to fit between 0% MPE and 100 % MPE. This allows the generation of dose-response curves and the calculation of ED 50 values (50% effective doses) with attendant confidence intervals. These calculations then allow for the determination of relative potencies of different drugs and allow for the isobolographic determination of possible synergistic effects. Instances where the test latency is less than the basal latency produces a negative % MPE, which is meaningless unless one is measuring hyperalgesia. By convention, these values are set to 0% MPE when the expected drug effect is antinociception or no activity.
  • the standard protocol for the evaluation of tactile hyperesthesia is to determine the paw withdrawal threshold of the hindpaw of the rats in response to probing with von Frey filaments.
  • Thermal hyperalgesia is indicated by a significant reduction in paw withdrawal latency to noxious radiant heat projected onto the plantar aspect of the hindpaw of the rat.
  • Tests are conducted with systemic (SC) and intrathecal (IT) administration.
  • SC systemic
  • IT intrathecal
  • sham-operated animals are also required. Since sham-operated rats do not develop tactile hyperesthesia, only responses to thermal stimuli are tested. Testing of sham-operated rats requires an additional 48 animals. Approximately 26 rats are be used for initial dose-finding experiments. Animals are tested within 7 to 10 days of SNL. Surgery and testing may be staggered to optimize testing efficiency.
  • the intrathecal drug administration studies require implantation of catheters 7 days prior to the SNL surgery, and testing at 10 days after SNL surgery. Carrageenan-Induced Inflamed Paw Model
  • Models of inflammation that produce more persistent pain include the injection of carrageenan into the footpad of the limb; the potential analgesic and/or anti-inflammatory properties of putative analgesics substances can be evaluated in this model. See generally Bhalla T.N. & Tangri, K.K. "The time course of the carrageenan-induced oedema of the paw of the rat.” J. Pharm. Pharmacol. 22:721 (1970); Randall, L.O. & Selitto, J.J., "A method for measurement of analgesic activity on inflamed tissue," Arch. Int. Pharmacodyn. Ther. 777:409-419 (1957); Hargreaves, K., et al. "A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.” Pain 52:77-88 (1988).
  • rats are handled and acclimatized to the behavioral testing equipment over a minimum of 2 days prior to testing. Behavioral tests are performed on all rats on the day prior to dosing to establish baseline values, and the animals are randomized into treatment groups based on these pre-dose responses.
  • An assessment of the inflammatory agent (carrageenan) is performed prior to the main study, using the chosen behavioral tests. On the day of dosing, an inflammatory response is induced in the left hind paw of each rat by an intraplantar injection (approx. 0.05 mL) of carrageenan (0.6% w/v), under brief anesthesia.
  • the test substance, reference substance, or vehicle is generally administered 30 minutes prior to carrageenan administration for oral dosing.
  • Paw Volume Each animal is gently restrained, their hind limb extended, and the paw placed in the pre-filled chamber of a Digital Plethysmometer. The paw volume is then calculated based on the volume of liquid displaced in the chamber, for both the ipsilateral and contralateral hind paws.
  • Typical end points are a struggle response, paw withdrawal or a squeak response.
  • Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at the various time points: Baseline (0 hour - pain intensity only), 15, 30 and 45 minutes, and at 1, 1.5, 2, 3, 4, 5, 6, 7, 8 and 12 hours after administration of study medication, and immediately prior to the first rescue dose. Time to onset of perceptible and meaningful pain relief is evaluated using the two stopwatch method. Patients record their global evaluation of study medication at the completion of the 8-hour assessment or at the time of first rescue medication use.
  • Efficacy endpoints include Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and Sum of Pain Relief Intensity Difference (SPRID) at various time points, Time to First Rescue, Time Specific Pain Intensity Difference (PID), Time Specific Pain Relief (PR), Peak Pain Intensity Difference (PPID), Peak Pain Relief (PPR), Time to Confirmed Perceptible Pain Relief (stopwatch) and Time to Meaningful Pain Relief (stopwatch) and Patient Global Evaluation.
  • TOTPAR Total Pain Relief
  • SPID Sum of Pain Intensity Difference
  • SPRID Sum of Pain Relief Intensity Difference
  • Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at representative time points, e.g., Baseline (pain intensity only), 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours after administration of study medication and immediately prior to the first remedication. Time to onset of perceptible and meaningful pain relief is evaluated using the double-stopwatch method. Patients complete a global evaluation of study medication at the completion of the 8-hour assessment or just prior to the first remedication. Following completion of the single- dose phase (8 hours or just prior to first remedication, if ⁇ 8 hours), patients begin the multiple dose phase of the study. During the multiple dose phase, patients record their overall pain intensity since the previous scheduled dose, their current pain intensity and a patient global, immediately prior to each scheduled dose of study medication and at early termination.
  • Measures of efficacy in the single-dose phase include Sum of Pain Intensity
  • Measures of efficacy in the multiple-dose phase include the time specific overall pain intensity, current pain intensity and patient global at the time of scheduled remedication, the average of overall pain intensity, current pain intensity and patient global over 0-24, 24-48 and 48-72 and number of doses of rescue analgesic over 0-24, 24-48 and 48-72 and 0-72 hours.
  • composition of the invention may, in some preferred embodiments, be demonstrated in repeated dose randomized, double-blind, controlled studies comparing subanalgesic and analgesic doses of the invention.
  • patients who meet the American College of Rheumatology criteria for knee and/or hip OA are washed off their analgesics for 2 to 7 days to allow for pain of moderate to severe intensity to return.
  • Once a stable baseline pain score is established patients are randomized to treatment, usually for a period of one to 12 weeks.
  • Pain, joint stiffness and physical function can be measured with a multidimensional instrument, such as the WOMAC, quality of life with the SF- 12 or SF-36 and adverse events with a non-directed questionnaire at baseline and at post- baseline return visits. Response to pain, stiffness, physical function, quality of life and adverse events are calculated as change from baseline and compared between treatments. Sample sizes in the studies are sufficient to demonstrate the increased therapeutic benefit of the invention.
  • the increased therapeutic benefits associated with the administration of a composition of the invention may, In some preferred embodiments, be demonstrated in patients with migraine headaches, typically in a prospective, randomized, double-blind, parallel group, single-dose, placebo-controlled, study. Crossover studies are also possible.
  • the study population consists of male and non-pregnant female subjects, 18 to 65 years of age with a primary headache diagnosis of either migraine attack without aura or migraine attack with aura, as diagnosed according to the International Classification of Headache Disorders-2 criteria. To qualify, the subject must typically have a history, on average, of at least one migraine attack per month, but an average of no more than 6 migraine attacks each month during the past year.
  • headache diary subjects are instructed to treat and evaluate the headache pain and symptoms associated with one eligible migraine attack, with or without aura, with at least moderate headache pain intensity.
  • Eligible subjects are randomly assigned to receive the test drug or placebo to treat one migraine attack, with or without aura, with headache pain of at least moderate pain intensity as determined by them migraine questionnaire they are asked to take a single dose of study drug, according to their randomized treatment assignment.
  • Headache pain intensity, nausea, photophobia, phonophobia, vomiting, and ability to function are assessed at baseline, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 16 and 24 hours post-dose.
  • the recurrence of pain and use of any rescue mediation is documented.
  • Primary efficacy variables typically consist of the percent of subjects who are without: (i) pain; (ii) nausea; (iii) photophobia and, (iv) phonophobia, each at 2 hours post-dosing.
  • Secondary efficacy variables typically consist of headache pain intensity and associated symptoms at each evaluation time point, incidence of vomiting, patient function, sum of pain intensity difference at each evaluation time (SPID), percent of subjects who experience headache recurrence up to 24 hours, and the median time to recurrence.
  • Recurrence is defined as the reduction in pain from moderate or severe pain to none at 2 hours after taking study drug, followed by: (i) an increase to mild, moderate or severe pain within 24 hours after taking the study drug, or (ii) consuming a rescue medication within 24 hours after taking the study drug.
  • agent are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial effect. In general, this includes therapeutic agents in all of the major therapeutic areas, also including proteins, peptides, oligonucleotides, and carbohydrates as well as inorganic ions, such as calcium ion, lanthanum ion, potassium ion, magnesium ion, phosphate ion, and chloride ion.
  • “Pharmaceutically or therapeutically acceptable excipient or carrier” refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the hosts, which may be either humans or animals, to which it is administered.
  • Pharmaceutically or therapeutically acceptable excipients or carriers are well known in the art.
  • “Pharmaceutically or therapeutically acceptable excipient or carrier” or “excipient” may include compounds found on the FDA EAFUS database (http://vm.cfsan.fda.gov/ ⁇ dms/eafus.html); FDA Food Additives Status List (http://www.cfsan.fda.gov/ ⁇ dms/opa-appa.html); FDAGRAS list and database; FDA Color Additive Status List (http://www.cfsan.fda.gov/ ⁇ dms/opa-appc.html); FDA Inactive Ingredients Database (http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm); Rowe, Sheskey and Owen, Handbook of Pharmaceutical Excipients, APhA Publications; 5th edition (2006); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker, eds, 1 lth ed., McGraw Hill (2005); Rem
  • complex means any physical combination of two or more discrete chemical compounds.
  • a complex includes, but is not limited to, a salt, a physical mixture, a chelate, and the like.
  • a complex includes a salt; a physical mixture; a solid wherein two or more discrete chemical compounds are associated by hydrogen bonding; a solid wherein two or more discrete chemical compounds are associated by hydrophobic bonding; a solid wherein two or more discrete chemical compounds are associated by ionic bonding; a solid wherein two or more discrete chemical compounds are associated by hydrogen, ionic, and or hydrophobic bonding; a co-crystal containing two or more discrete chemical compounds.
  • the complex can be constructed through several modes of molecular recognition including hydrogen- bonding, pi-stacking, guest-host complexation, and Van-Der-Waals interactions.
  • subanalgesic dose “subanalgesic doses”, “subanalgesic dosage” and
  • SAD refers to a dosage of compounds chosen from the group of compounds defined herein as selected combination analgesics, which when given alone (i.e., individually or in the absence of the combination) do not result in the production of meaningful analgesia when administered to a human or antinociception when administered to non-human subjects requiring alleviation of pain.
  • Dosage ranges and the lower threshold of doses required to produce meaningful analgesia when administered to a human or antinociception when administered to non-human subjects are well known in the art (e.g., in Gilman et al., eds., Goodman And Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill (2001); Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); and Martindale: The Complete Drug Reference, 34th Edition, Pharmaceutical Press (2004); Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No.
  • AHRQ Healthcare Research and Quality
  • subanalgesic dosage includes within its scope dosages falling below such lower thresholds.
  • This term will also cover direct administration of each compound from the list of selected combination analgesics, as well as administration which includes controlled-release, sustained release, modified release or extended release by parenteral routes of administration.
  • administration which includes controlled-release, sustained release, modified release or extended release by parenteral routes of administration.
  • a subanalgesic dosage from the list of selected combination analgesics in accordance with the invention will be dependent upon the mode or route of administration thereof (e.g., intravenous vs. intrathecal).
  • “Therapeutically effective amount” refers to the amount of an active agent or combination sufficient to induce a desired biological result. That result may be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • the term "effective amount” means the quantity of a compound or combination of compounds according to the invention necessary to prevent, to cure, or at least partially arrest a symptom of local pain or discomfort in a subject.
  • a subject is any animal, preferably any mammal, more preferably a human. Amounts effective for creating a substantially local therapeutic effect will, of course, depend on the severity of the disease causing the painful condition, and the weight and general state of the subject. Typically, animal models, such as those described in the Background and Examples herein, may be used to determine suitable dosages to be used.
  • parenteral and “parenteral administration” herein encompasses administration of a composition by means other than through the gastrointestinal tract such as into or through the skin of a subject, and includes intradermal, subcutaneous, intramuscular, intravenous, intramedullary, intra-articular, intrasynovial, intraspinal, epidural, intrathecal and intracardiac administration.
  • parenteral and “parenteral administration” herein also encompasses infiltration or topical application to a surgical site, open wound and local site of pain or inflammation. Any known device or delivery system useful for parenteral injection or infusion of drugs can be used to effect such administration. .
  • particularly preferred parenteral routes of administration include intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration, epidural or intrathecal route.
  • particularly preferred method of administration include PCA and PCEA.
  • subject for purposes of treatment includes any animal subject who has any one of the known forms of pain.
  • the subject is preferably a mammal and more preferably is a human.
  • the subject can of course include other non-human animals, preferably horses, livestock, cattle, domesticated animals, cats, dogs, and the like.
  • the pain is acute pain or acute exacerbation of chronic pain.
  • peripheral neuropathic pain e.g., acute and chronic inflammatory demeyelinating polyradiculopathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome (CRPS) Type I and Type II, entrapment neuropathies (e.g., carpal tunnel syndrome), HIV sensory neuropathy, iatrogenic neuralgias (e.g., postthoracotomy pain, postmastectomy pain), idiopathic sensory neuropathy, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, radiculopathy (e.g., cervical thoracic, lumbosacral), sciatica, acute herpes zoster pain, temporomandibular joint disorder pain and postradiation plexopathy; and (ii) central n
  • neuropathic pain is pain initiated or caused by a primary lesion or dysfunction of the nervous system and includes (i) peripheral neuropathic pain and (ii) central neuropathic pain.
  • chronic pain includes all non-neuropathic pain lasting more than 30 days, including inflammatory pain, non-inflammatory pain, muscle pain, joint pain, fascia pain, visceral pain, bone pain and idiopathic pain.
  • antipyretic As used herein, the term “antipyretic”, “anti-fever” or “fever reducing” refers to pharmaceutical agents that prevent or reduce fever by lowering the body temperature from a raised state.
  • Perceptible Pain Relief is assessed and defined as follows: At the time of dosing with the study medication, a trained member of study staff starts two stopwatches for each patient. The patient is instructed to stop the first stopwatch at the time of perceptible pain relief and the second stopwatch at the time when they first experience meaningful pain relief.
  • the usual definitions of the perceptible and meaningful pain relief are as follows: Perceptible Pain Relief is when the patient begins to feel any pain relieving effect from the drug. The patient is typically instructed as follows: “I would like you to stop the first stopwatch when you first feel any pain relief whatsoever.
  • Meaningful Pain Relief is when the patient feels their pain relief is meaningful to them. The patient is typically instructed as follows: “I would like you to stop the second stopwatch when you have meaningful pain relief. That is, when the relief from the pain is meaningful to you”. Confirmed Perceptible Pain Relief is Perceptible Pain Relief in those patients who go on to also have Meaningful Pain Relief.
  • NNT or “the number needed to treat” is the number of patients who need to be treated in order for one patient to obtain > 50% pain relief or > 50% reduction in pain intensity at a specified timepoint.
  • Responde d/ is the number of patients who have a 30% postbaseline reduction in pain at a specified timepoint.
  • Fever also known as "pyrexia", or a “febrile response” refers to an increase in internal body temperature to levels that are above normal (i.e., above 37 0 C or 98.6°F). Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, usually by about 1-2°C. When a patient has or is suspected of having a fever, that person's body temperature is measured using a thermometer.
  • Fever may be present if: (i) the rectal temperature is at, or higher than 38°C (100.4 0 F); (ii) the oral temperature is at, or higher than 37.5 0 C (99.5°F); or (iii) axillary temperature is at, or higher than 37.2°C (99°F).
  • Fever is usually classified as: (i) low- grade: 38 - 39°C (100.4 - 102.2 0 F); (iii) moderate: 39 - 40 0 C (102.2 - 104 0 F); (iii) high- grade: > 40 0 C (> 104 0 F) or (iv) hyperpyrexia: > 42 0 C (> 107.6 0 F).
  • Hyperpyrexia is a medical emergency because it approaches the upper limit compatible with human life.
  • Fever is a common symptom of many medical conditions, including infectious diseases, immune response, tissue destruction, malignancies, metabolic disorders, thromboembolic processes, drug induced and idiopathic
  • equianalgesic doses also referred to as “analgesic equivalence” is a term used by practitioners of the art to refer to approximately comparable doses of analgesics required to provide a similar magnitude of analgesia.
  • analgesic equivalence is a term used by practitioners of the art to refer to approximately comparable doses of analgesics required to provide a similar magnitude of analgesia.
  • analgesic conversion tables provide what in the art is called “analgesic equivalence” or “equianalgesic doses” (Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, Fourth Edition, 5 th ed, American, Pain Society (2003); Gutstein HB & Akil H. Opioid Analgesics. In: Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 10th Ed., Hardman JG & Limbird LE (Eds), p 569-619, McGraw-Hill, New York, NY); ; Roberts U & Morrow JD. Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the - - -
  • Examples 1 to 11 involve complexes of ketoprofen, dexketoprofen and piroxicam with ethylenediamine and/or piroxicam. These examples demonstrate, among other things, the feasibility of preparing complexes of selected NSAIDS with ethylenediamine and/or piroxicam to enhance solubilization, to facilitate small volume delivery, to facilitate bolus injections of selected NSAIDS (compared to the generally administered slow IV infusions) and to administer the dosage forms rapidly with decreased injection site pain, injection site inflammation, injection site irritation, phlebitis and thrombophlebitis.
  • Example 12 is a randomized double-blind clinical trial of a selected NSAID, ketoprofen in patients following surgery.
  • the ketoprofen was administered as a bolus IV injection at two dose levels, the minimum approved intravenous dose (100 mg) and at 50% of the minimum approved dose (50 mg). Results are presented comparing the efficacy on standardized pain measures to the maximum recommended bolus IV morphine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg) and 150% of the maximum approved IV bolus dose of tramadol (150 mg).
  • Ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) provided almost identical efficacy on all tested parameters, when compared with the minimum approved IV dose (100 mg) of ketoprofen. Both ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) and ketoprofen at the minimum approved IV dose (100 mg) provided far superior - -
  • ketoprofen is 51 mg/1000 mL or 0.051 mg/mL.
  • An aqueous mixture of 0.5 M of ketoprofen and 1.0 M and piperazine was sonicated until a clear solution was obtained.
  • the solution was then filtered with a 0.45 ⁇ m syringe filter (pH about 10.00 for filtered aliquot).
  • Small aliquots (about 0.250 mL) were placed in a 12- depression spot ceramic plate. The physical mixture precipitated out at ambient temperature over several days (2-3 days).
  • ketoprofen-piperazine complex was formed as a semisolid (physical mixture) having an aqueous solubility of greater than 360 mg/mL and a pH of about 9.4 (for a saturated solution).
  • ketoprofen is 51 mg/1000 mL or 0.051 mg/mL.
  • the ketoprofen-ethylenediamine complex was formed as a semisolid having an aqueous solubility of greater than 500 mg/mL and a pH of about 7.3 (for a saturated solution).
  • a 500 mg ketoprofen solution was serially diluted in normal saline (NS) and isotonic Sorensen phosphate buffer pH 7.4 (ISPB) separately. Dilutions were made by adding respective volumes of the solutions to NS or ISPB such that a range of 4-2560 fold dilution was covered. Thus, for the first dilution 1 part of solution was added to 3 parts of NS or ISPB resulting in a 4-fold dilution. Subsequent dilutions were made serially resulting in a final 8-, 16-, 32-, 64-, 128-, 256-, and 2560-fold dilution.
  • NS normal saline
  • ISPB isotonic Sorensen phosphate buffer pH 7.4
  • Ketoprofen-ethylenediamine passed the static dilution test. No precipitation or turbidity was observed visually upon passing laser beam for the entire range of dilution (4-2560 fold) both after 1 minute as well as 24 hours following dilution.
  • a 50 mg ketoprofen solution was serially diluted in normal saline (NS) and isotonic Sorensen phosphate buffer pH 7.45 (ISPB) separately. Dilutions were made by adding respective volumes of the solutions to NS or ISPB such that a range of 2-3200 fold dilution was covered. Thus, for the first dilution 1 part of solution was added to 1 parts of NS or ISPB resulting in a 2-fold dilution. Subsequent dilutions were made serially resulting in a final 4-, 8-, 16-, 32-, 320-, 3200-fold dilution. After every dilution vials were vortexed and allowed to stand for 1 minute. Presence of precipitation in the form of turbidity or cloudiness was tested visually using Laser Diffraction (Tyndall Effect). The pH was measured after every dilution. Vials were rechecked for the presence of precipitation after 24 hours.
  • NS normal saline
  • ISPB is
  • Ketoprofen-piperazine passed the static dilution test, i.e., no precipitation or turbidity was observed visually upon passing laser beam for the entire range of dilution (4-3200 fold) both after 1 minute as well as 24 hours following dilution.
  • ketoprofen formulations Two 50 mg/mL ketoprofen formulations (ketoprofen-ethylenediamine and ketoprofen-piperazine) were tested and compared for the occurrence of precipitation upon dynamic dilution in ISPB using a validated standard dynamic injection apparatus with high predictive value for phlebitis.
  • a validated standard dynamic injection apparatus with high predictive value for phlebitis.
  • Each solution at a flow rate of 5 mL/min was introduced to ISPB flowing at a rate of 5 mL/min in a tube for 30 seconds and passed through a flowcell.
  • Absorbance was measured at 540 nm using a UV spectrophotometer. The wavelength 540 nm was chosen since all the formulations had no or very small absorbance at that wavelength. The results of the tests are shown in the Figures.
  • P 2 is the density of water tj is the time taken by test solution to pass between two marks in the viscometer t 2 is the time taken by water to pass between two marks in the viscometer
  • ketoprofen-ethylenediamine 50 mg/mL and 500 mg/mL, as determined by the Ostwald-Cannon-Fenske viscometer were 1.2 and 26 cP, respectively.
  • C j is the concentration of the ionic species
  • Z j is the charge on the ionic species
  • the ionic strength of ketoprofen-ethylenediamine 50 and 500 mg/mL was 0.295 and 2.95, respectively.
  • the ionic strength of ketoprofen-piperazine 12.7 and 50 mg/mL solutions was
  • Ketoprofen at a flow rate of 5 mL/min was introduced to ISPB flowing at a rate of 5 mL/min in a tube for 30 seconds and passed through a flowcell. Absorbance was measured at 540 run using a UV spectrophotometer. The wavelength 540 nm was chosen since all the formulations had no or very small absorbance at that wavelength. The results were compared with ketoprofen- ethylenediamine and ketoprofen-piperazine (without any pH adjustment or additives). - -
  • ketoprofen as the ethylenediamine salt (0.1 M) at an initial concentration of 50 mg/mL and ketoprofen as the piperazine crystalline salt at an initial concentration of 10 mg/mL were retested after 3 months storage at room temperature using an HPLC analytical method. There was no significant degradation of ketoprofen. The detected concentration of ketoprofen after three months was 49.4 mg/mL (98.8%) and 9.94 mg/mL (99.4%) for ketoprofen-ethylenediamine and ketoprofen-piperazine, respectively, which is within the range of experimental error.
  • Ketoprofen solution at a concentration of 50 mg/mL was prepared in 0.1 N NaOH. The pH was gradually increased over 4 hours in order to avoid the presence of excess sodium hydroxide. The pH was increased using solid sodium hydroxide. The final pH of the solution was 8.72 (constant over 12 hours). The solution was filtered with a 0.45 ⁇ m syringe filter into a sterile evacuated vial.
  • Treatment A Kertoprofen 5 mg/0.1 mL or Treatment B (Ketoprofen 15 mg/0.3 mL) intravenously into a marginal vein of each ear, over one minute (i.e., Ketoprofen 5 mg/0.1 mL over one minute or Ketoprofen 15 mg/0.3 mL over one minute). All animals were treated on Day 1 of the study.
  • the test sites were identified with indelible marker. Intravenous sites were marked with an indelible marker at the area of entry of the needle, approximately at the end of its progress and approximately 1 cm from that point.
  • Treatment A The intravenous administration of Treatment A (Ketoprofen: 5mg/0.1 mL) resulted in well defined erythema and slight edema were observed at the 24 hour observation period.
  • Treatment B The intravenous administration of Treatment B (Ketoprofen: 15mg/0.3 mL) resulted in very slight to moderate to severe erythema and very slight edema at the 24 hour observation period.
  • Treatment B Keratin: 15 mg/0.3 mL
  • the irritation was progressive over time and displayed the potential for a dose related response.
  • NSAIDs versus their respective ethylenediamine and piperazine salts when administered intravenously to rabbits, using a validated model for assessment of venous irritation and thrombophlebitis and a randomized design.
  • Test articles consisted of unsalified ketoprofen, unsalified dexketoprofen, unsalified piroxicam, ketoprofen-ethylenediamine, dexketoprofen-ethylenediamine, piroxicam-ethylenediamine, ketoprofen-piperazine, and dexketoprofen-piperazine. Eight rabbits each were allocated to each group as follows:
  • Piroxicam vs. Piroxicam-Ethylenediamine At the 1-hour post-infusion time point, piroxicam-ethylenediamine was not statistically different from unsalified piroxicam on the erythema (p ⁇ 0.38) and edema (p ⁇ 0.38) scores. At the 24-hour post-infusion time - -
  • piroxicam-ethylenediamine produced significantly lower erythema (p ⁇ 0.0001) and edema (p ⁇ 0.00006) scores than unsalified piroxicam.
  • Ketoprofen vs. Ketoprofen-Ethylenediamine At the 1-hour post-infusion time point, ketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0002) scores than unsalified ketoprofen. Similarly, at the 24-hour post- infusion time point, ketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0008) scores than unsalified ketoprofen.
  • Ketoprofen vs. Ketoprofen-Piperazine At the 1-hour post-infusion time point, ketoprofen-piperazine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0003) scores than unsalified ketoprofen. Similarly, at the 24-hour post-infusion time point, ketoprofen piperazine produced significantly lower erythema (p ⁇ 0.0003) and edema (p ⁇ 0.0001) scores than unsalified ketoprofen.
  • Dexketoprofen vs. Dexketoprofen-Ethylenediamine At the 1-hour post- infusion time point, dexketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0001) and edema (p ⁇ 0.0003) scores than unsalified dexketoprofen. Similarly, at the 24-hour post-infusion time point, dexketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0006) and edema (p ⁇ 0.021) scores than unsalified dexketoprofen.
  • Dexketoprofen vs. Dexketoprofen-Piperazine: At the 1-hour post-infusion time point, dexketoprofen-piperazine produced significantly lower erythema (p ⁇ 0.0019) and edema (p ⁇ 0.0019) scores than unsalified dexketoprofen. Similarly, at the 24-hour post- infusion time point, dexketoprofen-piperazine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0024) scores than unsalified dexketoprofen.
  • Piroxicam vs. Piroxicam-Ethylenediamine Piroxicam-ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified piroxicam, which had an intermediate incidence. Similarly, piroxicam-ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified piroxicam which had an intermediate incidence.
  • Ketoprofen vs. Ketoprofen-Ethylenediamine Ketoprofen-ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified ketoprofen, which had a high incidence. Similarly, ketoprofen ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified ketoprofen which had a high incidence.
  • Ketoprofen vs. Ketoprofen-Piperazine Ketoprofen-piperazine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified ketoprofen, which had a high incidence. Similarly, ketoprofen-piperazine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified ketoprofen which had a high incidence.
  • Dexketoprofen vs. Dexketoprofen-Ethylenediamine Dexketoprofen- ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified dexketoprofen, which had an intermediate incidence. Similarly, dexketoprofen-ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified dexketoprofen which had an intermediate incidence.
  • Dexketoprofen vs. Dexketoprofen-Piperazine Dexketoprofen-piperazine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified. dexketoprofen, which had an intermediate incidence. Similarly, dexketoprofen piperazine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified dexketoprofen which had an intermediate incidence.
  • Study Design The study was a randomized, double blind controlled clinical trial in patients with moderate to severe postsurgical pain after removal of bony impacted third molars.
  • Treatments The study included the following treatments administered by IV bolus injection, ketoprofen 100 mg (the minimum approved dose of IV ketoprofen); ketoprofen 50 mg (50% of the minimum approved dose of IV ketoprofen); tramadol 150 mg (150% of the maximum approved dose of bolus IV tramadol; tramadol 100 mg (the maximum approved dose of bolus IV tramadol); and morphine 4 mg (the maximum recommended bolus dose of IV morphine).
  • ketoprofen 100 mg the minimum approved dose of IV ketoprofen
  • ketoprofen 50 mg 50% of the minimum approved dose of IV ketoprofen
  • tramadol 150 mg 150% of the maximum approved dose of bolus IV tramadol
  • tramadol 100 mg the maximum approved dose of bolus IV tramadol
  • morphine 4 mg the maximum recommended bolus dose of IV morphine
  • Diagnosis and main criteria for inclusion Male and female patients, 18 to 40 years of age (inclusive), and with a body weight of 50 kg to 115 kg (inclusive) who had surgical extraction of 2 or more third molars were eligible provided that one was a bony impacted mandibular third molar, and if only 2 third molars were extracted, they were ipsilateral. Qualified patients had moderate or severe pain within 6 hours of completion of surgery as measured by the categorical PI scale and a VAS measurement for PI of > 50 mm at Baseline. Patients provided written informed consent prior to participation in the study, were in good health as determined by the Investigator, and demonstrated the ability to properly complete the pain assessments, to understand the English language, and to cooperate with study procedures. Female patients of childbearing potential were non- lactating, had a negative urine pregnancy test within 24 hours before surgery, and practiced abstinence or a medically acceptable form of contraception.
  • Safety was assessed by incidence of AEs, changes in clinical laboratory testing, vital signs (heart rate, respiration rate, blood pressure), and physical examinations.
  • ITT insulin receptor RI
  • PI post baseline PI or PR measurement
  • the time to perceptible pain relief was the time recorded by the first stopwatch, and the time to meaningful pain relief was the time recorded by the second stopwatch.
  • Time to confirmed perceptible pain relief was defined as the time to perceptible pain relief only if both perceptible and meaningful pain relief were experienced.
  • Time to perceptible pain relief, confirmed perceptible, meaningful pain relief; time to re- medication; time to first change from the Baseline assessment in PID (categorical) of > 1; and time to pain half gone were estimated using Kaplan-Meier method. Summary information including the median time estimates and 95% confidence intervals on the median time for the above time variables was provided using Kaplan-Meier methodology and the method of Simon and Lee, and treatment groups were compared using the log- rank test. Peak PID, peak PR, and the patient global evaluation were analyzed using the stratified rank-sum test, stratified by baseline pain. The proportions of patients with 50% pain gone, with meaningful pain relief, and re-medicated were analyzed using the Chi- square test.
  • ketoprofen 100 mg (the minimum approved dose of IV ketoprofen); ketoprofen 50 mg (50% of the minimum approved dose of IV ketoprofen); tramadol 150 mg (150% of the maximum approved dose of bolus IV tramadol; tramadol 100 mg (the maximum approved dose of bolus IV tramadol); and morphine 4 mg (the maximum recommended bolus dose of IV morphine).
  • ketoprofen 50 mg The efficacy results were not significantly different for ketoprofen 50 mg versus ketoprofen 100 mg.
  • ketoprofen 50 mg or 100 mg demonstrated efficacy results that were statistically significantly superior to those of a single IV dose of placebo or morphine 4 mg for all efficacy measures, and significantly superior to a single IV dose of tramadol 100 mg or tramadol 150 mg for almost all efficacy measures.
  • ketoprofen 50 mg or 100 mg received a global evaluation of
  • the proportions of patients with at least one adverse event for ketoprofen 50 mg, and ketoprofen 100 mg groups was 60.6%, and 64.5%, respectively.
  • the proportions of patients with at least one adverse event for morphine 4 mg, tramadol 100 mg and tramadol 150 mg was 72.7%, 72.7% and 86.4%, respectively
  • ketoprofen groups were mild or moderate in intensity; only 1/33 patients treated with ketoprofen 50 mg had severe adverse events (dry mouth [dry socket] and postoperative infection), and 2/31 patients treated with ketoprofen 100 mg reported one severe adverse event each (application site swelling and abdominal pain).
  • the majority of adverse events in the tramadol 100 mg group were mild or moderate; whereas, all adverse events in the tramadol 150 mg group were moderate or severe.
  • Five of 33 patients in the 100 mg group and 13/22 patients in the 150 mg group had severe adverse events.
  • Three of 33 patients in the morphine 4 mg group had severe adverse events.
  • Ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) provided almost identical efficacy on all tested parameters, when compared with the minimum approved IV dose (100 mg) of ketoprofen. Both ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) and ketoprofen at the minimum approved IV dose (100 mg) provided far superior efficacy when compared with the maximum recommended bolus IV morphine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg), and 150% of the maximum approved IV bolus dose of tramadol (150 mg), P ⁇ 0.05 to ⁇ 0.001.

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Abstract

The present invention is directed to parenteral pharmaceutical compositions involving combinations of two or more analgesics and the use thereof for treating and preventing pain, inflammation and fever, wherein each component of the combination, selected from a different pharmacologic class, is given parenterally at a subanalgesic dose and wherein the combination provides robust analgesia with improved safely. The present invention is also directed to a method of parenteral administration of pharmaceutical compositions of two or more analgesics to provide effective analgesic, anti-inflammatory and antipyretic effects and the use thereof for treating and preventing pain, inflammation and fever.

Description

SUBANALGESIC DOSES OF DRUG COMBINATIONS
[0001] The application claims the benefit of U.S. Provisional Application No.
60/907,244, filed March 26, 2007, which is herein incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention is directed to parenteral pharmaceutical compositions involving combinations of two or more analgesics and the use thereof for treating and preventing pain, inflammation and fever, wherein each component of the combination, selected from a different pharmacologic class, is given parenterally at a subanalgesic dose and wherein the combination provides robust analgesia with improved safety. The present invention is also directed to a method of parenteral administration of pharmaceutical compositions of two or more analgesics to provide effective analgesic, anti-inflammatory and antipyretic effects and the use thereof for treating and preventing pain, inflammation and fever.
Background Art
[0003] Acute pain is usually a consequence of an identifiable insult, such as surgery or other trauma, or a consequence of a disease, e.g. , kidney stones, mechanical low back pain, etc. According to public health statistics, several hundred million people worldwide undergo inpatient or outpatient surgery each year. In addition, several hundred million visits are made annually to the emergency room. Of these emergency room visits, it is estimated by survey data that more than 20% require analgesic treatment. Recent studies have shown that more than 60% of patients who undergo surgery experience moderate to severe pain despite analgesic treatment.
[0004] Currently, medical practitioners may choose from several well-accepted classes of pharmaceutical agents in their attempts to alleviate pain. Acute pain is managed with a variety of drugs, frequently in combination, including opioid analgesics, e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine; acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs) e.g., ketoprofen, ibuprofen, naproxen, tiaprofenic acid, aceclofenac, diclofenac, piroxicam, loxaprofen, fenoprofen, flurbiprofen, tenoxicam, lornoxicam, acetylsalicylic acid, flufenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, diflunisal, etodolac, fenbufen, isoxicam, pirprofen, sulindac, tolmetin, and piketoprofen and more recently, cyclo-oxygenase isoform 2 (COX-2) selective NSAIDs, e.g., celecoxib, valdecoxib, piketoprofen, etoricoxib, rofecoxib, and lumiracoxib.
[0005] Additionally, a number of other drugs with analgesic properties are being investigated, including neuro-active steroids; beta adrenergic agonists, e.g., albuterol; selective prostanoid receptor antagonists; NMDA antagonists; neuronal nicotinic receptor agonists; calcium channel antagonists; serotonin 5-HT(lB/lD) receptor agonists sodium channel blockers; cannabinoid agonists; superoxide dismutase mimetics; p38 MAP kinase inhibitors; triptans, TRPVl agonists; ketamine; NKl receptor antagonists; gabapentinoids; and glycine receptor antagonists.
[0006] Treatment of acute pain is usually with the oral route of administration. However, parenteral drug formulations have become a very important component in the arsenal of available drug delivery options, particularly for drugs having analgesic, anti- inflammatory or antipyretic effects. Parenteral routes of administration, including subcutaneous, intramuscular, intrathecal, epidural and intravenous injection, offer numerous benefits over oral delivery in particular situations, for a wide variety of drugs. For example, parenteral administration of a drug typically results in attainment of a therapeutically effective blood concentration of the drug in a shorter time than is achievable by oral administration. This is especially true of intravenous injection, whereby the drug is placed directly into the bloodstream. Parenteral administration by the intramuscular or subcutaneous routes can also offer rapid onset of effect in setting where intravenous access is possible or practical, such is in the usual family primary care physician's office or in settings where self-administration (e.g., subcutaneous administration) is possible to treat unexpected pain (e.g., breakthrough pain, migraine, etc). Parenteral administration can also result in more predictable blood serum concentrations of a drug, because drug loss in the gastrointestinal tract due to absorption, distribution, metabolism, binding to food and other causes are eliminated. Parenteral administration is generally the preferred method of drug delivery in emergency situations, and is also useful in treating subjects who are uncooperative, unconscious, or otherwise unable or unwilling to accept oral medication.
[0007] Parenteral drugs are particularly useful for treating a condition such as pain, inflammation or fever when: 1) the condition is of severe intensity; 2) there is a need for rapid onset of effect; 3) there is a need for a robust effect; 4) there is a need for rapid or frequent dose titration to keep condition under control; 5) the patient is unable to receive oral medication e.g., due to nausea, vomiting, confusion, obtundation, loss of consciousness and bowel obstruction.; and/or 6) the patient already has venous access or is in a medical facility (e.g., hospital or clinic).
[0008] Of the many challenges that occur when pharmacologically treating any disease or pathological condition, including pain, fever and inflammation, alleviating the symptoms without causing counterproductive side effects is often the greatest. This challenge presents itself when medical practitioners use medicinal agents to treat pain, fever, and inflammation. Although the aforementioned pharmacological classes are frequently effective for the treatment of certain types of pain, fever, and/or inflammation, use of these analgesic agents produces a number of significant undesirable side effects.
[0009] Morphine is extensively utilized for the management of severe pain due to its global availability, extensive clinical experience, significant pharmacokinetic and pharmacodynamic data, low cost and the availability of various extended release formulations (Babul et. al, J Clin Pharmacol, 1998;38:74-81). However, the incidence and severity of side effects limits the use of morphine in some patients (Hagen and Babul, Cancer 1997;79: 1428-37). In patients with renal impairment, morphine's principal metabolites, morphine-3-glucuronide and morphine-6-glucuronide can accumulate. Morphine-3-glucuronide accumulation has been implicated in hyperalgesia, respiratory stimulation, and behavioral excitatory properties through nonopioid receptor mechanisms. Morphine-6-glucuronide accumulation has been implicated in increasing levels of nausea and sedation in patients with renal impairment (Babul and Darke, Clin Pharm Ther, 1993;54:286-92). Similarly, the principal metabolite of hydromorphone, hydromorphone- 3-glucuronide can accumulate in patients with renal impairment and has been found to be more neurotoxic than morphine-3-glucuronide (Babul and Darke, Pain, 1992;51:260-61; Hagen et al., J Clin Pharmacol, 1995;35:38-45; Babul et al., J Pain Symptom Manage, - -
1995;10:184-86; Wright et al., Life Sci, 1998;63:401-l l; Wright et al., Life Sci, 2001;69:409-20.).
[0010] There are now many compounds with pharmacological properties similar to those produced by morphine. Although there can be striking variability in response to opioids in an individual patient, none of the commercially available opioids have proven to be clinically superior to morphine in relieving pain when used at equianalgesic doses in carefully controlled clinical trials. Non-limiting examples of morphine-like opioids include alfentanil, carfentanil, diamorphine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, lofentanil, meperidine, oxycodone, oxymorphone, racemorphan, remifentanil and sufentanil.
[0011] Unlike doses of non-opioid analgesics, partial opioid agonists and mixed opioid agonist-antagonists, pure or full opioid agonists such as morphine, hydromorphone, oxycodone, fentanyl, carfentanil, lofentanil, alfentanil and sufentanil do not have a "dose ceiling". In other words, their doses can be increased almost indefinitely, being limited only by the occurrence of side effects.
[0012] Among the many side effects of opioids are nausea, vomiting, constipation, sedation, fatigue, pruritus, blurred vision, urinary retention, respiratory depression, convulsions, mood changes and alterations of the endocrine and autonomic nervous systems. Many of these side effects are sufficiently bothersome as to require: i) use of additional medications to treat the iatrogenic symptoms; ii) more intensive patient management; iii) use of lower doses that leave patients in continued pain; or iv) in other cases, complete discontinuation of analgesic therapy. Opioids can also produce potentially fatal respiratory depression at high doses. (Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No. 02-E002, October 2001; Carr et al. J Nat Cancer Inst Monograph 2004;32:23-31; Agency for Health Care Policy and Research Clinical Practice Guidelines for Cancer Pain Management, Guideline No. 9, AHCPR Publication No. 94-0592, March 1994; Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005).
[0013] Fear of opioid side effects and efforts to minimize same often lead to the administration of opioid doses that do not completely relieve pain. In the case of acute postsurgical pain, poorly managed pain has been shown to lengthen hospital stays and increase the number of re-admissions. Severe postsurgical pain can interfere with breathing, digestion, recovery, rehabilitation and discharge. In the case of chronic pain, poorly managed pain adversely affects the patient's quality of life, sleep, psychological state and restoration of physical function.
[0014] In one recent study of postsurgical patients, nausea and vomiting (67%), and rash, hives, or itching (33.5%) were the most common opioid related adverse effects. Patients with opioid related side effects had significantly longer hospital stays (0.53 days) and costs (16% or $840.) than control patients [J Pain Symptom Management, 2003; 25:276- 83]. In another study of postsurgical patients [Journal of Pain, 2006; 7:51], patients with opioid related side effects had significantly increased total hospital costs (mean 9.0% increase) and increased length of hospitalization (mean 12.5% increase).
[0015] In the above studies, patients experiencing opioid-related side effects had significantly increased median total hospital costs (7.4% increase; 95% CI 3.83 to 10.96; p < 0.001) and increased median LOS (10.3% increase; 95% CI 6.5 to 14.2; p < 0.001) compared with matched non-ADE controls. The increased costs attributable to side effects, by surgery type, were general surgery ($676.51; 95% CI 351.50 to 1001.50), orthopedics ($861.50; 95% CI 448.20 to 1274.80), and obstetrics/gynecology ($540.90; 95% CI 281.40 to 800.40). Similarly, increased LOS attributable to side effects, by surgery type, were general surgery (0.64 days; 95% CI 0.40 to 0.88), orthopedics (0.52 days; 95% CI 0.33 to 0.71), and obstetrics/gynecology (0.53 days; 95% CI 0.33 to 0.72). Higher doses of opioids were associated with increased risk of experiencing side effects (OR 1.3; 95% CI 1.07 to 1.60; p = 0.01). Opioid-related side effects following surgery were associated with significantly increased LOS and hospitalization costs. These side effects occurred more frequently in patients receiving higher doses of opioids.
[0016] Undertreatment of pain may also occur when higher doses of opioid analgesics are required to manage the patient's pain due to: 1) prescribing resistance by clinicians and 2) patient and family barriers to dose escalation. Physicians frequently have exaggerated fears about the risk of iatrogenic addiction, respiratory depression and the risk of adverse regulatory sanctions. Similarly, patients and family members have fears about drug addiction and in some cases, equating increased opioid requirement with terminal disease, death and dying. - -
[0017] Opioids exert effects on the neuroendocrine system, including hypothalamic inhibition of the release of gonadotropin releasing hormone and corticotropin-releasing factor, thereby decreasing circulating concentrations of luteinizing hormone, follicle stimulating hormone, adrenocorticotropin and β-endorphin. As a result of the decreased concentrations of pituitary trophic hormones, plasma concentrations of testosterone and Cortisol decline. The administration of opioids increases plasma prolactin concentrations, most likely by reducing the dopaminergic inhibition of prolactin secretion.
[0018] Opioid side effects are managed in a variety of ways, including: i) adjusting the dose; ii) adding a non-analgesic drug to manage side effects (e.g., a laxative or antiemetic); iii) switching to another opioid; and iv) using analgesic doses of a non-opioid analgesic.
[0019] In some patients, no intervention is effective in attaining an optimal balance between analgesia and acceptable side effects. For this reason, there has been an ongoing but so far unsuccessful effort to develop opioid and non-opioid analgesics with a superior side effect profile than currently available opioids.
[0020] An alternative strategy to provide optimal analgesia without intolerable side effects has involved use of lower doses of an opioid analgesic in combination with analgesic doses of one or more non-opioid drugs, thereby reducing the side effects that might otherwise occur from higher opioid doses given alone.
[0021] Reference may be made to U.S. Patent No. 2,770,569 which is directed to a combination of the opioid antagonist levo-3-hydroxy-N-allyl-morphinan with various opioid agonists, including alphaprodine, desomorphine, levorphanol, meperidine and morphine, which is aimed reducing the side effects of opioid agonists.
[0022] Reference also may be made to U.S. Patent No. 4,126,684 which discloses a method of reducing the addiction liability or withdrawal symptoms in patients receiving an opioid or barbiturate by administering 4-amino-3-p-halophenylbutyric acids.
[0023] Reference also may be made to U.S. Patent No. 4,487,252 which discloses a method for providing enhanced analgesic effects by co-administering hydrocodone and ibuprofen.
[0024] Reference may be made to U.S. Patent No. 4,569,937 which is directed to pharmaceutical compositions of ibuprofen and the opioid analgesic oxycodone which exhibit synergism enabling the use of lower doses of either or both drugs with a concomitant reduction in risk of possible side effects.
[0025] Reference also may be made to U.S. Patent No. 4,769,372 which describes a method for treating chronic pain in a patient while preventing or alleviating the development of constipation or other symptoms of intestinal hypomotility wherein the opioid analgesic morphine, meperidine, oxycodone, hydromorphone, codeine and hydrocodone is administered together with an opioid antagonist such as naloxone and nalmefene.
[0026] Reference may also be made to U.S. Patent No. 5,041,446 which discloses a method of inhibiting the development of tolerance to morphine by coadministering it with dapiprazole.
[0027] Reference may also be made to U.S. Patent No. 5,057,519 which discloses a method for delaying the onset of opioid tolerance by coadministration of a benzamide- type 5-HT3 antagonist.
[0028] Reference also may be made to U.S. Patent No. 5,317,022 which describes a composition for the selective blockade of CNS opioid binding sites responsible for respiratory depression while maintaining analgesia, comprising an analgesic effective amount of a codeinone derivative and in a mass ratio of 1:2-3 morphine or a morphine derivative indicated therein.
[0029] Reference may also be made to U.S. Patent No. 5,336,691 which discloses a method of treating pain comprising co-administration of tramadol and acetaminophen, said composition and method providing synergistic effects with less opioid side-effects.
[0030] Reference also may be made to U.S. Patent No. 5,512,578 which is directed to a method for selectively enhancing the analgesic potency (inhibitory effects) of a bimodally acting opioid agonist such as morphine and simultaneously attenuating the development of physical dependence, tolerance and other undesirable side effects caused by chronic administration thereof, comprising co-administration of a bimodally acting opioid agonist and an opioid receptor antagonist which selectively inactivates excitatory opioid receptor-mediated side effects.
[0031] Reference may also be made to U.S. Patent No. 5,919,826 which discloses a method of alleviating pain which comprises administering the opioid agonist tramadol -o-
and a tramadol analgesia-enhancing, but essentially subanalgesic dose of the NMDA antagonist's dextromethorphan or dextrorphan.
[0032] Reference may also be made to U.S. Patent No. 6,007,841 which discloses an analgesic composition comprising a narcotic agonist-antagonist analgesic selected from the group consisting of pentazocine, nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, nalorphine, cyclazocine and an NMDA receptor antagonist.
[0033] Reference also may be made to U.S. Patent Application No. 10/824,357 which describes a method of treating or preventing pain comprising administering a μ, K or δ opioid receptor agonist and a beta adrenergic agonist wherein the beta adrenergic agonist produces an enhanced effect of the μ, K or δ opioid receptor agonist.
[0034] Reference also may be made to U.S. Patent No. 6,310,072 which describes an analgesic composition comprising a subanalgesic dosage of a μ-opioid agonist selected from the group consisting of morphine, fentanyl, sufentanil, alfentanil and hydromorphone, or a pharmaceutically acceptable salt thereof, and a subanalgesic dosage of oxycodone which is a putative K2 opioid agonist, said compositions having a higher analgesic potency and lower propensity for causing side effects.
[0035] Reference may be made to U.S. Patent No. 5,352,680 which is directed to a therapeutic method for treating opioid tolerance comprising administering a δ-opioid receptor antagonist to reduce the tolerance of μ-opioid receptor agonist such as morphine.
[0036] Reference also may be made to U.S. Patent No. 5,319,087 which discloses the blocking of the μ or κ-opioid receptors in the brain using trans-3,4-l-substituted-3- substituted-4-methyl-4-(3-substituted phenyl)-piperidines as opioid antagonists.
[0037] From the foregoing, a number of non-toxic substances have been defined which may ameliorate some of the undesirable side effects resulting from prolonged administration of strong opioids. In addition, combinations of experimental substances have been defined including μ, δ, κ-agonists which result in a synergistic increase in analgesia.
[0038] The Evidence Based Report of the U.S. Agency for Healthcare Research and
Quality (AHRQ) on the Management of Cancer Pain (Report No. 35, AHRQ Publication No. 02-E002, October 2001) supports the three tier approach. "The first tier, for mild to moderate pain, consists of NSAIDs and acetaminophen with or without adjuvant medications. As pain escalates or persists, treatment progresses to the second tier, in which a weak opioid, such as codeine or hydrocodone, is added to the NSAID with or without an adjuvant drug." "If pain still persists, treatment progresses to the third tier: substitution of the "weak" opioid for a "strong" opioid (i.e., one more readily titrated to doses with greater analgesic efficacy). The latter category includes morphine, hydromorphone, methadone, fentanyl, and levorphanol, all full opioid agonists at the morphine or mu receptor." The AHRQ report further notes that "if pain relief is not achieved at the maximum recommended dose of a particular NSAID or opioid, it should be discontinued and another drug from the same class tried before abandoning that class. Case series indicate that on an individual basis, other drugs from the same class may prove more effective or be better tolerated." The Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on Acute Pain Management (Guideline No. 1, AHRQ Publication No. 92-0032, February 1992) supports a generally similar approach to acute pain management.
[0039] The NSAIDs, as a class, are highly effective as analgesics. They are used to treat both acute and chronic pain, usually by the oral route of administration. The main mechanism by which NSAIDs exert an analgesic effect is through the inhibition of the synthesis of certain prostaglandin, or prostanoids. The synthesis of prostanoids utilizes two distinct COX enzymes: COX-I and COX-2. Traditional NSAIDs inhibit both enzymes. NSAIDs may also inhibit other lipogenic enzymes, such as 5-lipooxygenase. Although NSAIDs are not addictive, they are not without significant toxic effects, such as gastrointestinal injury, hepatotoxicity and decrease clotting ability.
[0040] Ketorolac is presently the only NSAID available in parenteral form in the United
States. However, the clinical utility of parenteral ketorolac is limited due to its adverse effect profile and a restriction on duration of use. In a number of countries, including injectable ketorolac has been withdrawn from the market by the local health authorities, due to its high propensity to cause serious and life threatening side effects. Injectable ketorolac must be given every 4 to 6 hours to provide continuous relief of pain. In some countries, other parenteral NSAIDs such as diclofenac and lornoxicam are also available, but in most countries, ketorolac still remains by far the most frequently used injectable NSAID. [0041] Parecoxib, a parenteral COX-2 selective NSAID, has been approved in Europe with restrictions on its use and has been twice denied approval by the United States Food and Drug Administration for the management of acute post-surgical pain. Although parecoxib (the injectable prodrug of the now withdrawn drug, valdecoxib) is an effective analgesic, there remain serious unanswered questions about the safety of short-term use in the postsurgical setting. An important early adverse postsurgical safety signal came from a CABG study included in the original U.S. NDA. In the parecoxib and valdecoxib group, 19.0% had serious adverse events, versus 9.9% in the placebo group. Citing deficiencies in the data, including a numerically higher incidence of myocardial infarctions (1.9% vs. 0.7%) and cerebrovascular events (2.6% vs. 0.7%) and deaths (4 vs. 0), parecoxib received a non-approvable letter from the FDA in 2001. FDA concluded that "the adverse event profile of parecoxib was generally worse than that of placebo in this trial. Although not statistically significantly different, the number of deaths, myocardial infarctions, cerebrovascular accidents, pulmonary embolisms, along with renal and pulmonary complications were also numerically more frequent for parecoxib during this IV dosing period than placebo. In fact, during the entire study period, the incidence of these clinically relevant adverse events associated with parecoxib/valdecoxib was statistically significantly different than placebo. Similarly, during the entire study period, more patients in the parecoxib/valdecoxib versus the placebo group withdrew from the study due to an adverse event." (FDA Medical Officer Review: Parecoxib NDA 21-294). Follow-up studies conducted with parecoxib have raised additional safety issues. In one trial, cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) occurred significantly more frequently in the parecoxib and valdecoxib group than on placebo (2.0 percent vs. 0.5 percent; P=0.03). In another trial, there were significantly more sternal wound infections on parecoxib than placebo (3.2% vs. 0%; P=0.03). (See Nussmeier et al, N. Engl. J. Med. 352:1081-91 (2005); Ott et al., J. Thorac. Cardiovasc. Surg. 125:1481-92 (2003) Babul et al, Anesthesia and Analgesia 2006; 102:644-56; Babul et al, Anesthesiology 2006;104:375). In 2002, the European Medicines Evaluation Agency (EMEA) issued a public statement on parecoxib concerning the risk of serious hypersensitivity and skin reactions, including Stevens- Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and exfoliative dermatitis as well as anaphylaxis and angioedema. The EMEA has since contraindicated the use parecoxib in patients with ischemic heart disease and stroke. Excluding individuals with silent ischemia, this translates to approximately 20 million at risk patients in the United States. For this reason, it has been recommended that non-selective NSAIDs may be a "better choice" than COX-2 selective agents in patients with cardiovascular disease. (See Stiller & Hjemdahl, J. Hypertension 21:1615-18 (2003)).
[0042] In view of the safety limitations of parenteral ketorolac and parenteral parecoxib, there is a need for safer, alternative parenteral NSAIDs.
[0043] When administered by the IV route, many NSAIDs are associated with one or more drawbacks, including poor solubility, pain on injection, venous irritation, thrombophlebitis, intramuscular pain and irritation, and the need to inject in a large volume of physiologic fluid and/or as a slow IV infusion (instead of as a bolus) to minimize local irritation. For example, Kostamovaara et al. (Br. J. Anaesth. 81:369-372 (1998)) found that after hip replacement surgery, 14% of patients receiving diclofenac 75 mg IV over 30 minutes followed by diclofenac 75 mg/15.5 hours and 10% of patients receiving ketoprofen 100 mg bolus over 30 min, followed by ketoprofen 100 mg/15.5 hours developed phlebitis. Campbell and Watters, Br. J. Anaesth. 62:545-547 (1989), evaluated patients after minor orthopedic, plastic, and general surgery who had received diclofenac 1 mg/kg over 10 min as a solution of 25 mg/mL or 5 mg/mL and found a higher incidence of phlebitis (hand, 85% & arm, 58%) in patients receiving 25 mg/mL compared with 5 mg/mL (p = 0.02). The incidence of thrombosis was reduced markedly in patients receiving diclofenac IV using a diluted infusion (38% hand veins; 8% arm veins).
[0044] In a further attempt to prevent thrombosis, Gopinath, Br. J. Anaesth. 67:803
(1991), diluted diclofenac in 100 to 200 mL of physiological fluid and infused it over 15 to 20 minutes using a fresh vein. Only delayed venous thrombosis (>72 hours) was observed, suggesting the value of diluted diclofenac infused over a longer period of time as a method for reducing venous sequelae of FV diclofenac. Morrow et al., Anaesth. 48:585-87 (1993), reported after diclofenac 75 mg or ketorolac 30 mg IM, the incidence of injection site pain was 31% and 3%, respectively. Claeys et al., Acta Anaesth. Scand. 36:270-275 (1992), reported that after major orthopedic surgery, 5% of patients receiving diclofenac 0.35 mg/kg IV, followed by diclofenac 0.90 mcg/min as a continuous IV infusion experienced phlebitis 6 hours after start of treatment. Tarkkila, et al, Can. J. Anesth. 43:216-20 (1996), administered diclofenac 1 mg/kg in 100 πiL saline every 12 hours x 2 doses to patients undergoing maxillofacial surgery and found that 10% of patients developed phlebitis. Pillans and O'Connor, Ann. Pharmacother. 29:264-6 (1995), reported six cases of severe local reactions associated with IM diclofenac. Three patients developed extensive tissue necrosis at the IM injection site. Necrotizing fasciitis in an additional three patients was associated with complications life threatening complications such as adult respiratory distress syndrome, renal failure, shock, and disseminated intravascular coagulation. Two of the six patients died. Rygnestad and Kvam, Acta Anaesthesiol. Scand. 39:1128-30 (1995), described extensive muscle necrosis and a fatal case of streptococcal myositis 48 hours after an IM injection of diclofenac to one patient.
[0045] In some European countries, a formulation of injectable diclofenac is approved as a 75 mg/3 mL solution for IM administration. It contains benzyl alcohol as a solubilizing agent. Benzyl alcohol has been associated with a fatal toxic syndrome in premature infants, and parenteral preparations containing the benzyl alcohol are not recommended in neonates. (See British National Formulary, No. 49, March 2005). The 3 mL volume for IM administration is more that the 2 mL maximum recommended volume and therefore it may be associated with increased frequency and intensity of injection site pain. Some regulatory health authorities have required the following dosing language for IM diclofenac acid (Voltarol Ampoules. U.K. Summary of Product Characteristics, March 2005):
"The following directions for intramuscular injection must be adhered to in order to avoid damage to a nerve or other tissue at the injection site. One ampoule once (or in severe cases twice) daily intramuscularly by deep intragluteal injection into the upper outer quadrant. If two injections daily are required it is advised that the alternative buttock be used for the second injection. Alternatively, one ampoule of 75 mg can be combined with other dosage forms of diclofenac (tablets or suppositories) up to the maximum daily dosage of 15 mg."
[0046] A different 75 mg/3 mL formulation of diclofenac is approved for intravenous use
(the IM formulation is contraindicated for intravenous use) in some countries with the following language (Voltaren Injection Data Sheet, New Zealand, Sept 7, 1999):
"Diclofenac must not be given as an intravenous bolus injection. Diclofenac must be diluted with 100-500 mL of either sodium chloride solution (0.9%) or glucose solution (5%). Both solutions should be buffered with sodium bicarbonate solution (0.5 mL 8.4% or 1 mL 4.2%). Only clear solutions should be used. Two alternative regimens are recommended: For the treatment of moderate to severe post-operative pain, 75 mg should be infused continuously over a period of 30 minutes to 2 hours. If necessary, treatment may be repeated after 4-6 hours, not exceeding 150 mg within any period of 24 hours. For the prevention of post-operative pain, a loading dose of 25 to 50 mg should be infused after surgery over 15 minutes to 1 hour, followed by a continuous infusion of approximately 5 mg per hour up to a maximum daily dosage of 150 mg."
[0047] In other countries, such as South Africa, as is the case with ketoprofen, diclofenac solubilized with benzyl alcohol is strictly prohibited for any IV use. {See ACU- Diclofenac Injection Package Insert, March 23, 1993 & Q-Med Diclofenac Injection Package Insert, April 29, 1996).
[0048] A review of injection related complications over the period 1992 to 2003 in New
Zealand revealed that 22.6% of all accepted claims for injection related complications were due to IM administration of diclofenac, resulting in inflammation, protracted pain, abscesses and nerve injury (Matthews R. Medical Misadventure Unit, January & February, 2003, New Zealand).
[0049] Recently an intravenous formulation of diclofenac 75 mg/2mL containing hydroxypropyl-beta-cylcodextrin (Dyloject™) has been introduced in some European countries. The inclusion of hydroxypropyl-beta-cylcodextrin into an intravenous formulation of diclofenac improves its solubility and reduces IV injection site pain, when compared with the commercially available Voltarol™ formulation infused over a longer period of time. However, this potential safety benefit is not accompanied by a greater magnitude of pain relief and needs to be counterbalanced against the know renal toxicity of hydroxypropyl-beta-cylcodextrin. When Dyloject™ is given by IV bolus and compared with Voltarol™ given by slow IV infusion (a disadvantage for the Voltarol™ treatment in acute pain, where bolus administration is associated with a higher Cmax and faster Tmax), a 75 mg dose provides comparable pain relief. Furthermore, the addition of hydroxypropyl-beta-cylcodextrin to diclofenac does not provide a statistically greater magnitude of analgesia, when compared with a diclofenac formulation devoid of cyclodextrin. (Medicines and Healthcare products Regulatory Agency, UKPAR, Dyloject 75 mg/2 mL Solution for Injection, PL 25053/0001). [0050] Pain as a consequence of administration of a drug intended to ameliorate other pains can lead to patient refusal to accept therapy and require diagnostic workup to rule out infiltration, extravasation and infection at the injection site. It can also lead to further medical complications, increased reliance on opioid analgesics for pain relief, delayed discharge from hospital and increased cost of therapy. Patients report the pain sensation as stinging, burning, soreness, tenderness, aching, throbbing, cramping, gripping and radiating. It may be localized to the injection site or it may radiate to the proximal area, e.g., the arm. It may or may not be accompanied by redness.
[0051] Among the contributing factors to venous irritation and injection site pain are the dose of the NSAID, the intrinsic irritating properties of the drug, the duration and frequency of IV infusion, the pH and osmolality of the infusate, catheter placement techniques, the health of the patient's veins, and the likelihood of precipitation of drug upon contact with blood. This phenomenon is frequently referred to as peripheral vein infusion thrombophlebitis, or phlebitis, and it is one of the most common complications of IV therapy. Phlebitis can result from mechanical irritation, chemical irritation, or as a pharmacological response by the vein wall cells to the drug.
[0052] Phlebitis is an inflammation of the vein in which endothelial cells of the venous wall become irritated and cells roughen, allowing the adherence of platelets. The site is tender to touch and can be very painful. Phlebitis can prolong hospitalization unless it is treated early. The process of phlebitis formation involves increased capillary permeability, resulting in leakage of proteins and fluids into interstitial space. The traumatized tissue continues to be irritated chemically. This in turn provokes an immune reaction, resulting in mobilization of leukocytes release of inflammatory mediators [Phillips, LD, Manual of LV. Therapeutics, 3rd Edition (2001), p. 352-61, FA Davis Co., Philadelphia; Weinstein S.M., Plumer's Principles & Practice of Intravenous Therapy, 7th Edition (2001), p.149-77, Lippincott, Philadelphia; Josephson DL, Intravenous Infusion therapy for Nurses, 2nd Edition (2004), p. 92-119, Thomson Delmar Learning, New York].
[0053] Intravenous administration of NSAIDs in racemic or enantiomeric form, including aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, felbinac, fenbufen, fenoprofen, fiufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen, indobufen, indomethacin, isonixin, isoxicam, ketorolac, ketoprofen, lomoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, mofebutazone, nabumetone, naproxen, nifenazone, nifiumic acid, nimesulide, oxaprozin, piketoprofen, piroxicam, pirprofen, pranoprofen, proquazone, salicylic acid, salsalate, sulindac, suprofen, tenidap, tetridamine, tiaprofenic acid, tenoxicam, tolfenamic acid, tolmetin and zaltoprofen can produce phlebitis. Phlebitis occurs when a vein becomes inflamed by irritation or vesicant solutions or drugs. Although the use of a 0.5 to 1.0 micron inline filter can remove particulate matter not visible to the naked eye, it cannot eliminate the precipitation that occurs when the drug comes in contact with blood. Precipitation is considered to be a major cause of injection site pain, venous irritation and phlebitis.
[0054] In the case of mechanical irritation, precipitated molecules can be irregular or needle shaped and can act like sandpaper, scraping the vein walls as they are carried through the blood stream. Even relatively small quantities of particulate matter in infusate can cause phlebitis. For this reason, many IV fluids are passed through an in-line filter before injection. However, pre-injection filtration is not effective in cases where the offending particulate matter is created by dilution of the formulation in the bloodstream.
[0055] Chemical irritation results from direct contact of irritants with the vein wall cells.
Solvents, acids and bases, and some drugs can damage living tissue. In addition, some dissolved drugs can produce undesirable pharmacological effects by reacting with specific receptors on the vein walls. The undesirable effects caused pharmacologically and chemically are worsened by direct cellular contact with the highly concentrated precipitate. As a result, regardless of the cause, precipitation of the drug within the vein upon dilution significantly exacerbates the irritation and is a key factor in determining the duration and severity of the irritation.
[0056] One approach to reducing mechanical, chemical and idiopathic IV NSAID irritation is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
[0057] One approach to reducing pain, irritation and muscular or subcutaneous toxicity after IM or SC (SQ) administration is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect. - -
[0058] One approach to reducing pain, irritation and muscular or subcutaneous toxicity after IM or SC (SQ) administration is to drastically reduce the volume of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
[0059] One approach to reducing and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic or anti-inflammatory effect.
[0060] In view of the poor solubility (and therefore large required parenteral volume) of
NSAIDS, epidural and intrathecal administration are contraindicated. When the dose of NSAID is drastically reduced, the volume is commensurately reduced, thereby providing the option of epidural and intrathecal NSAID administration.
[0061] One approach to improving the tolerability of NSAIDS after parenteral administration is to drastically reduce the dose of NSAID administered to the patient, thereby reducing the need for irritating and otherwise toxic or disagreeable pharmaceutical excipients such as benzyl alcohol.
[0062] The parenteral route of NSAID administration is usually used in the post-surgical pain, post-traumatic pain or intensive or critical care setting, where the patient is particularly predisposed metabolic stress, gastrointestinal perforation, ulcers and bleeding, and bleeding from the site of surgery or trauma. These adverse effects, along with the aforementioned injection site effects are particularly important with the use of parenteral NSAIDS. Most of the adverse effects of NSAIDS are dose related. Consequently the lowest possible dose of an NSAID associated therapeutic effectiveness is usually suggested.
[0063] Although NSAID side effects can occur in any patients, some patient groups are at particular risk. Patients at particular risk include those who: (i) are elderly; (ii) are cachectic' (iii) are immunocompromised; (iv) have a malignancy; (iv) are receiving corticosteroids; (v) with a history of significant alcohol consumption; (vi) are smokers; (vii) are receiving long-term NSAID therapy; (viii) are receiving high doses of NSAID's; (ix) have prior history of peptic ulcer disease, perforations and GI bleeding; (x) have ischemic heart disease; (xi) are undergoing CABD surgery; (xii) have a history of stroke; (xiii) are anticoagulated; (xiv) have a history of renal impairment and renovascular - -
disease; (xv) have hepatic impairment; and (xvi) have a history of hypertension. Additional information on risk factors for NSAID toxicity may be found in the scientific and medical literature.
[0064] Given the significant therapeutic drawbacks and side effects that accompany the use of NSAIDs for parenteral administration (e.g., intravenous [IM], intramuscular [IM], subcutaneous [SC], intrathecal [IT], epidural], particularly IV administration, there is a need for new therapeutic methods and pharmaceutical compositions that have analgesic, anti-inflammatory and antipyretic activity. More specifically, there is a need for new analgesic, anti-inflammatory and antipyretic methods and pharmaceutical compositions that are: (i) readily soluble; (ii) have a reduced injection volume; (iii) have a rapid onset of effect; (iv) have a robust peak effect; (v) have a long duration of action; (vi) have a reduced incidence and severity of injection site pain, venous irritation and phlebitis; (vii) have a reduced propensity for gastrointestinal side effects, including dyspepsia, ulceration, perforation and bleeding; (viii) have a reduced frequency and severity of bleeding from or near the site of surgery or trauma; (ix) have a reduced frequency and severity of cardiovascular side effects; (x) have a reduced frequency and severity of injection site pain and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration; and (xi) have a reduced frequency and severity of other NSAID side effects.
[0065] An ideal parenteral NSAID formulation should provide robust analgesic, antiinflammatory, and antipyretic effects (rapid onset and high efficacy), as well as good tolerability at and around the injection site. Further, an ideal parenteral NSAID formulation should be safe for administration by the IM, IV, SC, IT and epidural routes. Additionally, an ideal parenteral NSAID formulation should be safe for administration by the IM, IV, SC, IT and epidural routes by avoiding the use of large quantities of potentially toxic solubilizing agents, e.g., benzyl alcohol and by avoiding or minimizing the risk of precipitation following injection.
[0066] It is known in the art that if a drug is not soluble in the desired injection volume, it must be solubilized by the addition of one or more water miscible adjuvants. The most common adjuvants are buffers, surfactants and cosolvents, with due consideration of the role of other factors, including pH, osmolality and stability. Unfortunately, drugs solubilized by these means can still precipitate when diluted or injected into the - -
bloodstream. If a therapeutic agent precipitates in a vein, the potential for venous irritation due to mechanical irritation and prolonged local drug exposure at the vein wall increases greatly. This is an important cause of iatrogenic inflammation of the vein wall, peripheral vein infusion thrombophlebitis (phlebitis), following IV drug administration.
[0067] One approach of the invention to encourage clinicians to liberally utilize parenteral NSAIDs and optimize pain control, especially in the setting of acute pain (e.g., acute postsurgical pain, trauma, renal colic, burn pain, etc) is to reduce the frequency and severity of NSAID associated side effects while providing an effective therapeutic intervention. Unfortunately, the goals of safety and efficacy of NSAIDs are frequently in conflict and clinicians are forced either manage pain, inflammation and fever sub- optimally or provide adequate analgesia while risking patient safety.
[0068] One approach of the invention to reducing the various know toxicities of parenteral NSAID therapy while providing robust analgesic, anti-inflammatory and antipyretic is to utilize subanalgesic doses of parenteral NSAID's in combination with subanalgesic doses of other analgesics, said combinations providing robust analgesia without side effects that plague the use of analgesic doses of such drugs.
[0069] While subanalgesic doses of parenteral NSAIDS can reduce the know toxicities of
NSAIDS and other drugs (e.g., acetaminophen) administered intermittently (e.g., Q4H, Q6H, Q8H, Q12H PRN) through a significant reduction in the single, individual or unit dose of the administered NSAID and the total daily administered dose of the NSAID, each individual dose provides a shorter duration of action. This in turn requires a more frequent dosing and can adversely impacts on: (i) nursing, pharmacy and other institutional resources; (ii) the cost of drug and supplies (syringes, alcohol swabs, sterile solution, infusion devices, etc); (iii) sterility and the risk of infection.
[0070] One approach of the invention to mitigate against the adverse consequences of increased dosing frequency is to administer the subanalgesic doses of parenteral NSAIDS and other drugs (e.g., acetaminophen) using patient controlled analgesia (e.g, patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration). Current standard of care does not recommend administration of NSAIDS and acetaminophen by patient controlled analgesia. Indeed, the standard of care recommends against administration of NSAIDS by patient controlled analgesia and for a majority of NSAIDS of the invention, there are no recommendations or working examples of NSAID administration by patient controlled analgesia. For example, Welchew et. al. note "The slow onset and relatively long duration (several hours) of nonsteroidal anti-inflammatory drugs make their use in patient controlled analgesia inappropriate. However, several of these drugs have been found to reduce the total requirement of opiate in patient controlled analgesia after surgery while conferring improved pain relief (Principles and Practice Series: Patient Controlled Analgesia, BMJ Publishing Group, Page 61, 1995, London, U.K.).
[0071] The present invention stems, in part from the surprising discovery that usual recommended doses of parenteral analgesics, with their associated adverse safety profile are not required to provide effective analgesic, anti-inflammatory and antipyretic effects. Such effects may be achieved with subanalgesic doses, which have a reduced propensity for side effects.
[0072] The present invention stems, in part from the surprising discovery that usual recommended doses of parenteral NSAIDS given by IV infusion (e.g., over 5, 10, 15, 20 or 30 minutes), with their associated adverse safety profile are not required to provide effective analgesic, anti-inflammatory and antipyretic effects. Said effects may be achieved with subanalgesic doses NSAIDS given by IV bolus in combination with other drugs, which have a reduced propensity for side effects.
[0073] Furthermore, in some embodiments, by combining two counterintuitive strategies, namely the administration of subanalgesic doses NSAIDS and other drugs (e.g., acetaminophen) and patient controlled analgesia, and by controlling variables such as the demand dose and lock-out interval, subanalgesic doses of NSAIDS and other drugs (e.g., acetaminophen) can provide robust analgesic, anti-inflammatory and antipyretic effects, with reduced toxicity and without the inconvenience associated with frequent administration.
[0074] In some other embodiments, the subanalgesic doses the combination analgesic is preceded by one or more loading doses of the non-opioid analgesic of the combination by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said non-opioid by said route.
[0075] BRIEF SUMMARY OF THE INVENTION
[0076] In some embodiments, the present invention involves the use of subanalgesic doses (hereinafter, "SAD") of selected combination analgesics to provide effective analgesia.
[0077] In some embodiments, the present invention involves the use of SAD of selected combination analgesics to provide effective anti-inflammatory effects.
[0078] In some embodiments, the present invention involves the use of SAD of selected combination analgesics to provide effective antipyretic effects.
[0079] In some embodiments, the present invention involves the use of SAD of selected combination analgesics to provide effective analgesic, anti-inflammatory and/or antipyretic effects while reducing the frequency and intensity of side effects.
[0080] In some embodiments, the present invention involves the use of SAD of selected combination analgesics given by bolus injection to provide effective analgesic, antiinflammatory and/or antipyretic effects while reducing the frequency and intensity of side effects.
[0081] In some embodiments, the present invention involves the use of SAD of selected combination analgesics given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) to provide effective analgesic, anti-inflammatory and/or antipyretic effects while reducing the frequency and intensity of side effects.
[0082] The present invention involves the use of subanalgesic doses (SAD) of selected combination analgesics to provide effective analgesic, anti-inflammatory and antipyretic effects while reducing the frequency and intensity of selected combination analgesics side effects
[0083] A first aspect of the present invention is directed to a method and pharmaceutical compositions for eliciting a rapid analgesic, anti-inflammatory and antipyretic response after parenteral administration of selected combination analgesics, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0084] A second aspect of the present invention is directed to a method and pharmaceutical compositions for eliciting a robust peak analgesic, anti-inflammatory, and/or antipyretic response after parenteral administration of selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0085] A third aspect of the present invention is directed to a method and pharmaceutical compositions for improving the IV tolerability of a selected combination analgesic, e.g., reduced venous irritation, injection site pain, and phlebitis after IV bolus injection, slow IV injections, short term infusions and continuous infusions, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0086] A fourth aspect of the present invention is directed to a novel method for improving the intramuscular tolerability of a selected combination analgesic, e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage after IM injection, e.g., into the gluteus, deltoid, vastus lateralis, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0087] A fifth aspect of the present invention is directed to a novel method for improving the SC tolerability of a selected combination analgesic, e.g., reduced injection site pain, subcutaneous irritation, inflammation and abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0088] A sixth aspect of the present invention is directed to a method and pharmaceutical compositions for directly administering a selected combination analgesic by the intravenous route without the need for prior dilution and/or administration through automated or gravity feed volume control devices, e.g., volutrol, minibag, large volume parenteral bag, syringe driver, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0089] A seventh aspect of the present invention is directed to a method and pharmaceutical compositions for safely administering a selected combination analgesic into soft tissue at the site of, or in close proximity to the pain and inflammation, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0090] An eighth aspect of the present invention is directed to a method and pharmaceutical compositions for improving the tolerability and safety of intrathecal and epidural administration of a selected combination analgesic, e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas after epidural or intrathecal administration, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0091] A ninth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of injection site pain, venous irritation and phlebitis of a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0092] A tenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of gastrointestinal side effects, including nausea, vomiting, retching, constipation, dyspepsia, ulceration, perforation, bleeding and biliary spasm from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0093] An eleventh aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of bleeding from or near the site of surgery from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0094] A twelfth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of cardiovascular, cerebrovascular and pulmonary side effects, (e.g., myocardial infarctions, hypertension, peripheral edema, cerebrovascular accidents and pulmonary embolism) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics. [0095] A thirteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of postsurgical wound complications (e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0096] A fourteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of postsurgical blood loss from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0097] A fifteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and amount of blood transfusion from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0098] A sixteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of renal and renovascular complications from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[0099] A fifteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of hepatic complications from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00100] A sixteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of surgical complications from orthopedic surgery or bone manipulation (e.g., non-union, malunion, avascular necrosis) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics. - -
[00101] A seventeenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of other NSAID side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00102] An eighteenth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of drug-drug interactions, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00103] A nineteenth aspect of the present invention is directed to pharmaceutical compositions comprising SAD of selected combination analgesics.
[00104] A twentieth aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of CNS side effects (e.g., sedation, fatigue, convulsions, obtundation, coma, mood changes, physical dependence, addiction, hyperalgesia and respiratory depression) from a selected combination analgesic, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00105] A twenty-first aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of other opioid side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00106] A twenty-first aspect of the present invention is directed to a method and pharmaceutical compositions reducing the frequency and severity of other acetaminophen and acetaminophen analog side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00107] A twenty-second aspect of the present invention is directed to a method and pharmaceutical compositions for reducing the volume for parenteral administration (e.g., less than 1 mL, or less than 2 mL, or less than 5 mL, or less than 10 mL), said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics. - -
[00108] A twenty-third aspect of the present invention is directed to a method and pharmaceutical compositions for allowing safe bolus parenteral administration, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00109] A twenty-third aspect of the present invention is directed to a method and pharmaceutical compositions for allowing longer duration of therapeutic effect, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00110] A twenty-fourth aspect of the present invention is directed to a method and pharmaceutical compositions for allowing longer duration of therapeutic effect, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00111] A twenty-fifth aspect of the present invention is directed to a method and pharmaceutical compositions for allowing safe parenteral over a few minutes (e.g., less than 1 minute, or less than 2 minutes, or less than 5 minutes), said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00112] A twenty-sixth aspect of the present invention is directed to a method and pharmaceutical compositions for providing comparable analgesia with reduced side effects, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00113] A twenty-seventh aspect of the present invention is directed to a method and pharmaceutical compositions for providing early patient ambulation and physiotherapy, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00114] A twenty-eighth aspect of the present invention is directed to a method and pharmaceutical compositions for providing reduce the risk of deep vein thrombosis and pulmonary embolism, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00115] A twenty-ninth aspect of the present invention is directed to a method and pharmaceutical compositions for providing faster restoration of normal bowel function - -
after anesthesia, particularly prolonged general anesthesia, after major surgery and after gastrointestinal and abdominal manipulation (e.g., shorter time to normal bowel sounds, shorter time to flatus, shorter time to fluid intake), said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00116] A thirtieth aspect of the present invention is directed to a method and pharmaceutical compositions for reducing the duration of hospitalization or medical facility stay, said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00117] A thirty-first aspect of the present invention is directed to a method and pharmaceutical compositions for reduced motor, psychomotor and cognitive impairment during the period of analgesic, anti-inflammatory and antipyretic administration (e.g., improved performance scores on driving simulation, reaction time, trail making, finger tapping, digit substitution and other tests known in the art), said method and pharmaceutical compositions comprising administering a therapeutically effective amount of SAD of selected combination analgesics.
[00118] A thirty second aspect of the present invention is directed to a method and pharmaceutical compositions for reducing pain, irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics, said combination analgesics administered in reduced injection volume of selected combination analgesics
[00119] A thirty third aspect of the present invention is directed to a method and pharmaceutical compositions for reducing pain, irritation, nerve damage, sterile abscess, and muscular or subcutaneous toxicity after IM or SC (SQ) administration, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics, said combination analgesics administered in reduced injection volume.
[00120] A thirty fourth aspect of the present invention is directed to a method and pharmaceutical compositions for improving the safety and tolerability of selected combination analgesics after parenteral administration, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics, said combination analgesics administered with a reduced need for irritating and otherwise toxic or disagreeable pharmaceutical excipients and solubilizing agents.
[00121] A thirty fifth aspect of the present invention is directed to a method and pharmaceutical compositions for improving the efficiency of pain management after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration)..
[00122] A thirty sixth aspect of the present invention is directed to a method and pharmaceutical compositions for reducing pharmacy, nursing and/or institutional resources for pain management after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration)..
[00123] A thirty seventh aspect of the present invention is directed to a method and pharmaceutical compositions for reducing drug and ancillary supply costs (e.g., sterile infusion containers, sterile swabs, syringes, etc) associated with parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
[00124] A thirty eighth aspect of the present invention is directed to a method and pharmaceutical compositions for reducing the risk of infection after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), preferably with a closed loop system. - -
[00125] A thirty ninth aspect of the present invention is directed to a method and pharmaceutical compositions for providing effective pain relief after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said SAD of selected combination analgesics having an improved safety profile compared with usual doses of selected combination analgesics.
[00126] A fortieth aspect of the present invention is directed to a method and pharmaceutical compositions for providing pain relief with reduced side effects after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics given by bolus injection.
[00127] A forty first eighth aspect of the present invention is directed to a method and pharmaceutical compositions for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral administration of selected combination analgesics, said method comprising administering one or more loading dose(s) of at least the non-opioid from the selected combination analgesics, followed by a therapeutically effective amount of SAD of selected combination analgesics given by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said non-opioid by the specified route of administration.
[00128] A forty second aspect of the present invention is directed to a method and pharmaceutical compositions for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics complexed to or in conjunction with ethylenediamine and/or piperazine.
[00129] A forty third aspect of the present invention is directed to a method and pharmaceutical compositions for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral administration of selected combination analgesics, said method comprising administering a therapeutically effective amount of SAD of selected combination analgesics in conjunction with glycine.
BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES
[00130] FIG. 1 illustrates a simulated plasma NSAID concentration after administration of drug as a rapid IV injection (IV bolus or IV push), as a slow IV infusion over 30 to 120 minutes, and after IM administration.
[00131] FIG. 2 illustrates the dynamic in vitro apparatus used for predicting mechanical phlebitis. A Harvard Apparatus Precision Syringe Pump 22 was used to direct ISPB (which is used as a blood surrogate in this experiment), at pH 7.4 and 25 C, through a 40- cm length of flexible Tygon® plastic tubing (type R-3603, inner diameter of 3mm), then through a Hellma QS quartz flow-through cell with a 1-cm path length at a 5 mL/min flow rate. This flow rate is comparable to that of human blood flow in readily accessible arm veins. ISPB at pH 7.4 was chosen over plasma because it has a buffer capacity of 0.03. A Beckman DU 640 ultraviolet spectrophotometer holding the flow-cell was used to read occlusion of light. The 22-gauge Becton Dickinson Precision Glide sterile stainless steel needle of a 20-mL latex-free Becton Dickinson plastic syringe containing each formulation to be tested was introduced into the flexible tubing at 10 cm upstream from the flow cell. If a formulation precipitates upon injection, it produces opacity in the tubing, which passes through the flow cell and is interpreted by the spectrophotometer as reduced transmittance or increased absorbance.
[00132] FIG. 3 illustrates a UV wavelength-scan for ketoprofen-ethylenediamine (50 mg/mL) demonstrating absence of absorbance at 540 nm.
[00133] FIG. 4 illustrates dynamic dilution test profile for ketoprofen-ethylenediamine (50 mg/mL) formulation at 540 nm.
[00134] FIG. 5 illustrates a UV wavelength-scan for ketoprofen-piperazine (50 mg/mL) demonstrating absence of absorbance at 540 nm.
[00135] FIG. 6 illustrates dynamic dilution test profile for ketoprofen-piperazine (50 mg/mL) formulation at 540 nm.
[00136] FIG. 7 illustrates a UV wavelength-scan for ketoprofen-piperazine (50 mg/mL) demonstrating absence of absorbance in a 1:1 ratio at 540 nm. [00137] FIG. 8 illustrates dynamic dilution test profile for ketoprofen-piperazine (50 mg/mL) formulation in a 1 :1 ratio at 540 nm
[00138] FIG 9 illustrates a UV wavelength-scan for phenytoin sodium (50 mg/mL), a drug with high phlebitis potential, demonstrating absence of absorbance at 540 nm.
[00139] FIG 10 illustrates dynamic dilution test profile for phenytoin sodium (50 mg/mL).
The Y axis is 10 times higher for phenytoin sodium compared to all other formulations.
[00140] FIG. 11 illustrates dynamic dilution test profile for unsalifϊed ketoprofen suspension (50 mg/mL) adjusted to pH 6.50 and filtered through a 0.45 micron filter before injection at 540 nm, showing approximately 80 and 440-fold greater propensity for precipitation relative to ketoprofen ethylenediamine and ketoprofen piperazine without pH adjustment, respectively.
[00141] FIG 12 shows pain relief over time on a five point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (□); 50% of the minimum approved dose of ketoprofen, 50 mg (♦); 150% of the maximum approved dose of tramadol, 150 mg (Δ); maximum approved dose of tramadol, 100 mg (• star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
[00142] FIG 13 shows total pain relief or TOTPAR over 0-2, 0-4, 0-6 and 0-8 hours derived from a five point categorical pain relief scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg (♦); 150% of the maximum approved dose of tramadol, 150 mg (Δ); maximum approved dose of tramadol, 100 mg (♦ star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
[00143] FIG 14 shows pain intensity difference or change in pain intensity from baseline over time on a four point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg (♦); 150% of the maximum approved dose of tramadol, 150 mg (Δ); maximum approved dose of tramadol, 100 mg (• star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
[00144] FIG 15 shows the sum of pain intensity difference (SPID) over time derived using a four point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg (♦); 150% of the maximum approved dose of tramadol, 150 mg (Δ); maximum approved dose of tramadol, 100 mg (* star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
[00145] FIG 16 shows pain intensity difference or change in pain intensity from baseline over time on 0-100 mm visual analog scale (VAS) in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg (♦); 150% of the maximum approved dose of tramadol, 150 mg (Δ); maximum approved dose of tramadol, 100 mg (* star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
[00146] FIG 17 shows the sum of pain intensity difference derived using a 0-100 mm visual analog scale (VAS) in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg (♦); 150% of the maximum approved dose of tramadol, 150 mg (Δ); maximum approved dose of tramadol, 100 mg (• star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
[00147] FIG 18 shows the sum of pain intensity and pain relief (SPRID) derived using the four point categorical pain intensity and the five point categorical pain relief scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg (♦); 150% of the maximum approved dose of tramadol, 150 mg (Δ); maximum approved dose of tramadol, 100 mg (* star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
[00148] FIG 19 shows the patient's global evaluation of treatment in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg; 50% of the minimum approved dose of ketoprofen, 50 mg; 150% of the maximum approved dose of tramadol, 150 mg; maximum approved dose of tramadol, 100 mg); and maximum recommended bolus dose of morphine, 4 mg; represented as percent of patients and collected using the following descriptors, from left to right: Poor, Fair, Good, Very Good and Excellent. Patients with Good, Very Good and Excellent are considered to have a positive or favorable treatment outcome. DETAILED DESCRIPTION OF THE INVENTION
[00149] The present invention provides a method of treating or preventing pain, inflammation or fever comprising administering to a subject in need of such treatment or prevention subanalgesic doses (SAD) of selected combination analgesics, in racemic, enantiomeric excess or enantiomeric form.
[00150] The phrase "one or more selected analgesic", "selected analgesic", "selected combination analgesic and "selected combination analgesics" as used herein, refers to administering a pharmaceutical composition comprising at least one compound each selected from at least two of the three groups below (a, b, c): a. one or more compounds selected from the class of drugs known in the art as NSAIDS (cyclooxygenases (COX-2 and/or COX-I inhibitors) including aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, celecoxib, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, flufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen, indobufen, indomethacin, isonixin, isoxicam, ketorolac, ketoprofen, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, mofebutazone, nabumetone, naproxen, nifenazone, niflumic acid, nimesulide, oxaprozin, parecoxib, piketoprofen, piroxicam, pirprofen, pranoprofen, proquazone, rofecoxib, salicylic acid, salsalate, sulindac, suprofen, tenidap, tetridamine, tiaprofenic acid, tenoxicam, tolfenamic acid, tolmetin, valdecoxib, zaltoprofen and nitric-oxide donating NSAIDs in racemic, enatiomeric or enantiomeric excess, pharmaceutically acceptable salts thereof of mixture thereof; and
b. one or more compounds selected from the class of drugs known in the art as opioid receptor agonists (i.e., mu (μ), delta (δ), kappa (K) and /or nociceptin/orphanin FQ (N/OFQ) opioid receptors), their subtypes and splice variants, including alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, brifentanil, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, - -
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmoφhine, metopon, mirfentanil, morphine, morphine-6- glucuronide (M6G), myrophine, nalbuphine, narceine, nicomorphine, norlevoφhanol, normethadone, naloφhine, nociceptin/oφhanin FQ (N/OFQ), normoφhine, noφipanone, ohmefentanyl, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, pholcodine, piminodine, piritramide, propheptazine, promedol, profadol, properidine, propiram, propoxyphene, racemoφhan, remifentanil, sufentanil, tapentadol, tramadol, trefentanil, tilidine, nalbuphine, or an opioid agonist having the same pentacyclic nucleus as nalmefene, naltrexone, buprenoφhine, levoφhanol, meptazinol, pentazocine, dezocine, any opioid having agonist activity at an opioid receptor belonging to the phenanthrene, moφhinan, benzomoφhan, methadone, phenylpiperidine, propionanilide 4-anilidopiperidine, 4- aryl piperidines, and 4-Heteroarylpiperidines class, any opioid having agonist activity at an opioid receptor having the same pentacyclic nucleus as nalmefene, naltrexone, buprenoφhine, levoφhanol, meptazinol, pentazocine and dezocine, and nitric-oxide donating opioids in racemic, enatiomeric or enantiomeric excess, pharmaceutically acceptable salts thereof of mixture thereof; and
c. one or more compounds selected from the class of drugs known in the art as acetaminophen analogs, including acetaminophen, propacetamol, prodrugs of acetaminophen, nitroparacetamol and nitric-oxide donating acetaminophen analogs in racemic, enatiomeric or enantiomeric excess, pharmaceutically acceptable salts thereof of mixture thereof.
In a preferred embodiment, the phrase "one or more selected analgesic", "selected analgesic", "selected combination analgesic and "selected combination analgesics" as - -
used herein, refers to administering a pharmaceutical composition comprising at least one compound each selected from at least two of the three groups below (a, b, c): a. one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and
b. one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and
c. one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof.
As used herein, the phrase "SAD" refers to "subanalgesic dose", "subanalgesic doses" and "subanalgesic dosage", wherein the subanalgesic compound is chosen from the group of compounds defined herein as selected combination analgesics. Subanalgesic doses are doses of selected combination analgesics given by a specified route of administration which are lower than the minimum approved or recommended unit dose, individual dose, and/or daily dose of the selected combination analgesics, where said "approved" or "recommended" is approval or recommendation with respect to a parenteral selected combination analgesics dose by a supranational, national, federal, regional, state, provincial, governmental and/or territorial health authority or drug regulatory authority, a major pharmacopeia (e.g., US Pharmacopeia, British Pharmacopeia, European Pharmacopeia, Japanese Pharmacopeia and the like), Physician's Desk Reference (PDR), Thomson Publications; Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker, eds, 11th ed., McGraw Hill (2005); or Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); or Martindale: The Complete Drug Reference, 35th Edition, Pharmaceutical Press (2007). For the purposes of the invention, in the absence of the forgoing approval or recommendation, "approved" or "recommended" refers to a recommended or suggested parenteral dose of selected combination analgesics by a specified route of administration in a peer review journal cited in MEDLINE™ or EMBASE™, or in its absence, the approved or recommended oral doses of the selected combination analgesics. The minimum approved or recommended dose is the approved or recommended dose, as defined, as of the priority date of this patent application.
[00153] In some embodiments the SAD of a specified combination analgesic refers to not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration.
[00154] In some embodiments the SAD of a specified combination analgesic refers to a dose of said analgesic given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration.
[00155] In some embodiments the SAD of a specified combination analgesic refers to a dose of said analgesic given by bolus injection, said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration.
[00156] In some embodiments the SAD of a specified combination analgesic refers to a dose of said analgesic given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or - -
recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration, wherein said SAD of the non-opioid is preceded by one or more loading dose of said non-opioid by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said analgesic by said route.
[00157] In some embodiments the SAD of a specified combination analgesic refers to a dose of said analgesic which is not more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same analgesic given by the same route of administration, wherein said SAD of non-opioid analgesic is preceded by one or more loading dose of said non-opioid by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said non-opioid by the specified route of administration.
[00158] As used herein, "usual dose" refers to and is used interchangeably with the
"minimum" approved or recommended dose of said combination analgesic given by the same route of administration.
[00159] Nonsteroidal anti-inflammatory drugs typically have analgesic, anti-inflammatory, and antipyretic properties. Their mode of action appears to involve inhibition of cyclooxygenases (COX-I and COX-2), leukotriene biosynthesis, and antibradykinin activity. NSAIDs may be non-selective (inhibit COX-I and COX-2 isozymes) or COX-2 selective (preferentially inhibit the COX-2 isozymes). NSAIDs can produce a wide variety of adverse effects. For each selected combination analgesic, standard of care, randomized clinical trials, evidence based medicine, anecdotal evidence, medical practice, tradition guide the selection of the range of doses utilized for the analgesic, anti- inflammatory and antipyretic effects in order to provide analgesia with the fewest possible side effects. Most NSAID analgesic use is by the oral route and for a majority of NSAIDs there are no data on efficacy or safety on their use by the parenteral route of administration. Although the exact mechanisms of adverse effects have not been clearly established, at least some appear related to COX-I inhibition, while at least some of the cardiovascular complications appear to be related to COX-2 inhibition. In addition to their gastrointestinal adverse effects, NSAIDs produce dose related inhibition of platelet aggregation, prolongation of bleeding time, renal impairment, and hepatotoxicity. Parenteral administration can produce injection site burning and pain.
[00160] Ketoprofen ((±)-2-(3-benzoylphenyl)propionic acid) or (Λ,5>2-(3-benzoylphenyl) propionic acid), is a NSAID with analgesic, anti-inflammatory and antipyretic properties. These properties of ketoprofen have been demonstrated in classical animal models and in vitro test systems. Its mode of action appears to be similar to that of other NSAIDs and includes inhibition of prostaglandin (COX-I and COX-2 inhibition) and leukotriene biosynthesis, antibradykinin activity, and lysosome membrane-stabilizing activity. Chemically, ketoprofen belongs to the group of substituted 2-phenylpropionic acids.
[00161] Ketoprofen as a racemate, or as the analgesically active enantiomer (+)-(5)-2-
(3-benzoylphenyl)propionic acid (dexketoprofen), is marketed in a number of countries in a variety of forms, including oral solids, suppositories, and a topical gel. Ketoprofen is soluble in benzene, ethanol, chloroform, acetone, ether, and alkaline solutions, but it is practically insoluble in water.
[00162] The analgesic effects of IM and IV ketoprofen have been evaluated in over 40 clinical trials in children and adults. Published studies with IV ketoprofen have involved single or multiple doses of 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 400 mg and 600 mg. Published studies where IV ketoprofen has been dosed on a mg/kg basis have included doses of 1 mg/kg, 1.35 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 2 mg/kg and 2.5 mg/kg. In a number of European countries, including France, Ketoprofen is marketed as an IM 100 mg/2 mL formulation (Profenid®, France, Aventis, Oruvail®, Hawgreen, UK) and as a lyophilized powder for intravenous use. The maximum daily dose by this route is 300 mg. In the U.K., only the IM formulation (containing benzyl alcohol) is available. This formulation is approved for deep intramuscular injection into the gluteal muscle, 50- 100 mg every 4 hours (max. 200 mg in 24 hours) for up to 3 days.
[00163] In a number of countries, an intramuscular (IM) form of ketoprofen is also available for deep intramuscular injection into the gluteus muscle. In countries where the IM solution containing arginine, benzyl alcohol, citric acid, and water for injection is commercially available, its use by the IV route is prohibited due to toxicity of the formulation. IM administration does not provide a very rapid onset of effect, and it is painful, especially with repeated administration or with a large injection volume. Most clinicians and hospitals discourage the repeated IM administration of drugs and the use of - -
IM injection volumes greater than 1 mL. IM injection volumes greater than 2 mL are generally strongly discouraged or prohibited from routine use. Furthermore, IM administration is not appropriate in many patients due to an absence of adequate muscle mass and the possibility of bleeding and hematoma formation, especially if anticoagulated with drugs like heparin or warfarin. IM administration of the acid formulation of NSAIDs has also been associated with sever nerve damage, muscle tissue necrosis, and even death.
[00164] A separate IV formulation of racemic ketoprofen is available in a few countries as a lyophilized powder containing sodium hydroxide, glycine, and citric acid. It is recommended by the manufacturer that IV ketoprofen be diluted in 100 to 150 mL of 5% dextrose in water or 0.9% saline and administered over approximately 20 minutes. There are numerous disadvantages of this method of administration to a patient with severe acute pain. It requires considerable nursing and pharmacy time and additional material, e.g., IV catheter, infusion set, IV sterile solution, swabs, infusion device, and a delay in administering the drug to a patient in severe pain. Furthermore, compared with rapid IV injection, e.g., IV bolus or IV push, an infusion of ketoprofen over 20 minutes means that the onset of analgesia is delayed and the peak pain relief is lower, owing to lower maximal blood concentrations.
[00165] Furthermore, IV infusion of ketoprofen can cause significant side effects, including venous irritation. (See, e.g., Castagnera, L., et al., Sem Hop Paris 64(32):2179- 2182 (1988); Semaine des hospitaux (Paris) 32:2179-88 (1988)).
[00166] The use of ketoprofen by the intravenous route has been limited by the poor solubility of the drug, the need to administer it in a large volume of solution (100 to 150 mL), the need to infuse the dose over 15 to 20 minutes and the need to use solubilizers that can be toxic and that can result in drug precipitation upon injection. PCT Patent application number PCT/US2006/016078 discloses novel formulations of ketoprofen, dexketoprofen, piroxicam and tenoxicam, with ethylenediamine and/or piperazine.
[00167] Piroxicam is an N-heterocyclic carboxamide of 1,2 benzothiazine 1,1 dioxide with analgesic and anti-inflammatory activity. It has an extended half-life of about 40 hours and is suitable for once daily administration. It is primarily biotransformed in the liver to inactive metabolites; less than 10% of a dose appears unchanged in the urine. Evidence from clinical trials indicates that piroxicam 20 mg per day is comparable to daily doses of aspirin 3 to 6 g, indomethacin 75 to 150 mg, naproxen 500 mg, ibuprofen 1200 to 2400 mg, diclofenac 75 mg and fenbufen 600 mg. Gastrointestinal adverse events are the most frequently reported side effects and their frequency and severity appears to be dose- related. Piroxicam has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, acute gouty arthritis, ankylosing spondylitis, acute musculoskeletal disorders, dysmenorrhea, renal colic and acute postsurgical pain. The usual adult dose of oral piroxicam is 20 to 40 mg given once a day.
[00168] Tenoxicam, an NSAID with an oxicam structure (4-Hydroxy-2-methyl-N-2- pyridinyl-2H-thieno(2,3-e)-l,2-thiazine-3-carboxamide 1,1 -dioxide), is entirely ionized at physiological pH, has minimal lipophilic properties, high plasma protein binding, does not accumulate in fatty tissue and skin and thus has a small volume of distribution. It is completely absorbed via the oral route and is about 99% protein bound in human plasma. Food consumption delays its rate of absorption without affecting its bioavailability. An elimination half-life of 50 to 80 hours has been estimated. Tenoxicam demonstrates linear pharmacokinetics over the 10 to 100 mg dose range. As a consequence of its low lipophilicity and high percent ionization, tenoxicam is poorly distributed into body tissues. Tenoxicam is primarily biotransformed in the liver. Its two major metabolites, the 5'-hydroxy and 6-O-glucuronidated products are inactive and are excreted in urine and bile, respectively. Tenoxicam demonstrates linear pharmacokinetics during multiple- dosing. As a result of its long half-life, tenoxicam can be administered once daily. Clinical trials in patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout suggest that tenoxicam 20 mg daily is an effective anti-inflammatory and analgesic agent. Gastrointestinal symptoms are the most frequently reported side effects. Compared with many other NSAIDs, tenoxicam offers certain advantages in that it is conveniently administered once daily and dosage adjustment is not required in the elderly or in patients with renal or hepatic.
[00169] Ketorolac ((±)-5-Benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid) is a chiral NSAID which is marketed for analgesia as the racemate. It is administered as the water soluble tromethamine salt and is available in tablets or as an intramuscular and intravenous injection. The absorption of ketorolac is rapid, with peak plasma concentrations occurring between 20 to 60 minutes post-dose. The oral bioavailability of ketorolac is estimated to range from 80 to 100%. The drug is extensively bound to plasma - -
proteins and has a volume of distribution comparable to other NSAIDs. The elimination half-life is between 4 and 6h. Ketorolac is extensively metabolized through glucuronidation and oxidation and very little is excreted unchanged. Most of the dose of ketorolac is recovered in the urine as conjugate. Ketorolac is the only nonsteroidal anti- inflammatory drug (NSAID) in widespread clinical use that is available in an injectable form. Ketorolac is presently the only NSAID available in parenteral form in the United States.
[00170] The analgesic efficacy of parenteral ketorolac has been extensively evaluated in the postsurgical pain setting, in both inpatients and outpatients. Following major abdominal, orthopedic or gynecological surgery or ambulatory surgical procedures, ketorolac provides efficacy comparable to that standard doses of opioid analgesics. In the ER, parenteral ketorolac has demonstrated efficacy in patients with renal colic, migraine headache and musculoskeletal pain. However, the utility of ketorolac in acute pain is somewhat limited due to a prolonged time to onset of analgesia. Additionally, the clinical utility of parenteral ketorolac is limited due to its adverse effect profile and a restriction on duration of use. In a number of countries, including France, Germany, The Netherlands, Portugal, and Greece, injectable ketorolac has been withdrawn from the market by the local health authorities, due to its high propensity to cause serious and life threatening side effects.
[00171] Diclofenac (2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid) is an effective analgesic, antipyretic, and anti-inflammatory. It is rapidly absorbed after oral administration, undergoes extensive protein binding and has a short half-life. It undergoes significant first-pass metabolism, with approximately 50% of the dose biotransformed upon first pass through the liver. Diclofenac is metabolized in the liver by CYP2C to 4-hydroxydiclofenac, its primary metabolite, and to other hydroxylated forms. Following glucuronidation and sulfation the metabolites are excreted in the urine and bile. Diclofenac is approved in the United States for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Diclofenac has also been extensively studied in the short-term treatment of acute musculoskeletal pain, postsurgical pain and dysmenorrhea. The major adverse events with diclofenac are gastrointestinal (approximately 20%). Elevations in hepatic transaminases occur in a significant number of patients. In some patients, transaminase levels may increase more than 3-fold. Other - -
side effects of diclofenac include rashes, allergic reactions, fluid retention and edema. Among available NSAIDs, diclofenac appears to have the greatest risk of adverse cardiovascular outcomes.
[00172] Ibuprofen (α-Methyl-4-(isobutyl)phenylacetic acid), the most commonly used
NSAID in the United States, was the first member of the propionic acid class of NSAIDs to become commercially available. Naproxen, flurbiprofen, fenoprofen, ketoprofen, and oxaprozin are other drugs in the propionic acid class of NSAIDs that have been widely commercialized. Naproxen has a longer half-life than ibuprofen. Oxaprozin also has a long half-life and may be given once daily. Propionic acid derivatives are approved for use in the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain (e.g., postsurgical pain, musculoskeletal pain, primary dysmenorrhea). The pharmacodynamics of the propionic acid derivatives do not differ greatly. Ibuprofen has a half-life of approximately 2 hours. It is rapidly absorbed and undergoes significant hepatic biotransformation, followed by renal excretion of metabolites. Gastrointestinal adverse events are common with ibuprofen. Other side effects include rashes, headache, dizziness, fluid retention, and edema. Ibuprofen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain.
[00173] Naproxen ((1S)-(+)-2-(6-Methoxy-2-naphthyl)propionic acid) is almost completely absorbed upon oral administration. Food delays the rate of absorption. Peak naproxen concentrations in plasma occur within 2 to 4 hours. Naproxen is about 99% protein bound. The half-life of naproxen in plasma is about 14 hours in the young, with a 2-fold increase observed in elderly patients. Approximately one-third of the dose of naproxen undergoes 6-demethylation. This metabolite, along with naproxen is excreted as conjugated products. Gastrointestinal side effects are common. Other side effects include drowsiness, headache, dizziness and fatigue. Naproxen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain.
[00174] Flurbiprofen (2-Fluoro-α-methyl-4-biphenylacetic acid ) is a chiral NSAID of the
2-arylpropionic acid class. Although it possesses a chiral centre, with the S-(+)- enantiomer possessing most of the beneficial therapeutic activity, both enantiomers appear to possess therapeutic effects all flurbiprofen preparations are marketed as - -
racemates. Flurbiprofen is rapidly and almost completely absorbed when given orally. The area under the plasma concentration-time curve of flurbiprofen is proportional to the dose administered to patients. Flurbiprofen binds extensively to plasma albumin and substantial concentrations of the drug are attained in synovial fluid. It is eliminated following extensive glucuronidation. Metabolites are primarily excreted in urine and approximately 20% of flurbiprofen is eliminated unchanged. Flurbiprofen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain. Side effects include hypertension, congestive heart failure, gastrointestinal ulceration, bleeding and perforation, renal and hepatic impairment.
[00175] Lornoxicam (6-Choloro-4-Hydroxy-2-methyl-N-2-pyridinyl-2H-thieno(2,3-e)- l,2-thiazine-3-carboxamide 1,1 -dioxide or chlorotenoxicam) is a nonsteroidal antiinflammatory drug of the oxicam class. Unlike other oxicams, lornoxicam has a relatively short plasma half-life (of approximately 3 to 5 hours. Lornoxicam is eliminated through hepatic metabolism to 5'-hydroxylornoxicam. Lornoxicam's metabolites are excreted in urine and feces. Lornoxicam and its major metabolites bind extensively to plasma proteins. Lornoxicam has been shown to be effective in the treatment of acute and chronic pain, including postsurgical pain and osteoarthritis. Lornoxicam's side effects are consistent with its NSAJD pharmacology.
[00176] NSAID associated toxicity, including intravenous tolerability (e.g., venous irritation, injection site pain and reduced phlebitis), intramuscular tolerability, (e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage), subcutaneous tolerability (e.g., injection site pain, subcutaneous irritation and abscesses), intrathecal and epidural tolerability (e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas), cardiovascular side effects (e.g., hypertension, peripheral edema, fluid retention, congestive heart failure and myocardial infarction), renal and hepatic complications, complications from orthopedic surgery or bone manipulation (e.g., nonunion, malunion, avascular necrosis), gastrointestinal side effects (e.g., including dyspepsia, ulceration, perforation and bleeding), postsurgical wound complications (e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling) and postsurgical blood loss can be measured using known methods. - -
[00177] There are no available data on the efficacy of parenteral celecoxib. Oral celecoxib, was the first specific inhibitor of COX-2 approved to treat patients with rheumatoid and osteoarthritis. It was subsequently approved for the treatment of acute pain and dysmenorrhea. The selective inhibition of COX-2 is thought to lead to a reduction in the unwanted effects of NSAIDs. Upper gastrointestinal complication rates in clinical trials are significantly lower for celecoxib than for traditional nonselective NSAIDs (e.g. naproxen, ibuprofen and diclofenac), although COX-2 selective NSAIDS have a higher incidence of cardiovascular complications. The rate of absorption of celecoxib is moderate when given orally, with a Cmax of approximately 2 to 4 hours. Celecoxib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455 ± 166 L. The extent of absorption of celecoxib increases in proportion to increasing oral doses between 100 and 800 mg. It is eliminated following biotransformation to carboxylic acid and glucuronic acid metabolites that are excreted in urine and feces. Celecoxib has an elimination half-life of approximately 11 hours in healthy individuals. In randomized clinical trials, celecoxib is superior to placebo and similar in efficacy as conventional NSAIDS for osteoarthritis and rheumatoid arthritis. In patients with osteoarthritis of the knee and/or hip, celecoxib 100 and 200 mg and naproxen 500 mg twice daily provide similarly efficacy. In patients with stable rheumatoid arthritis, celecoxib 200 mg twice daily shows efficacy comparable to twice daily slow-release diclofenac 75 mg over a 24-week period.
[00178] Parecoxib, a prodrug of valdecoxib is the only parenterally administered cyclooxygenase-2-selective inhibitor available. The recommended dose is 40 mg administered IV or IM, followed every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. Clinical trials of parecoxib demonstrate comparable efficacy with ketorolac in a variety of postsurgical pain states. However, parecoxib has significant adverse cardiovascular risk (Babul et al, Anesthesia and Analgesia 2006;102:644-56; Babul et al., Anesthesiology 2006; 104:375).
[00179] Lumiracoxib is a selective COX-2 inhibitor with an oral bioavailability of 74%. It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. It has a short elimination half-life from plasma of approximately 4 hours and demonstrates dose-proportional plasma pharmacokinetics. Lumiracoxib is extensively metabolized prior to excretion, with only a small amount - -
excreted unchanged in urine or feces. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen. In randomized clinical trials, lumiracoxib 100 to 200 mg per day has been shown to be superior to placebo in patients with osteoarthritis, with clinical efficacy comparable to diclofenac 150 mg/day, celecoxib 200 mg/day and rofecoxib 25 mg/day. In acute pain due to dysmenorrhea or surgery, lumiracoxib 400 mg/day is as effective as standard doses of NSAIDs and other coxibs. Liver function test abnormalities were more frequent with lumiracoxib than with the comparator NSAIDS. There are no data on the efficacy of parenterally administered lumiracoxib. Lumiracoxib has been withdrawn from the market in a number of countries due to serious hepatic adverse effects.
[00180] There are no data on the efficacy of parenterally administered etoricoxib
Etoricoxib is a selective inhibitor of COX-2. Extensive clinical trials have confirmed its analgesic and anti-inflammatory efficacy to be comparable to nonselective NSAIDS. Like other COX-2 selective NSAIDS, etoricoxib displays improved gastrointestinal safety compared with nonselective NSAIDS. It is rapidly and completely absorbed following oral administration providing a rapid onset of action. Its long plasma half-life allows for once-daily dosing. Etoricoxib is currently approved in a number of countries for various indications including the treatment of acute pain, acute gouty arthritis, chronic back pain, dysmenorrhea, osteoarthritis and rheumatoid arthritis. The usual recommended dose of etoricoxib is 30 mg once daily (maximum daily dose, 60 mg) for OA, 90 mg once daily for RA (maximum daily dose, 90 mg) and 120 mg once daily for acute gouty arthritis (maximum daily dose, 120 mg for up to 8 days).
[00181] Of all the available NSAIDs, less than a handful have been administered parenterally, and even fewer have been administered intravenously. Of the commercially available NSAID that have been given intravenously, only one (ketorolac) has been approved for bolus administration and administration in a volume of less than 5 mL. The remainder of drugs need to diluted in a considerable volume of infusate and this diluted volume is usually given over 10 to 20 minutes.
[00182] Given the dose related side effects of NSAIDs, there is a need for optimized strategies to provide robust analgesic, anti-inflammatory and antipyretic effects, without the frequency and severity of side effects seen at usual doses of NSAIDs. NSAID associated side effects are well documented in the scientific and medical literature. For - -
parenterally administered NSAIDs, such strategies can reduce NSAID side effects including: (i) intravenous injection site pain, venous irritation and phlebitis; (ii) the propensity for gastrointestinal side effects, including dyspepsia, ulceration, perforation and bleeding; (iii) bleeding from or near the site of surgery; (iv) bleeding from nonsurgical sites; (v) cardiovascular, cerebrovascular and pulmonary side effects, including myocardial infarctions, hypertension, peripheral edema, cerebrovascular accidents and pulmonary; (vi) the injection site pain and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration; (vii) intramuscular injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage; (viii) bleeding and bleeding risk in anticoagulated patients; (ix) renal and renovascular impairment; (x) hepatic impairment; and (xi) subcutaneous injection site pain, subcutaneous irritation, inflammation and abscesses.
[00183] Acetaminophen is administered intravenously as a prodrug (propacetamol) and more recently as the unsalified product. Propacetamol and acetaminophen can produce venous irritation and have only modest analgesia, comparable to approximately 30 to 50% that provided by analgesic doses of NSAIDs even when the dose of intravenous acetaminophen is doubled to 2 g, its efficacy is significantly inferior to analgesic doses of NSAIDs. Additionally, 1 gram intravenous acetaminophen in postsurgical pain demonstrates a duration of action of less than three hours. Since the maximum permissible daily dose of acetaminophen is 4 grams per day, 24-hour analgesic coverage is not achievable with intravenous acetaminophen. In addition to its suboptimal efficacy, acetaminophen does not possess an anti-inflammatory effects which have now been deemed. Acetaminophen is devoid of meaningful anti-inflammatory effects which are now believed to be important for the optimal control of post-surgical pain. There are also safety significant concerns about the use of acetaminophen in the setting of both acute and chronic pain, including untoward renal and hepatic effects. Intravenous acetaminophen and propacetamol require dilution in a large volume of infusate and is then given over 10 to 20 minutes. There is therefore a need for alternative strategies that optimize the analgesic and antipyretic effects of acetaminophen and that also provide anti-inflammatory effects.
[00184] Levorphanol (7-3-Hydroxy-N-methylmorphinan) tartrate dihydrate is a potent narcotic analgesic with a molecular formula of Ci7H23NO . C4H6O6 . 2H2O and molecular weight 443.5. Each mg of levorphanol tartrate dihydrate is equivalent to 0.58 mg levorphanol base. Following IV administration, levorphanol undergoes rapid (<1 hr) distribution and redistribution and has a steady-state volume of distribution of from 10-13 L/kg. The clearance of levorphanol is very high. In one study, the clearance of levorphanol was reported as 0.75-1.0 L/kg/hr. Levorphanol clearance has been reported to be approximately one half of the hepatic blood flow. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins.
[00185] Levorphanol is well absorbed after PO administration with peak blood levels occurring 1 hour after dosing. The extent of first-pass metabolism of levorphanol is not well defined, but is likely to lie within the range of 30-70% based on a comparison of blood levels after oral and parenteral administration. The relative bioavailability of levorphanol tablets compared to IM or IV administration is not known. The parenteral to oral potency of levorphanol is 2:1. The half-life of levorphanol has been evaluated in two subjects after oral administration and found to be 16 hours and 30 hours. This is significantly longer than the half-life of other opioids such as morphine, hydromorphone and oxycodone.
[00186] The usual recommended starting dose for oral immediate release levorphanol tartrate is 2 mg. The approved prescribing information for Levorphanol, indicates that immediate release levorphanol should be dosed "3-6 hours as needed". The effective daily dosage range, depending on the severity of the pain, is 8-16 mg in 24 hours in the non-tolerant (opioid naive) patient. Total daily doses of more than 16 mg are generally not recommended as starting doses in opioid-naive patients. In a recently completed clinical trial in neuropathic pain, the mean daily dose of PRN levorphanol was 8.9 mg (approx. 90% CL: 3-15 mg). However in patients with severe pain or advanced disease, particularly those with pharmacologic tolerance to the analgesic effects of opioids, much higher doses may be used. There is no dose ceiling for levorphanol, the dose being chosen based on pain relief and tolerability of side effects. Some patients may require less than 10 mg per day for optimal analgesia, while others may require hundreds of milligrams per day and even several grams per day.
[00187] Levorphanol is an alternative to morphine and other strong opioid agonists in patients with moderate to severe acute and chronic pain. At equipotent or equianalgesic doses, levorphanol is believed to produce analgesia comparable to morphine, oxycodone, - -
hydromorphone, fentanyl and other strong opioids (Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005; Clinical Practice Guidelines for Cancer Pain Management, Agency for Health Care Policy and Research Guideline No. 9, AHCPR Publication No. 94-0592, March 1994).
[00188] Levorphanol has demonstrated efficacy and safety in acute and chronic pain and in neuropathic pain.
[00189] Oxycodone (4, 5-epoxy-14-hydroxy- 3-methoxy-17-methylmorphinan-6-one) is a semisynthetic opioid analgesic that has been in clinical use since 1917. When given orally, oxycodone has a higher oral bioavailability (approximately 60% to 85%) and is approximately twice as potent than morphine. Like all full (or pure) opioid agonists, there is no ceiling effect to analgesia, such as is seen with partial agonists or non-opioid analgesics. Oxycodone is extensively metabolized to noroxycodone, oxymorphone, and their respective glucuronides. The major circulating metabolite is noroxycodone which is reportedly a considerably weaker analgesic than oxycodone. Oxymorphone concentrations following oral oxycodone administration are low and are unlikely to contribute significantly to oxycodone analgesia. Biotransformation of oxycodone to oxymorphone, but not noroxycodone, is mediated by CYP2D6 and as such its formation can be affected by inhibitors of CYP2D6. The analgesic activity of oxycodone is primarily due to the parent drug oxycodone.
[00190] The efficacy of oxycodone is comparable to that of morphine and hydromorphone in patients with cancer pain (Hagen and Babul, Cancer 1997;79: 1428-37; Bruera et al., Journal of Clinical Oncology 1998; 16:3222-3229). Oxycodone has demonstrated efficacy in acute postsurgical pain, osteoarthritis, low back pain, cancer pain and neuropathic pain (Watson and Babul, Neurology 1998;50:1837-41; Hagen and Babul, Cancer 1997; Matsumoto, Babul and Ahdieh, Pain Medicine 2005;6:357-66; Sunshine et al., J Clin Pharmacol. 1996;36:595-603; Sloan and Babul, Expert Opinion on Drug Delivery 2006;3:489-97; Caldwell et al., Journal of Rheumatology 1999;26:862-9; Hale et al., Clinical Journal of Pain 1999;15:179-83).
[00191] Methadone (6-dimethylamino-4,4-diphenylheptan-3-one) is a synthetic opioid that has been available for approximately 50 years. Methadone a schedule II under the United States Controlled Substances Act. It was initially used solely for detoxification treatment and maintenance treatment ("methadone maintenance") within licensed opioid addiction - -
programs. This restriction was lifted in 1976 and methadone is now prescribed by physicians in the USA for the treatment of pain. It is widely used by the oral route for the treatment of cancer pain, chronic non-cancer pain and neuropathic pain. In addition to its effects at the mu opioid receptor, methadone is also an agonist at the delta opioid receptor and an NMDA antagonist.
[00192] The pharmacokinetics of methadone differ from morphine in that methadone has a higher bioavailability, a much longer half-life, and is hepatically metabolized by cytochrome P450 enzymes. The pharmacokinetics of methadone are quite variable. An understanding of the factors that impact the onset, magnitude, and duration of analgesia is paramount to optimize treatment outcomes. Caution is advised when switching to methadone, from other opioids, due to a variable equianalgesic dose ratio and the potential for late-onset toxicity due to its accumulation kinetics. Methadone is approved for oral and intramuscular use, although it is also used rectally, intravenously, subcutaneously, epidurally, and intrathecally. Oral methadone has a bioavailability of approximately 80 percent compared with approximately 30 to 35% for morphine. Methadone is metabolized in the liver and unlike morphine, it has no known active metabolites. The elimination half-life of methadone is highly variable (mean half-life approximately 22 hours). Unlike morphine, it usually is not necessary to adjust the dosage of methadone in patients with renal insufficiency. The duration of analgesia is approximately 4 to 6 hours, although upon repeated dosing, methadone has been administered every 8 to 12 hours in some instances. Due to its long half-life, it may take up to 7 to 10 days to reach steady state plasma concentrations. Methadone continues to be used for detoxification treatment and opioid maintenance treatment and increasingly for the treatment of cancer pain, chronic non-cancer pain and neuropathic pain.
[00193] Tramadol hydrochloride [(±)αs-2-[(dimethylamino)methyl]-l-(3-methoxyphenyl) cyclohexanol hydrochloride] is a widely available synthetic, centrally acting aminocyclohexanol opioid analgesic which was first marketed in Germany in 1977 and approved for sale in the United States in 1995. In the United States, tramadol is presently available as an oral immediate release single-entity tablet from a number of manufacturers "for the management of moderate to moderately severe pain" and as a fixed-dose combination with acetaminophen. Oral tramadol is also available in the United States as a once-a-day extended release formulation for the "management of - -
moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time". Tramadol exerts its analgesic effects through a binding of parent and Ml metabolite to μ-opioid receptors and inhibition of re-uptake of norepinephrine and serotonin.
[00194] Hydromorphone [4,5α-epoxy-3-hydroxy-17 methylmorphinan-6-one] is a semisynthetic congener of morphine differing structurally from morphine by the substitution of an oxygen for the 6-hydroxyl group and the hydrogenation of the 7-8 double bond. It was introduced into clinical medicine in 1926. Hydromorphone is metabolized primarily to hydromorphone-3-glucuronide (H3G) in a reaction catalyzed by UDP-glucuronyl transferase and to a much lesser extent to dihydromorphine and dihydroisomorphine via NADPH dihydromorphinone ketone reductase. H3G accumulates significantly in patients with renal impairment. The efficacy of hydromorphone has been established in postsurgical pain, post-traumatic pain, cancer pain and chronic non-cancer pain when administered intravenously, epidurally, intramuscularly, subcutaneously and orally. Hydromorphone is approximately five times as potent as morphine on a milligram per milligram basis and has efficacy comparable to morphine and oxycodone Hagen and Babul, Cancer 1997;79: 1428-37; Babul and Darke, Journal of Pain and Symptom Management 1995;10:184-86; Babul and Darke, Pain 1992;51:260-61; Hays et al., Cancer 1994;74:1808-16; Hagen et al., Journal of Clinical Pharmacology 1995;35:38- 45).
[00195] The efficacy and safety of tramadol has been established following oral, rectal, intravenously and intramuscularly administration to adults or children in randomized, placebo and positive controlled clinical trials. Tramadol has been evaluated in acute pain following single-dose and short-term, repeated-dose administration to patients following third molar extraction, post-orthopedic surgery pain and post-Cesarean section pain. The clinical efficacy of tramadol has been established in numerous studies in chronic pain states, including cancer pain, neuropathic pain, fibromyalgia, low back pain and osteoarthritis (Lee et al., 1993; U.S., Ultram Package Insert, 2003; Rodrigues & Rodrigues, 1989; Grond et al., 1992; Osipova et al., 1991; Wilder-Smith et al., 1994; Roth, 1998; Harati et al., 1998; Biasi et al., 1998; Raber et al., 1999b; Schnitzer et al., 1999; Harati et al., 2000; Schnitzer et al., 2000; Sindrup et al., 1999; Mullican and Lacy, 2001; Wilder-Smith et al, 2001; Adler et al., 2002; Peloso et al., 2002; Silverfield et al., 2002; Babul et al., 2004; Boureau et al., 2003). In these studies, tramadol has been found to be superior to placebo and comparable to established positive controls.
[00196] Oxymorphone is (4, 5α -epoxy-3, 14-dihydroxy-17-methylmorphinan-6-one or
14-hydroxydihydromorphinone), is a semisynthetic opioid agonist derived from thebaine whose principal therapeutic action is analgesia. It is structurally related to morphine, differing in a ketone group substitution at the C-6 position of morphine and saturation of the 7-8 double-bond. The ketone group substitution makes the molecule more lipid soluble, conferring greater potency and more rapid onset of action than the hydroxylated parent compound morphine. Oxymorphone was first approved by for use by the US FDA in 1959. In addition to analgesia, other pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. The absolute oral bioavailability of oxymorphone is approximately 10%. Oxymorphone is not extensively bound to human plasma proteins; binding is in the range of 10% to 12%. Oxymorphone is highly metabolized principally in the liver and undergoes reduction or conjugation with glucuronic acid to form both active and inactive metabolites. The major metabolite of oxymorphone is oxymorphone-3-glucuronide. The mean plasma AUC for oxymorphone-3-glucuronide is approximately 90-fold higher than the parent compound. 6-OH-oxymorphone has been shown in animal studies. Less than <1% of the administered dose is excreted unchanged in the urine. Approximately 30 to 40% of the administered dose is excreted in the urine as oxymorphone-3-glucuronide and 0.25% to 0.62% excreted as 6-OH-oxymorphone in subjects with normal renal and hepatic function. The bioavailability of oxymorphone is increased in patients with renal and hepatic impairment.
[00197] The efficacy of oxymorphone as an oral extended release formulation has been demonstrated in patients with acute postsurgical pain, cancer pain and osteoarthritis (Matsumoto, Babul and Ahdieh, Pain Medicine 2005;6:357-66; Ahdieh, Ma, Babul et al., , Journal of Clinical Pharmacology, 2004; 44:767-776; Sloan et al., Supportive Care in Cancer 2005; 13:57-65). [00198] Morphine-6-glucuronide (M6G) is the principal active metabolite of morphine.
Unlike morphine, M6G is not metabolized; rather is excreted through the kidneys. M6G exhibits a delay in its analgesic effect (blood-effect site equilibration half-life 4-8 h), which is in part related to slow transfer of drug across the blood-brain barrier and subsequent distribution within the brain. In humans, M6G's potency is just approximately one-half that of morphine. In clinical trials, M6G is well tolerated and produces adequate and long lasting postsurgical pain relief. According to Kilpatrick and Smith (Med Res Rev 2005;25:521-44), "The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the μ-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the μ-opioid receptor, (3) M6G has a lower affinity for the κ-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine." Another major challenge with the use of M6G is the delay in onset of effect with initial dose and each subsequent intermittent dose. This problem is eliminated by use of the present invention.
[00199] Racemorphan {d,l 3-hydroxy-N-methylmorphinan) is a potent opioid analgesic with a molecular formula of Ci7H23NO, developed approximately 60 years ago. It is an alternative to morphine, hydromorphone, oxycodone, oxymorphone and other strong opioid agonists in patients with moderate to severe acute and chronic pain. At equipotent or equianalgesic doses, racemorphan produces analgesia comparable to morphine, oxycodone, hydromorphone, fentanyl and other strong opioids.
[00200] Given the dose related side effects of opioids, there is a need for optimized strategies to provide robust analgesic and additionally, anti-inflammatory and antipyretic effects, without the frequency and severity of side effects seen at usual doses of opioids. Opioid associated side effects are well documented in the scientific and medical literature. For parenterally administered opioids, such strategies can reduce opioid side effects including nausea, vomiting, constipation, sedation, fatigue, pruritus, rash, hives, blurred vision, urinary retention, respiratory depression, convulsions, obtundation, coma, mood changes, alterations of the endocrine and autonomic nervous systems, physical -5 -
dependence and addiction, and hyperalgesia. Reducing such opioid related side effects, as with he present invention can improve both the inconvenience and health risk posed to patients and improve patient outcomes such as early ambulation and physiotherapy, reduced risk of deep vein thrombosis and pulmonary embolism, shorter time to oral fluid and food intake, reduced duration of hospitalization. ] Given the significant therapeutic drawbacks and side effects that accompany the use of selected combination analgesics for parenteral administration (e.g., intravenous [IM], intramuscular [IM], subcutaneous [SC], intrathecal [IT], epidural]), particularly IV administration, there is a need for new therapeutic methods and pharmaceutical compositions that have analgesic, anti-inflammatory and antipyretic activity. More specifically, there is a need for new analgesic, anti-inflammatory and antipyretic methods and pharmaceutical compositions administered as selected combination analgesics that: (i) have reduced intravenous injection site pain, venous irritation and phlebitis; (ii) have reduced epidural and intrathecal injection site pain, irritation, hematoma, abscess, inflammatory lesions and granulomas; (iii) have reduced intramuscular injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage; (iv) have reduced subcutaneous injection site pain, subcutaneous irritation, inflammation and abscesses; (v) have reduced bleeding and bleeding risk in anticoagulated patients; (vi) have reduced bleeding from or near the site of surgery; (vii) have reduced bleeding from non-surgical sites; (viii) have reduced renal, renovascular and hepatic impairment; (ix) have a reduced gastrointestinal side effects, including nausea, vomiting, retching, constipation, dyspepsia, ulceration, perforation, bleeding and biliary spasm; (x) have reduced cardiovascular, cerebrovascular and pulmonary side effects, including myocardial infarctions, hypertension, peripheral edema, cerebrovascular accidents and pulmonary embolism; (xi) have reduced CNS side effects, including sedation, fatigue, convulsions, obtundation, coma, mood changes, physical dependence, addiction, hyperalgesia and respiratory depression; (xii) have reduced pruritus, rash, hives, blurred vision, urinary retention, , (xiii) have reduced opioid side effects; (xiv) have reduced NSAID side effects; (xv) have reduced side effects from acetaminophen, propacetamol, nitroparacetamol and acetaminophen analog administration; (xvi) require a reduced volume for parenteral administration; (xvii) can be give by IV bolus injection; (xviii) can be given over less than five minutes; (xix) can be given in less than 5 mL of injection volume; (xx) are readily soluble in less than 5 raL; (xxi) have a rapid onset of effect; (xxii) have a robust peak effect; (xxiii) have a long duration of action; (xxiv) provide comparable analgesia with reduced side effects; (xxv) allow early patient ambulation and physiotherapy; (xxvi) reduce the risk of deep vein thrombosis and pulmonary embolism; (xxvii) provide for a shorter time to oral fluid and food intake; and (xxviii) reduce the duration of hospitalization.
[00202] In preferred embodiments, the pharmaceutical composition is administered IV,
IM, SC, IT or epidurally.
[00203] In some preferred embodiments, when given by the intravenous route, the pharmaceutical composition of the selected analgesic may be administered by rapid IV injection, e.g., IV bolus, IV push, or slow 2 minute IV injection for rapid onset of effect and a more robust peak effect, or alternatively by longer duration infusions. Furthermore, in certain preferred embodiments, when administered by intravenous route, the pharmaceutical composition produces little to substantially no precipitation of in the subject's vein.
[00204] In some preferred embodiments, when given by the intravenous route, the pharmaceutical composition may be administered by slow IV infusion.
[00205] Alternatively, the pharmaceutical composition can be administered directly into epidurally or into the intrathecal space.
[00206] In certain preferred embodiments, the SAD of selected combination analgesics is less than about 1% of the usual dose of the said analgesic by the specified parenteral route of administration. In other embodiments, the SAD of the said analgesic is less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose of the said analgesic by the same parenteral route of administration.
[00207] In certain preferred embodiments the doses of the specified SAD combination analgesic by the parenteral route are for the treatment of pain of mild intensity. In other said doses are for the treatment of pain of moderate intensity, moderately severe intensity or severe intensity.
[00208] In certain preferred embodiments the specified SAD combination analgesic by the parenteral route is for the treatment of pain in children, in which case the adult dose may - -
be multiplied by the weight of the child (in kilograms) and then divided by 70 kilograms to provide the dose for the child in milligrams (e.g., if the adult dose in a particular embodiment is 5 mg and the child weighs 35 kg, then the dose for the child for the said embodiments is 2.5 mg)
[00209] In certain preferred embodiments, the SAD of the selected combination analgesic is less than about 1% of the usual dose of the selected combination analgesic by the specified parenteral route of administration, said dose administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration. In other embodiments, the SAD of the selected combination analgesic is less than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose of the same combination analgesic by the same parenteral route of administration.
[00210] In certain preferred embodiments, the SAD of the selected combination analgesic is administered by the specified parenteral route of administration in a volume that is less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% the minimum approved or recommended dose by the same route of administration.
[00211] In certain preferred embodiments, the SAD of the selected combination analgesic is administered at a rate that is at least about 10, 20, 30, 40, 50, 60, 70, 80, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 1000% faster than the minimum approved or recommended rate of administration for the minimum approved or recommended dose by the same route of administration.
[00212] In certain preferred embodiments, the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, individual dose, demand dose or daily dose is administered or solely administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration.
[00213] In certain preferred embodiments, the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose comprises the demand dose to be administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration. Preferably, the patient controlled analgesia is by the intravenous route (PCA). In certain preferred embodiments, said demand dose is preceded by one or more loading doses, preferably one loading dose, with the same drug by the same route of administration, said loading dose at least equal to the minimum recommended or approved dose for the intended route of administration or for oral administration. In certain preferred embodiments, the demand dose must be preceded by one or more loading doses, preferably one loading dose, with the same drug by the same route of administration, said loading dose at least equal to the minimum recommended or approved dose for the intended route of administration or for oral administration.
[00214] In certain preferred embodiments, the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose comprises the demand dose, said demand dose administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration, said demand dose to be administered at a frequency not to exceed a prespecified dosing frequency (the lockout period), said lockout period determined by a qualified clinician or medical practitioner. Preferably, the lockout period for patient controlled analgesia is programmed or preprogrammed into the patient controlled analgesia device or pump. In certain preferred embodiments, the demand dose by patient controlled analgesia must be associated with a lockout period.
[00215] In certain preferred embodiments, the lockout period for administration of a demand dose by patient controlled analgesia is at least about 5, 6, 7, 8, 10, 12, 15, 18, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 240, 270, 300, 330 or 360 minutes. Preferably, the lockout period is not more than about 15, 30, 45, 60, 90, or 120 minutes.
[00216] In certain preferred embodiments, the lockout period for administration of a demand dose by patient controlled analgesia is not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended dosing frequency of the unit dose or individual dose of the combination analgesic by the same route of administration or by the oral route of administration. [00217] In certain preferred embodiments, the SAD of the selected combination analgesic specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose is: (1) preceded by a loading dose; (ii) given as a demand dose by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration, preferably by the intravenous route (PCA); (iii) administered not more frequently then the lockout period; (iv) administered at a cumulative daily or 24 hour dose not to exceed 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70 of the minimum approved or recommended daily dose of the said combination analgesic by the same route of administration or by the oral route of administration.
[00218] In certain preferred embodiments, the SAD of the selected combination analgesic may be adjusted upwards or downwards based on the patients efficacy and safety response, tolerability of therapy, desired outcome and speed of outcome, provided that the each individual, unit or demand dose does not exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended dose by the same route of administration or by the oral route of administration.
[00219] In certain preferred embodiments, the SAD of the selected combination analgesic may be adjusted upwards or downwards based on the patients efficacy and safety response, tolerability of therapy, desired outcome and speed of outcome, provided that the daily or 24 hour dose does not exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended daily or 24 hour dose by the same route of administration or by the oral route of administration.
[00220] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less gastrointestinal side effects (e.g., nausea, vomiting, retching, constipation, dyspepsia, heartburn, ulceration, perforation, bleeding and biliary spasm) compared to administration of usual doses of the selected analgesics. [00221] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less venous irritation, injection site pain or phlebitis after IV bolus injection, slow IV injections, short term infusions and continuous infusions, compared to administration of usual doses of the selected analgesics.
[00222] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more intramuscular tolerability, e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation or nerve damage after IM injection, e.g., into the gluteus, deltoid, vastus lateralis, compared to administration of usual doses of the selected analgesics.
[00223] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more intra-articular safety and tolerability, compared to administration of usual doses of the selected analgesics.
[00224] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more subcutaneous tolerability, e.g., reduced injection site pain, subcutaneous irritation, subcutaneous inflammation, injection site redness, or sterile or nonsterile abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions, compared to administration of usual doses of the selected analgesics. [00225] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% more intrathecal and epidural tolerability, e.g., reduced injection site pain and irritation, reduced epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions or intrathecal granulomas after epidural or intrathecal administration, compared to administration of usual doses of the selected analgesics.
[00226] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less bleeding from or near the site of surgery, compared to administration of usual doses of the selected analgesics.
[00227] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less postsurgical wound complications (e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling), compared to administration of usual doses of the selected analgesics.
[00228] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less surgical complications from orthopedic surgery or surgery involving bony manipulation (e.g., non-union, malunion, avascular necrosis), compared to administration of usual doses of the selected analgesics.
[00229] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less postsurgical blood loss, compared to administration of usual doses of the selected analgesics.
[00230] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% lower requirement for blood transfusions, compared to administration of usual doses of the selected analgesics.
[00231] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% improved tolerability upon infiltration into soft tissue, compared to administration of usual doses of the selected analgesics.
[00232] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less elevation of liver function tests (e.g., AST, ALT, ALP, GGT, bilirubin and albumin), compared to administration of usual doses of the selected analgesics.
[00233] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less elevation of renal function tests (e.g., BUN and creatinine), compared to administration of usual doses of the selected analgesics.
[00234] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, - -
450, 475, 500, 550, 600, 650, 700% less peripheral edema, compared to administration of usual doses of the selected analgesics.
[00235] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less elevation in systolic or diastolic blood pressure, compared to administration of usual doses of the selected analgesics.
[00236] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less myocardial infarction, particularly in patients at high risk (e.g. patients with significant ischemic heart disease, angina, coronary occlusion and stenosis, angioplasty candidates, or CABG surgery candidates), compared to administration of usual doses of the selected analgesics.
[00237] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less congestive heart failure, particularly in patients at high risk, compared to administration of usual doses of the selected analgesics.
[00238] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less pulmonary side effects (e.g., pulmonary embolism), particularly in patients at high risk, compared to administration of usual doses of the selected analgesics.
[00239] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, - -
120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less cerebrovascular events (e.g., cerebrovascular accidents, stroke, TIA, etc), particularly in patients at high risk, compared to administration of usual doses of the selected analgesics.
[00240] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less aggregate cardiovascular adverse events, compared to administration of usual doses of the selected analgesics.
[00241] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less CNS side effects (e.g., sedation, fatigue, convulsions, obtundation, coma, mood changes, physical dependence, addiction, hyperalgesia and respiratory depression), compared to administration of usual doses of the selected analgesics.
[00242] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% greater postsurgical, post-bum and posttraumatic wound healing, compared to administration of usual doses of the selected analgesics.
[00243] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% greater postsurgical and posttraumatic bone repair and bone growth, compared to administration of usual doses of the selected analgesics.
[00244] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less NSAID-associated side effects, compared to administration of usual doses of the selected analgesics.
[00245] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less opioid-associated side effects, compared to administration of usual doses of the selected analgesics.
[00246] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less acetaminophen, propacetamol, nitroparacetamol or acetaminophen analog-associated side effects, compared to administration of usual doses of the selected analgesics.
[00247] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less NSAID-associated side effects, or opioid- associated side effects or acetaminophen-associated side effects in the aggregate, compared to administration of usual doses of the selected analgesics.
[00248] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less NSAID and opioid-associated side effects, or acetaminophen and opioid-associated side effects or NSAID and acetaminophen- associated side effects in the aggregate, compared to administration of usual doses of the selected analgesics. [00249] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% less drug-drug interactions, compared to administration of usual doses of the selected analgesics.
[00250] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% reduced risk of bleeding during concurrent anticoagulation therapy (e.g., warfarin, heparin, etc), compared to administration of usual doses of the selected analgesics.
[00251] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% reduced pruritus, rash, hives, blurred vision or urinary retention, compared to administration of usual doses of the selected analgesics.
[00252] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700%, 1000%, 1300%, 1600%, 2000%, 3000%, 4000%, 5000%, 6000%, 7000%, 8000%, 9000%, 10,000%, 12,000%, 14,000%, 16,000%, 18,000%, 20,000% reduced volume for parenteral administration, compared to administration of usual doses of the selected analgesics.
[00253] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700%, 1000%, 1300%, 1600%, 2000%, 3000%, 4000%, - -
5000%, 6000%, 7000%, 8000%, 9000%, 10,000%, 12,000%, 14,000%, 16,000%, 18,000%, 20,000% shorter parenteral administration time (e.g., IV injection time, IV infusion time, SC infusion time, epidural infusion time, intrathecal infusion time), compared to administration of usual doses of the selected analgesics.
[00254] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% earlier patient ambulation and physiotherapy, compared to administration of usual doses of the selected analgesics.
[00255] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% reduced risk of deep vein thrombosis and pulmonary embolism, compared to administration of usual doses of the selected analgesics.
[00256] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% shorter time to oral fluid and food intake, compared to administration of usual doses of the selected analgesics.
[00257] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% shorter duration of hospitalization or stay in a supervised medical facility, compared to administration of usual doses of the selected analgesics.
[00258] In certain preferred embodiments, the method of the invention, comprising administration of SAD of selected combination analgesics will produce about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700% faster restoration of normal bowel function after anesthesia (particularly prolonged general anesthesia), after major surgery and after gastrointestinal and abdominal manipulation, including time to normal bowel sounds, time to first flatus, time to fluid intake, compared to administration of usual doses of the selected analgesics.
[00259] In certain preferred embodiments, the SAD of selected combination analgesics is less than about 1% of the usual dose of the selected combination analgesics by the specified parenteral route of administration. In other embodiments, the subanalgesic doses (SAD) of selected combination analgesics is less than about 1.5%, or less than about 2%, or less than about 2.5%, or less than about 3%, or less than about 3.5%, or less than about 4%, or less than about 4.5%, or less than about 5%, or less than about 5.5%, or less than about 6%, or less than about 6.5%, les than about 7%, or less than about 7.5%, or less than about 8%, or less than about 8.5%, or less than about 9%, or less than about 9.5%, or less than about 10%, or less than about 10.5%, or less than about 11%, or less than about 12%, or less than about 13%, or less than about 14%, or less than about 15%, or less than about 16%, or less than about 17%, or less than about 18%, or less than about 19%, or less than about 20%, or less than about 22%, or less than about 24%, or less than about 26%, or less than about 28%, or less than about 30%, or less than about 32%, or less than about 34%, or less than about 36%, or less than about 38%, or less than about 40%, or less than about 42%, or less than about 44%, or less than about 46%, or less than about 48%, or less than about 50%, or less than about 52%, or less than about 54%, or less than about 56%, or less than about 58%, or less than about 60%, or less than about 62%, or less than about 64%, or less than about 66%, or less than about 68%, or less than about 70%, or less than about 72%, or less than about 74%, or less than about 76%, or less than about 78%, or less than about 80%, or less than about 82%, or less than about 84%, or less than about 86% or less than about 90% of the usual dose of the selected combination analgesics by the specified parenteral route of administration.
[00260] In certain preferred embodiments, the SAD of selected combination analgesics obtain total pain relief (TOTPAR), sum of pain intensity difference (SPID) or sum of pain relief intensity difference (SPRID) at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax, and this dose obtains a TOTPAR of Ay, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains a TOTPAR of not less than 3y. In certain other embodiments, the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration, obtains a TOTPAR, SPID or SPRID at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00261] In certain preferred embodiments, the SAD of selected combination analgesics obtain pain intensity difference (PID) and pain relief (PR) at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax, and this dose obtains a PID or PR of Ay, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains a PID or PR of not less than 3y. In certain other embodiments, the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a PID and PR at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected combination analgesic which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00262] In certain preferred embodiments, the SAD of selected combination analgesics obtain peak pain relief (PPR) or peak pain intensity difference (PPID) for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax, and this dose obtains a PPR or PPID of 4y, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains a PPR or PPID of not less than 3y. In certain other embodiments, the SAD of the selected combination analgesic, obtains a PPR or PPID for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00263] In certain preferred embodiments, the SAD of selected combination analgesics obtain a "number of patients with pain who need to be treated to obtain > 50% pain relief in one patient" (NNT, i.e., number needed to treat or NNT) at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax, and this dose obtains an NNT of Ay, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains an NNT of not less than 3y. In certain other embodiments, the SAD of the selected combination analgesic, obtains an NNT for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than - -
1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00264] In certain preferred embodiments, the SAD of selected combination analgesics obtain a percentage of patients who have a 30% postbaseline reduction in pain (Responder30%) at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax, and this dose obtains a Responder3o% of Ay, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains an NNT of not less than 3y. In certain other embodiments, the SAD of the selected combination analgesic, obtains a Responder30o/o for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00265] In certain preferred embodiments, the SAD of selected combination analgesics obtain a time to confirmed perceptible pain relief using a double stopwatch method after first administration for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax, and this dose obtains a time to confirmed perceptible pain relief using a double stopwatch method of 40 minutes, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains a time to confirmed perceptible pain relief of not less than 30 minutes. In certain other embodiments, the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration, obtains a time to confirmed perceptible pain relief using a double stopwatch method for the selected combination analgesic which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00266] In certain preferred embodiments, the SAD of selected combination analgesics obtain a time to meaningful pain relief using a double stopwatch method for the selected combination analgesic after first administration by the specified parenteral route of administration which is not less than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is Ax, and this dose obtains a time to meaningful pain relief using a double stopwatch method of 80 minutes, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains a time to meaningful pain relief of not less than 60 minutes. In certain other embodiments, the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a time to meaningful pain relief using a double stopwatch method for the selected combination analgesic which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00267] In certain preferred embodiments, the SAD of selected combination analgesics obtain a median time to rescue analgesic use for the selected combination analgesic after first administration by the specified parenteral route of administration which is not more than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected combination analgesic. For example, if the usual analgesic dose of the selected combination analgesic by the intravenous route is 4x, and this dose obtains a median time to rescue analgesic use of 100 minutes, and the dose of the SAD selected combination analgesic is 2x, than this dose obtains a median time to rescue analgesic use of not less than 75 minutes. In certain other embodiments, the SAD of the selected combination analgesic after first administration by the specified parenteral route of administration obtains a median time to rescue analgesic use for the selected combination analgesic which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected combination analgesic.
[00268] Analgesic efficacy measures, including PID, PR, PPID, PPR, SPID, SPRID,
TOTPAR, time to confirmed perceptible pain relief, time to meaningful pain relief, NNT and Responder3o% can be measured using known methods.
[00269] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of acute pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of chronic pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of acute exacerbations of chronic pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of breakthrough pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of renal colic. In other embodiments, the SAD of the selected combination analgesic is for the treatment of signs and symptoms of migraine, including pain, phonophobia, photophobia and nausea. In other embodiments, the SAD of the selected combination analgesic is for the treatment of cancer pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of chronic non-cancer pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of acute exacerbations of chronic pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of neuropathic pain.
[00270] In other embodiments, the SAD of the selected combination analgesic is for the treatment of burn pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of burn dressing change pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of posttraumatic pain. In other embodiments, the SAD of the selected combination analgesic is for the treatment of acute musculoskeletal pain. In certain preferred embodiments, the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain. In certain preferred embodiments, the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain following major surgery. In certain particularly preferred embodiments, the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in the inpatient setting (i.e., a medically supervised setting where the patient has been admitted into the hospital, clinic or medical facility, usually involving an overnight stay). In certain other particularly preferred embodiments, the SAD of the selected combination analgesic is for the treatment of acute postsurgical pain for use in the day surgery or outpatient surgery setting (i.e., a medically supervised setting where the patient is expected to be rapidly discharged, usually not involving an overnight stay). In certain other particularly preferred embodiments, the SAD of the selected combination analgesic is for the treatment of acute headache (e.g., migraine) or acute renal colic, or acute posttraumatic pain in the emergency room. In certain particularly preferred embodiments, the SAD of the selected combination analgesic is for the treatment of pain for conditions under which the standard of care or the usual standard of care involves the presence of or insertion of an indwelling sterile catheter for subcutaneous, venous, epidural or intrathecal access.
[00271] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of mild pain. In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain of at least moderate severity (i.e., moderate intensity). In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain of moderately severe intensity. In certain particularly preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain of that is of severe intensity.
[00272] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain.
[00273] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends parenteral analgesics.
[00274] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends intravenous analgesics.
[00275] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain only by intermittent analgesia, short term infusions or prolonged infusions but excluding all administration by patient controlled (intravenous) analgesia (PCA).
[00276] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain but excluding all administration by patient controlled epidural analgesia (PCEA).
[00277] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain but excluding all administration by the subcutaneous route.
[00278] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain but excluding all administration by the intramuscular route. [00279] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends subcutaneous analgesics.
[00280] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends intramuscular analgesics.
[00281] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends epidural or intrathecal analgesics.
[00282] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain of dysmenorrhea.
[00283] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain of headache (e.g., migraine or tension headache).
[00284] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding dental pain.
[00285] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding pain following third-molar extractions.
[00286] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain associated with metatarsophalangeal surgery (e.g., bunionectomy, hammer toe repair).
[00287] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention for infiltration analgesia. [00288] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention by patient controlled analgesia, also know as patient controlled intravenous analgesia or PCA. [00289] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention by patient controlled epidural analgesia or PCEA. [00290] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the use of the invention by the intra-articular route. [00291] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain associated with podiatric surgery. [00292] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding the pain associated with sore throat or mucositis. [00293] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by administration by the infiltration route in proximity to the field of surgical incision. [00294] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by administration by the infiltration route in proximity to source of pain. [00295] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding renal colic. [00296] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by intraarticular administration. [00297] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding mild pain (i.e., pain of mild intensity). [00298] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding moderate pain (i.e., pain of moderate intensity). [00299] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain excluding pain treated by intravenous infusions of the SAD selected combination analgesic (i.e., intravenous administration lasting longer than about 5 minutes). [00300] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding chronic pain. [00301] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding neuropathic pain. [00302] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding cancer pain. [00303] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain in patients receiving concomitant opioid analgesics. [00304] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain, excluding concomitant use with opioid analgesics. [00305] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic pharmaceutical composition for the treatment of pain, said composition devoid of opioid analgesics. [00306] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by the parenteral route, said parenteral route excluding intra-articular administration. [00307] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is for the treatment of pain by the parenteral route, said parenteral route excluding administration by local tissue infiltration. - -
[00308] In certain preferred embodiments, both the dose and the total daily dose of the selected combination analgesic given as SAD selected combination analgesic is significantly lower than the usual dose and daily dose of selected combination analgesic; said lower dose of the selected combination analgesic given as a SAD of the selected combination analgesic resulting in a shorter duration of analgesia for each administered dose compared with the usual dose of the selected combination analgesic; said lower dose of the SAD selected combination analgesic providing about the same overall or total analgesic or pain relieving effect by virtue of being given more frequently than the usual dose of the selected combination analgesic given at its usual dosing frequency; said invention still providing a significantly lower total daily dose despite about the same analgesic or pain relieving effect as the usual dose of the selected combination analgesic.
[00309] In certain preferred embodiments, the dose of the selected combination analgesic given as SAD selected combination analgesic is not significantly lower than the usual dose; however, the daily dose of selected combination analgesic given as SAD selected combination analgesic is significantly lower than the usual daily dose of selected combination analgesic; said composition still providing some or all of the benefits of the present invention.
[00310] The invention requires that the subanalgesic dose (SAD) of the selected combination analgesics comprising a pharmaceutical composition of at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof. [00311] In certain preferred embodiments, the parenteral dose of the invention will vary depending on the method of administration. For example, the intravenous dose of an analgesic administered by PCA is usually much smaller than intravenous dose administered by intermittent injection. This is because the IV PCA analgesic "demand dose" is self-administered and can be re-administered by the patient as required, only subject to a lock-out period programmed into the PCA device. To illustrate this further, the adult IV PCA demand dose of morphine is usually 0.5 to 2.5 mg and the usual starting dose is 1 mg (after an initial loading dose), the adult PCA demand dose of hydromorphone is usually 0.05 to 0.4 mg and the usual starting dose is 0.2 mg (after an initial loading dose). The usual IV PCA lockout period for the aforementioned morphine and hydromorphone demand doses ranges from 5 to 10 minutes (usual starting lockout period is 8 minutes). In contrast, the usual intermittently administered dose of morphine and hydromorphone is 10 mg and 1.5 mg, respectively, given every 2 to 4 hours. (Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, American Pain Society, 5th Edition, 2003, Glenview, IL). As a general rule, the IV PCA dose is approximately one-fifth to one-tenth the intermittent IV dose.
[00312] In a preferred embodiment, the at one or more compounds of the selected combination analgesic is chosen from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof
[00313] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketoprofen adult dose of the invention (i.e., the adult SAD dose of the ketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 30 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20.5 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or - -
less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than 0.05 mg. [00314] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketoprofen adult dose of the invention (i.e., the adult SAD dose of the ketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.65 mg/kg, or less than about 0.6 mg/kg, or less than about 0.55 mg/kg, or less than about 0.5 mg/kg, or less than about 0.45 mg/kg, or less than about 0.4 mg/kg, or less than about 0.38 mg/kg, or less than about 0.36 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.32 mg/kg, or less than about 0.30 mg/kg, or less than about 0.29 mg/kg or less than about 0.28 mg/kg or less than about 0.27 mg/kg or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.21 mg/kg or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg.
[00315] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexketoprofen adult dose of the invention (i.e., the adult SAD dose of the dexketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 25 mg, or less than about 22.5 mg, or less than about 20 mg, or less than about 17.5 mg, or less than about 15 mg, or less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg, or less than about 0.25 mg, or less than about 0.15 mg, or less than about 0.1, or less than about 0.05 mg.
[00316] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexketoprofen dose of the invention (i.e., the SAD dose of the dexketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.357 mg/kg, or less than about 0.35 mg/kg, or less than about 0.325 mg/kg, or less than about 0.3 mg/kg, or less than about - -
0.275 mg/kg, or less than about 0.25 mg/kg, or less than about 0.225 mg/kg, or less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg.
[00317] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural diclofenac adult dose of the invention (i.e., the adult dose of the SAD diclofenac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 20 mg, or less than about 18 mg, or less than about 16 mg or less than about 15 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less - -
than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg.
[00318] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural diclofenac dose of the invention (i.e., the SAD dose of the diclofenac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.3 mg/kg, or less than about 0.29 mg/kg, or less than about 0.28 mg/kg, or less than about 0.25 mg/kg, or less than about 0.22 mg/kg, or less than about 0.20 mg/kg, or less than about 0.18 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.065 mg/kg, or less than about 0.06 mg/kg, or less than about 0.055 mg/kg, or less than about 0.54 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg, or less than about 0.043 mg/kg, or less than about 0.042 mg/kg, or less than about 0.041 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg.
[00319] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural piroxicam adult dose of the invention (i.e., the adult SAD dose of the piroxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 10 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg.
[00320] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural piroxicam dose of the invention (i.e., the SAD dose of the piroxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1.42 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.0714 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.067 mg/kg, or less than about 0.066 mg/kg, or less than about 0.065 mg/kg, or less than about 0.064 mg/kg, or less than about 0.063 mg/kg, or less than about 0.062 mg/kg, or less than about 0.061 mg/kg, or less than about 0.06 mg/kg, or less than about 0.059 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg, or less than about 0.043 mg/kg, or less than about 0.042 mg/kg, or less than about 0.041 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg or less than about 0.00025 mg/kg.
[00321] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ibuprofen adult dose of - -
the invention (i.e., the adult SAD dose of the ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 180 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 85 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 67.5 mg, or less than about 65 mg, or less than about 62.5 mg, less than about 60 mg, or less than about 57.5 mg, or less than about 55 mg, or less than about 52.5 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg or less than about 0.4 mg, or less than about 0.3, or less than about 0.2, or less than about 0.1 mg. In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ibuprofen dose of the invention (i.e., the SAD dose of the ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 2.58 mg/kg, or less than about 2.57 mg/kg, or less than about 2.5 mg/kg, or less than about 2.4 mg/kg, or less than about 2.3 mg/kg, or less than about 2.2 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 - 5-
mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg, or less than about 0.043 mg/kg, or less than about 0.042 mg/kg, or less than about 0.041 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than 0.0001 mg/kg.
[00323] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(+)-ibuprofen (dexibuprofen) adult dose of the invention (i.e., the adult SAD dose of the S(+)-ibuprofen - -
by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 90 mg, or less than about 85 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, less than about 55 mg or less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 30 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20.5 mg, or less than about 20 mg, less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, or less than about 0.25 mg.
[00324] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(+)-ibuprofen (dexibuprofen) dose of the invention (i.e., the SAD dose of the S(+)-ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 01.29 mg/kg, or less than about 1.28 mg/kg, or about 1.2 mg/kg, or about 1.1 mg/kg, or less than about 1 mg/kg, less than about 0.9 mg/kg or less than about 0.8 mg/kg or less than about 0.7 mg/kg or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.357 mg/kg, or less than about 0.35 mg/kg, or about 0.34 mg/kg, or about 0.32 mg/kg, or less than about 0.30 mg/kg, less than about 0.29 mg/kg or less than about 0.28 mg/kg or less than about 0.27 mg/kg or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.21 mg/kg or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than - -
about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0025, or less than about 0.001. [00325] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketorolac adult dose of the invention (i.e., the adult SAD dose of the ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 9 mg, or less than about 8.75 mg, or less than about 8.5 mg, or less than about 8.25 mg,.or less than about 8 mg, or less than about 7.75 mg, or less than about 7.5 mg, or less than about 7.25 mg, or less than about 7 mg, or less than about 6.75 mg, or less than about 6.5 mg, or less than about 6.25 mg, or less than about 6 mg, or less than about 5.9 mg, or less than about 5.8 mg, or less than about 5.7 mg, or less than about 5.6 mg, or less than about 5.5 mg, or less than about 5.4 mg, or less than about 5.3 mg, or less than about 5.2 mg, or less than about 5.1 mg, or less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than - -
about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg.
[00326] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketorolac dose of the invention (i.e., the SAD dose of the ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain is less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.067 mg/kg, or less than about 0.066 mg/kg, or less than about 0.065 mg/kg, or less than about 0.064 mg/kg, or less than about 0.063 mg/kg, or less than about 0.062 mg/kg, or less than about 0.061 mg/kg, or less than about 0.06 mg/kg, or less than about 0.059 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg, or less than about 0.043 mg/kg, or less than about 0.042 mg/kg, or less than about 0.041 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about - -
0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg or less than about 0.00025 mg/kg.
[00327] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(-)-ketorolac adult dose of the invention (i.e., the adult SAD dose of the S(-)-ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 5 mg, less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, less than about 2.45 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg, or less than about 0.0005 mg.
[00328] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(-)-ketorolac dose of the invention (i.e., the SAD dose of the S(-)-ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.07 mg/kg, or less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg.
[00329] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural naproxen adult dose of the invention (i.e., the adult SAD dose of the naproxen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) is or less than about 245 mg, or less than about 240 mg, or less than about 230 mg, or less than about 220 mg, or less than about 210 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 125 mg, or less than about 120 mg, or less than about 115 mg, or less than about 110 mg, or less than about 105 mg, or less than about 100 mg, or less than about 98 mg, or less than about 96 mg, or less than about 95 mg, or less than about 94 mg, or less than about 92 mg, or less than about 90 mg, or less than about 88 mg, or less than about 86 mg, or less than about 85 mg, or less than about 84 mg, or less than about 82 mg, or less than about 80 mg, or less than about 79 mg, or less than about 78 mg, or less than about 76 mg or less than about 75 mg, or less than about 74 mg, or less than about 72 mg, or less than about 70 mg, or less than about 69 mg, or less than about 68 mg, or less than about 66 mg, or less than about 64 mg, or less than about 62 mg, or less than about 60 mg, or less than about 59 mg, or less than about 58 mg, or less than about 56 mg, or less than about 55 mg, or less than about 54 mg, or less than about 52 mg, or less than about 50 mg, or less than about 49 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.75 mg, or less than about 0.5 mg, or less than about 0.25 mg.
[00330] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural naproxen dose of the invention (i.e., the SAD dose of the naproxen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 2.9 mg/kg, or less than about 2.8 mg/kg, or less than about 2.7 mg/kg, or less than about 2.6 mg/kg, or less than about 2.5 mg/kg, less than about 2.4 mg/kg, or less than about 2.3 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.428 mg/kg, or less than about 1.4 mg/kg, or less than about 1.39 mg/kg, or less than about 1.38 mg/kg, or less than about 1.37 mg/kg, less than about 1.36 mg/kg, or less than about 1.35 mg/kg, or less than about 1.34 mg/kg, or less than about 1.32 mg/kg, or less than about 1.31 mg/kg, or less than about 1.3 mg/kg, or less than about 1.28 mg/kg, less than about 1.26 mg/kg, or less - -
than about 1.24 mg/kg, or less than about 1.22 mg/kg, or less than about 1.2 mg/kg, or less than about 1.18 mg/kg, or less than about 1.16 mg/kg, or less than about 1.14 mg/kg, less than about 1.12 mg/kg, or less than about 1.1 mg/kg, or less than about 1.08 mg/kg, or less than about 1.06 mg/kg, or less than about 1.04 mg/kg, or less than about 1.02 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.85 mg/kg, or less than about 0.8 mg/kg, or less than about 0.75 mg/kg, or less than about 0.7 mg/kg, or less than about 0.65 mg/kg, or less than about 0.6 mg/kg, or less than about 0.55 mg/kg, or less than about 0.5 mg/kg, or less than about 0.45 mg/kg, or less than about 0.4 mg/kg, or less than about 0.35 mg/kg, or less than about 0.3 mg/kg, or less than about 0.25 mg/kg, or less than about 0.2 mg/kg, or less than about 0.15 mg/kg, or less than about 0.1 mg/kg, or less than about 0.05 mg/kg, or less than about 0.025 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg, or less than about 0.005 mg/kg.
[00331] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tenoxicam adult dose of the invention (i.e., the adult SAD dose of the tenoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15.5 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12.5 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg.
[00332] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tenoxicam dose of the invention (i.e., the SAD dose of the tenoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2857mg/kg, or less than about 0.28 mg/kg, or less than about 0.27 mg/kg, or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.21 mg/kg, or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg or less than about 0.00025 mg/kg.
[00333] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural flurbiprofen adult dose - -
of the invention (i.e., the adult SAD dose of the flurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 100 mg, or less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg, or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.95 mg, or less than about 0.9 mg, or less than about 0.85 mg, or less than about 0.8 mg, or less than about 0.75 mg, or less than about 0.7 mg, or less than about 0.65 mg, or less than about 0.6 mg, or less than about 0.55 mg, or less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.4 mg, or less than about 0.35 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg.
[00334] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural flurbiprofen dose of the invention (i.e., the SAD dose of the flurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg or less than about 0.6 mg/kg or less than about 0.5 mg/kg or less than about 0.4 mg/kg, or less than about 0.3571 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.33 mg/kg, or less than about 0.32 mg/kg, or less than about 0.31 mg/kg, or less than about 0.30 mg/kg, or less than about 0.29 mg/kg or less than about 0.28 mg/kg or less than about 0.27 mg/kg or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.21 mg/kg or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.0075 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.00225 mg/kg, or less than about 0.002 mg/kg, or less than about 0.00175 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.00125 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg or less than about 0.00025 mg/kg.
[00335] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexflurbiprofen (S(+)- flurbiprofen)adult dose of the invention (i.e., the adult SAD dose of the dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 100 mg, or less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg, or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.95 mg, or less than about 0.9 mg, or less than about 0.85 mg, or less than about 0.8 mg, or less than about 0.75 mg, or less than about 0.7 mg, or less than about 0.65 mg, or less than about 0.6 mg, or less than about 0.55 mg, or less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.4 mg, or less than about 0.35 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg.
[00336] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexflurbiprofen dose of the invention (i.e., the SAD dose of the dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg or less than about 0.6 mg/kg or less than about 0.5 mg/kg or less than about 0.4 mg/kg, or less than about 0.3571 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.33 mg/kg, or less than about 0.32 mg/kg, or less than about 0.31 mg/kg, or less than about 0.30 mg/kg, or less than about 0.29 mg/kg or less than about 0.28 mg/kg or less than about 0.27 mg/kg or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.21 mg/kg or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.0075 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.00225 mg/kg, or less than about 0.002 mg/kg, or less than about 0.00175 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.00125 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg or less than about 0.00025 mg/kg.
[00337] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lornoxicam adult dose of the invention (i.e., the adult SAD dose of the lornoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for -9 -
the treatment of pain, inflammation and/or fever is less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg.
[00338] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lornoxicam dose of the invention (i.e., the SAD dose of the lornoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg, or less than about 0.043 mg/kg, or less than about 0.042 mg/kg, or less than about 0.041 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg or less than about 0.00025 mg/kg.
[00339] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural celecoxib dose of the invention (i.e., the adult SAD dose of the celecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg or less than about 30 mg, or less than about 28 mg, or less than about 25 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg.
[00340] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural celecoxib dose of the invention (i.e., the SAD dose of the celecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg, or less than about 0.043 mg/kg, or less than about 0.042 mg/kg, or less than about 0.041 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than 0.0001 mg/kg. [00341] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lumiracoxib dose of the invention (i.e., the adult SAD dose of the lumiracoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg or less than about 30 mg, or less than about 28 mg, or less than about 25 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg, or less than about 0.0015 mg, or less than about 0.001 mg. [00342] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lumiracoxib dose of the invention (i.e., the SAD dose of the lumiracoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg, or less than about 0.043 mg/kg, or less than about 0.042 mg/kg, or less than about 0.041 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or - -
less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than 0.0001 mg/kg.
[00343] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural parecoxib dose of the invention (i.e., the adult SAD dose of the parecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg, or less than about 0.25 mg, or less than about 0.15 mg, or less than about 0.1, or less than about 0.05 mg.
[00344] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural parecoxib dose of the invention (i.e., the SAD dose of the parecoxib by the intravenous, intramuscular, - -
subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg.
[00345] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural etoricoxib dose of the invention (i.e., the adult SAD dose of the etoricoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg, or less than about 0.25 mg, or less than about 0.15 mg, or less than about 0.1, or less than about 0.05 mg.
[00346] In certain preferred embodiments of the invention, the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural etoricoxib dose of the invention (i.e., the SAD dose of the etoricoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about - -
0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg.
[00347] In certain preferred embodiments of the invention, the intrathecal dose of the SAD selected combination analgesic invention (i.e., the intrathecal dose of the selected combination analgesic, preferably chosen from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen) dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam by the intrathecal route) for the treatment of pain is less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.015 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg, or less than about 0.00004 mg, or less than about 0.00003 mg, or less than about 0.00002 mg, or less than about 0.00001 mg, or less than about 0.000009 mg, or less than about 0.000008 mg, or less than about 0.000007 mg, or less than about 0.000006 mg, or less than about 0.000005 mg, or less than about 0.000004 mg, or less than about 0.000003 mg, or less than about 0.000002 mg, or less than about 0.000001 mg.
[00348] In certain preferred embodiments of the invention, the intrathecal dose of the SAD selected combination analgesic invention (i.e., the intrathecal dose of the selected combination analgesic, preferably chosen from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen) dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lomoxicam by the intrathecal route) for the treatment of pain is less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.00015 mg/kg, or less than about 0.00013 mg/kg, or less than about 0.00012 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg, or less than about 0.000009 mg/kg, or less than about 0.000008 mg/kg, or less than about 0.000007 mg/kg, or less than about 0.000006 mg/kg, or less than about 0.000005 mg/kg, or less than about 0.000004 mg/kg, or less than about 0.000003 mg/kg, or less than about 0.000002 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000007 mg/kg, or less than about 0.0000006 mg/kg, or less than about 0.0000005 mg/kg, or less than about 0.0000004 mg/kg, or less than about 0.0000003 mg/kg, or less than about 0.0000002 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000007 mg/kg, or less than about 0.0000006 - -
mg/kg, or less than about 0.0000005 mg/kg, or less than about 0.0000004 mg/kg, or less than about 0.0000003 mg/kg, or less than about 0.0000002 mg/kg, or less than about 0.0000001 mg/kg, or less than about 0.00000009 mg/kg.
[00349] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen adult dose of the invention (i.e., the adult SAD dose of the acetaminophen by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1000 mg, or less than about 900 mg, or less than about 800 mg, or less than about 750 mg, or less than about 650 mg, or less than about 645 mg, or less than about 600 mg, or less than about 645 mg, or less than about 600 mg, or less than about 550 mg, or less than about 500 mg, or less than about or less than about 475 mg, or less than about 450 mg, or less than about 425 mg, or less than about 400 mg, or less than about 375 mg, or less than about 350 mg, or less than about 325 mg, or less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 30 mg, or less than about 20 mg, or less than about 10 mg, or less than about 5 mg.
[00350] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen adult dose of the invention (i.e., the adult SAD dose of the acetaminophen by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less _
than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 88 mg, or less than about 86 mg, or less than about 84 mg, or less than about 82 mg, or less than about 80 mg, or less than about 78 mg, or less than about 76 mg, or less than about 74 mg, or less than about 72 mg, or less than about 70 mg, or less than about 68 mg, or less than about 66 mg, or less than about 64 mg, or less than about 62 mg, or less than about 60 mg, or less than about 58 mg, or less than about 56 mg, or less than about 54 mg, or less than about 52 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 18 mg, or less than about 16 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 9 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg. In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen dose of the invention (i.e., the SAD dose of the acetaminophen by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about 9.28 mg/kg, or less than about 9 mg/kg, or less than about 7.14 mg/kg, or less than about 7 mg/kg, or less than about 6.5 mg/kg, or less than about 6 mg/kg, or less than about 5.5 mg/kg, or less than about 5 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.5 mg/kg, or less than about 3 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than - -
about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg.
[00352] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural acetaminophen dose of the invention (i.e., the SAD dose of the acetaminophen by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 4.7 mg/kg, or less than about 4.6 mg/kg, or less than about 4.5 mg/kg, or less than about 4.4 mg/kg or less than about 4.3 mg/kg, or less than about 4.2 mg/kg, or less than about 4.1 mg/kg or less than about 4 mg/kg, or less than about 3.9 mg/kg, or less than about 3.8 mg/kg or less than about 3.7 mg/kg, or less than about 3.6 mg/kg, or less than about 3.5 mg/kg, or less than about 3.4 mg/kg or less than about 3.3 mg/kg, or less than about 3.2 mg/kg, or less than about 3.1 mg/kg or less than about 3 mg/kg, or less than about 2.9 mg/kg, or less than about 2.8 mg/kg or less than about 2.7 mg/kg, or less than about 2.6 mg/kg, or less than about 2.5 mg/kg, or less than about 2.4 mg/kg or less than about 2.3 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or les than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg.
[00353] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] acetaminophen adult dose of the invention (i.e., the adult SAD dose of the acetaminophen by the PCA [i.e., intravenous PCA route]) is less than about less than - -
about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg.
[00354] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] acetaminophen dose of the invention (i.e., the SAD dose of the acetaminophen by the PCA [i.e., intravenous PCA route]) is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or less than about 0.0.075 mg/kg, or less than about 0.05, or less than about 0.025 mg/kg, or less than about 0.015 mg/kg.
[00355] In certain preferred embodiments of the invention, the intrathecal acetaminophen adult dose of the invention (i.e., the adult SAD dose of the acetaminophen by the intrathecal route) is less than about less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg.
[00356] In certain preferred embodiments of the invention, the intrathecal acetaminophen dose of the invention (i.e., the SAD dose of the acetaminophen by the intrathecal route) is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or less than about 0.0.075 mg/kg, or less than about 0.05, or less than about 0.025 mg/kg, or less than about 0.015 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004, or less than about 0.003 mg/kg, or less than about 0.0029 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0027 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.0021 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg.
[00357] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol adult dose of the invention (i.e., the adult SAD dose of the propacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1000 mg, or less than about 900 mg, or less than about 800 mg, or less than about 750 mg, or less than about 650 mg, or less than about 645 mg, or less than about 600 mg, or less than about 645 mg, or less than about 600 mg, or less than about 550 mg, or less than about 500 mg, or less than about or less than about 475 mg, or less than about 450 mg, or less than about 425 mg, or less than about 400 mg, or less than about 375 mg, or less than about 350 mg, or less than about 325 mg, or less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 30 mg, or less than about 20 mg, or less than about 10 mg, or less than about 5 mg. In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol adult dose of the invention (i.e., the adult SAD dose of the propacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 88 mg, or less than about 86 mg, or less than about 84 mg, or less than about 82 mg, or less than about 80 mg, or less than about 78 mg, or less than about 76 mg, or less than about 74 mg, or less than about 72 mg, or less than about 70 mg, or less than about 68 mg, or less than about 66 mg, or less than about 64 mg, or less than about 62 mg, or less than about 60 mg, or less than about 58 mg, or less than about 56 mg, or less than about 54 mg, or less than about 52 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 18 mg, or less than about 16 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 9 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg.
[00359] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol dose of the invention (i.e., the SAD dose of the propacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about 9.28 mg/kg, or less than about 9 mg/kg, or less than about 7.14 mg/kg, or less than about 7 mg/kg, or less than about 6.5 mg/kg, or less than about 6 mg/kg, or less than about 5.5 mg/kg, or less than about 5 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.5 mg/kg, or less than about 3 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg.
[00360] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural propacetamol dose of the invention (i.e., the SAD dose of the propacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 4.7 mg/kg, or less than about 4.6 mg/kg, or less than about 4.5 mg/kg, or less than about 4.4 mg/kg or less than about 4.3 mg/kg, or less than about 4.2 mg/kg, or less than about 4.1 mg/kg or less than about 4 mg/kg, or less than about 3.9 mg/kg, or less than about 3.8 mg/kg or less than about 3.7 mg/kg, or less than about 3.6 mg/kg, or less than about 3.5 mg/kg, or less than about 3.4 mg/kg or less than about 3.3 mg/kg, or less than about 3.2 mg/kg, or less than about 3.1 mg/kg or less than about 3 mg/kg, or less than about 2.9 mg/kg, or less than about 2.8 mg/kg or less than about 2.7 mg/kg, or less than about 2.6 mg/kg, or less than about 2.5 mg/kg, or less than about 2.4 mg/kg or less than about 2.3 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or les than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg. In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] propacetamol adult dose of the invention (i.e., the adult SAD dose of the propacetamol by the PCA [i.e., intravenous PCA route]) is less than about less than about 400 mg, or less than about 350 mg, or less than about 300 mg, or less than about 250 mg, or less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg.
[00362] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] propacetamol dose of the invention (i.e., the SAD dose of the propacetamol by the PCA [i.e., intravenous PCA route]) is less than about 5.7 mg/kg, or less than about 5.5 mg/kg, or less than about 5.25 mg/kg, or less than about 5 mg/kg, or less than about 4.75 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.75 mg/kg, or less than about 3.5 mg/kg, or less than about 3.25 mg/kg, or less than about 3 mg/kg, or less than about 2.9 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or less than about 0.0.075 mg/kg, or less than about 0.05, or less than about 0.025 mg/kg, or less than about 0.015 mg/kg.
[00363] In certain preferred embodiments of the invention, the intrathecal propacetamol adult dose of the invention (i.e., the adult SAD dose of the propacetamol by the intrathecal route) is less than about less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about - -
19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg.
[00364] In certain preferred embodiments of the invention, the intrathecal propacetamol dose of the invention (i.e., the SAD dose of the propacetamol by the intrathecal route) is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or less than about 0.0.075 mg/kg, or less than about 0.05, or less than about 0.025 mg/kg, or less than about 0.015 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004, or less than about 0.003 mg/kg, or less than about 0.0029 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0027 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.0021 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg. In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural nitroparacetamol (nitroxyparacetamol or NO-acetaminophen) adult dose of the invention (i.e., the adult SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1000 mg, or less than about 900 mg, or less than about 800 mg, or less than about 750 mg, or less than about 650 mg, or less than about 645 mg, or less than about 600 mg, or less than about 645 mg, or less than about 600 mg, or less than about 550 mg, or less than about 500 mg, or less than about or less than about 475 mg, or less than about 450 mg, or less than about 425 mg, or less than about 400 mg, or less than about 375 mg, or less than about 350 mg, or less than about 325 mg, or less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 30 mg, or less than about 20 mg, or less than about 10 mg, or less than about 5 mg.
[00366] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural nitroparacetamol adult dose of the invention (i.e., the adult SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra- articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 225 mg, or less than about 200 mg, or less than about 190 mg, or less than about 180 mg, or less than about 175 mg, or less than about 170 mg, or less than about 160 mg, or less than about 150 mg, or less than about 140 mg, or less than about 130 mg, or less than about 120 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 90 mg, or less than about 88 mg, or less than about 86 mg, or less than about 84 mg, or less than about 82 mg, or less than about 80 mg, or less than about 78 mg, or less than about 76 mg, or less than about 74 mg, or less than about 72 mg, or less than about 70 mg, or less than about 68 mg, or less than about 66 mg, or less than about 64 mg, or less than about 62 mg, or less than about 60 mg, or less than about 58 mg, or less than about 56 mg, or less than about 54 mg, or less than about 52 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 18 mg, or less than about 16 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 9 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg.
[00367] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural - -
nitroparacetamol dose of the invention (i.e., the SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 14.2 mg/kg, or less than about 12.8 mg/kg, or less than about 12 mg/kg, or less than about 11 mg/kg, or less than about 10 mg/kg, or less than about 9.28 mg/kg, or less than about 9 mg/kg, or less than about 7.14 mg/kg, or less than about 7 mg/kg, or less than about 6.5 mg/kg, or less than about 6 mg/kg, or less than about 5.5 mg/kg, or less than about 5 mg/kg, or less than about 4.5 mg/kg, or less than about 4 mg/kg, or less than about 3.5 mg/kg, or less than about 3 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg. In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural nitroparacetamol dose of the invention (i.e., the SAD dose of the nitroparacetamol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 4.7 mg/kg, or less than about 4.6 mg/kg, or less than about 4.5 mg/kg, or less than about 4.4 mg/kg or less than about 4.3 mg/kg, or less than about 4.2 mg/kg, or less than about 4.1 mg/kg or less than about 4 mg/kg, or less than about 3.9 mg/kg, or less than about 3.8 mg/kg or less than about 3.7 mg/kg, or less than about 3.6 mg/kg, or less than about 3.5 mg/kg, or less than about 3.4 mg/kg or less than about 3.3 mg/kg, or less than about 3.2 mg/kg, or less than about 3.1 mg/kg or less than about 3 mg/kg, or less than about 2.9 mg/kg, or less than about 2.8 mg/kg or less than about 2.7 mg/kg, or less than about 2.6 mg/kg, or less than about 2.5 mg/kg, or less than about 2.4 mg/kg or less than about 2.3 mg/kg, or less than about 2.2 mg/kg, or less than about 2.1 mg/kg or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg or less than - -
about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or les than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg.
[00369] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] nitroparacetamol adult dose of the invention (i.e., the adult SAD dose of the nitroparacetamol by the PCA [i.e., intravenous PCA route]) is less than about 300 mg, or less than about 275 mg, or less than about 250 mg, or less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg.
[00370] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] nitroparacetamol dose of the invention (i.e., the SAD dose of the nitroparacetamol by the PCA [i.e., intravenous PCA route]) is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less - -
than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or less than about 0.0.075 mg/kg, or less than about 0.05, or less than about 0.025 mg/kg, or less than about 0.015 mg/kg.
[00371] In certain preferred embodiments of the invention, the intrathecal nitroparacetamol adult dose of the invention (i.e., the adult SAD dose of the nitroparacetamol by the intrathecal route) is less than about less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 110 mg, or less than about 100 mg, or less than about 95 mg, or less than about 80 mg, or less than about 75 mg, or less than about 70 mg, or less than about 65 mg, or less than about 60 mg, or less than about 55 mg, or less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 45 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, or less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg.
[00372] In certain preferred embodiments of the invention, the intrathecal nitroparacetamol dose of the invention (i.e., the SAD dose of the nitroparacetamol by the intrathecal route) is less than about 0.00428 mg/kg, or less than about 2.86 mg/kg, or less than about 2.85 mg/kg, or less than about 2.8 mg/kg, or less than about 2.6 mg/kg, or less than about 2.4 mg/kg, or less than about 2.2 mg/kg, or less than about 2 mg/kg, or less than about 1.9 mg/kg, or less than about 1.8 mg/kg, or less than about 1.7 mg/kg, or less than about 1.6 mg/kg, or less than about 1.5 mg/kg, or less than about 1.4 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.9 mg/kg, or less than about 0.8 mg/kg, or less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg, or less than about 0.0.075 mg/kg, or less than about 0.05, or less than about 0.025 mg/kg, or less than about 0.015 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004, or less than about 0.003 mg/kg, or less than about 0.0029 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0027 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.0021 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg.
[00373] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G adult dose of the invention (i.e., the adult SAD dose of the M6G by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg, or less than about 0.25 mg.
[00374] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G adult dose of the invention (i.e., the adult SAD dose of the M6G by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about 2 mg, or less than about 1.75 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.75 mg, or less than about 0.5 mg, or less than about 0.25 mg.
[00375] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G dose of the invention (i.e., the SAD dose of the M6G by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.42 mg/kg, or less than about 0.40 mg/kg, or less than about 0.38 mg/kg, or less than about 0.36 mg/kg, or less than about 0.34 mg/kg, or less than about 0.32 mg/kg, or less than about 0.3 mg/kg, or less than about 0.28 mg/kg, or less than about 0.26 mg/kg, or less than about 0.24 mg/kg, or less than about 0.22 mg/kg, or less than about 0.210 mg/kg, or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg, or less than about 0.0075 mg/kg, or less than about 0.005 mg/kg, or less than about 0.025 mg/kg.
[00376] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural M6G dose of the invention (i.e., the SAD dose of the M6G by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.07 mg/kg, or less than about 0.0675 mg/kg, or less than about 0.065 mg/kg, or less than about 0.0625 mg/kg or less than about 0.06 mg/kg, or less than about 0.0575 mg/kg, or less than about 0.055 mg/kg or less than about 0.0525 mg/kg, or less than about 0.05 mg/kg, or less than about 0.0475 mg/kg or less than about 0.045 mg/kg, or less than about 0.0425 mg/kg, or less than about 0.04 mg/kg or less than about 0.0375 mg/kg, or less than about 0.035 mg/kg, or less than about 0.0325 mg/kg or less than about 0.03 mg/kg, or less than about 0.0275 mg/kg, or less than about 0.025 mg/kg or less than about 0.02 mg/kg, or less than about 0.0175 mg/kg, or less than about 0.015 mg/kg, or less than about 0.0125 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg or less than about 0.001 mg/kg, or less than about 0.0005 mg/kg. [00377] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] M6G adult dose of the invention (i.e., the adult SAD dose of the M6G by the PCA [i.e., intravenous PCA route]) is less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about less than about 2 mg, or less than about 1.75 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than 0.75, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.05 mg, or less than about 0.025 mg.
[00378] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] M6G dose of the invention (i.e., the SAD dose of the M6G by the PCA [i.e., intravenous PCA route]) is less than about 0.072 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.066 mg/kg, or less than about 0.064 mg/kg, or less than about 0.062 mg/kg, or less than about 0.060 mg/kg, or less than about 0.058 mg/kg, or less than about 0.056 mg/kg, or less than about 0.069 mg/kg, or less than about 0.054 mg/kg, or less than about 0.052 mg/kg, or less than about 0.050 mg/kg, or less than about 0.048 mg/kg, or less than about 0.046 mg/kg, or less than about 0.044 mg/kg, or less than about 0.042 mg/kg, or less than about 0.040 mg/kg, or less than about 0.038 mg/kg, or less than about 0.036 mg/kg, or less than about 0.034 mg/kg, or less than about 0.032 mg/kg, or less than about 0.030 mg/kg, or less than about 0.028 mg/kg, or less than about 0.026 mg/kg, or less than about 0.024 mg/kg, or less than about 0.022 mg/kg, or less than about 0.020 mg/kg, or less than about 0.018 mg/kg, or less than about 0.016 mg/kg, or less than about 0.014 mg/kg, or less than about 0.012 mg/kg, or less than about 0.01 mg/kg, or less than about 0.008 mg/kg, or less than about 0.006 mg/kg, or less than about 0.004 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.00025 mg/kg.
[00379] In certain preferred embodiments of the invention, the intrathecal M6G adult dose of the invention (i.e., the adult SAD dose of the M6G by the intrathecal route) is less than - -
about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg, or less than about 0.00004 mg, or less than about 0.00003 mg, or less than about 0.00002 mg, or less than about 0.00001 mg, or less than about 0.000009 mg, or less than about 0.000008 mg, or less than about 0.000007 mg, or less than about 0.000006 mg, or less than about 0.000005 mg, or less than about 0.000004 mg, or less than about 0.000003 mg, or less than about 0.000002 mg, or less than about 0.000001 mg.
[00380] In certain preferred embodiments of the invention, the intrathecal M6G dose of the invention (i.e., the SAD dose of the M6G by the intrathecal route) is less than about 0.001425 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.000007 mg/kg, or less than about 0.000005 mg/kg, or less than about 0.000003 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000005 mg/kg. [00381] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone adult dose of the invention (i.e., the adult SAD dose of the oxymorphone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.5 mg, or less than about 0.475 mg, or less than about 0.45 mg, or less than about 0.425 mg, or less than about 0.4 mg, or less than about 0.375, or less than about 0.35 mg, or less than about 0.325 mg, or less than about 0.3 mg, or less than about 0.275 mg, or less than about 0.25 mg, or less than about 0.225 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.125 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg.
[00382] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone adult dose of the invention (i.e., the adult SAD dose of the oxymorphone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.125 mg, or less than about 0.12 mg, or less than about 0.115 mg, or less than about 0.11 mg, or less than about 0.105 mg, or less than about 0.1 mg, or less than about 0.095 mg, or less than about 0.09 mg, or less than about 0.085 mg, or less than about 0.08 mg, or less than about 0.075 mg, or less than about 0.07 mg, or less than about 0.065 mg, or less than about 0.06 mg, or less than about 0.055 mg, or less than about 0.05 mg, or less than about 0.045 mg, or less than about 0.04 mg, or less than about 0.035 mg, or less than about 0.03 mg, or less than about 0.025 mg.
[00383] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone dose of the invention (i.e., the SAD dose of the oxymorphone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) is less than about 0.00714 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg.
[00384] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxymorphone dose of the invention (i.e., the SAD dose of the oxymorphone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.00178 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg.
[00385] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] oxymorphone adult dose of the invention (i.e., the adult SAD dose of the oxymorphone by the PCA [i.e., intravenous PCA route]) is less than about less than about 0.3 mg, or less than about 0.275 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.125 mg, or less than about 0.1 mg, or less than about 0.075 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.0075 mg, or less than about 0.005 mg, or less than about 0.0025 mg.
[00386] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] oxymorphone dose of the invention (i.e., the SAD dose of the oxymorphone by the PCA [i.e., intravenous PCA route]) is less than about 0.00428 mg/kg, or less than about - -
0.0042, or less than about 0.004 mg/kg, or less than about 0.0038 mg/kg, or less than about 0.0036 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00005, or less than about 0.000025 mg/kg.
[00387] In certain preferred embodiments of the invention, the intrathecal oxymorphone adult dose of the invention (i.e., the adult SAD dose of the oxymorphone by the intrathecal route) is less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.15 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg, or less than about 0.00004 mg, or less than about 0.00003 mg, or less than about 0.00002 mg, or less than about 0.00001 mg, or less than about 0.000009 mg, or less than about 0.000008 mg, or less than about 0.000007 mg, or less than about 0.000006 mg, or less than about 0.000005 mg, or less than about 0.000004 mg, or less than about 0.000003 mg, or less than about 0.000002 mg, or less than about 0.000001 mg.
[00388] In certain preferred embodiments of the invention, the intrathecal oxymorphone dose of the invention (i.e., the SAD dose of the oxymorphone by the intrathecal route) is - -
less than about 0.00714 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001425 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.000007 mg/kg, or less than about 0.000005 mg/kg, or less than about 0.000003 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000005 mg/kg.
[00389] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol adult dose of the invention (i.e., the adult SAD dose of the levorphanol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1 mg, or less than about 0.95 mg, or less than about 0.9 mg, or less than about 0.85 mg, or less than about 0.8 mg, or less than about 0.75 mg, or less than about 0.7 mg, or less than about 0.65 mg, or less than about 0.6 mg, or less than about 0.55 mg, or less than about 0.5 mg, or less than about 0.475 mg, or less than about 0.45 mg, or less than about 0.425 mg, or less than about 0.4 mg, or less than about 0.375, or less than about 0.35 mg, or less than about 0.325 mg, or less than about 0.3 mg, or less than about 0.275 mg, or less than about 0.25 mg, or less than about 0.225 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.125 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg.
[00390] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol adult dose of the invention (i.e., the adult SAD dose of the levorphanol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.0005 mg.
[00391] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol dose of the invention (i.e., the SAD dose of the levorphanol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.0142 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg. [00392] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural levorphanol dose of the invention (i.e., the SAD dose of the levorphanol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg.
[00393] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] levorphanol adult dose of the invention (i.e., the adult SAD dose of the levorphanol by the PCA [i.e., intravenous PCA route]) is less than about less than about 0.3 mg, or less than about 0.29 mg, or less than about 0.28 mg, or less than about 0.27 mg, or less than about 0.26 mg, or less than about 0.25 mg, or less than about 0.24 mg, or less than about 0.23 mg, or less than about 0.22 mg, or less than about 0.21 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg.
[00394] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] levorphanol dose of the invention (i.e., the SAD dose of the levorphanol by the PCA [i.e., intravenous PCA route]) is less than about 0.00428 mg/kg, or less than about 0.0042, or less than about 0.004 mg/kg, or less than about 0.0038 mg/kg, or less than about 0.0036 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00005, or less than about 0.000025 mg/kg.
[00395] In certain preferred embodiments of the invention, the intrathecal levorphanol adult dose of the invention (i.e., the adult SAD dose of the levorphanol by the intrathecal route) is less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg, or - -
less than about 0.00004 mg, or less than about 0.00003 mg, or less than about 0.00002 mg, or less than about 0.00001 mg, or less than about 0.000009 mg, or less than about 0.000008 mg, or less than about 0.000007 mg, or less than about 0.000006 mg, or less than about 0.000005 mg, or less than about 0.000004 mg, or less than about 0.000003 mg, or less than about 0.000002 mg, or less than about 0.000001 mg.
[00396] In certain preferred embodiments of the invention, the intrathecal levorphanol dose of the invention (i.e., the SAD dose of the levorphanol by the intrathecal route) is less than about 0.0029 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0027 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.0021 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.000007 mg/kg, or less than about 0.000005 mg/kg, or less than about 0.000003 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000005 mg/kg.
[00397] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan adult dose of the invention (i.e., the adult SAD dose of the racemorphan by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 5 mg, is less than about 4 mg, or is less than about 3 mg, or is less than about 2 mg, or less than about 1.95 mg, or less than about 1.9 mg, or less than about 1.85 mg, or less than about 1.8 mg, or less than about 1.75 mg, or less than about 1.7 mg, or less than about 1.65 mg, or less than about 1.6 mg, or less than about 1.55 mg, or less than about 1.5 mg, or less than about 1.45 mg, or less than about 1.4 mg, or less than about 1.35 mg, or less than about 1.3 mg, or less than about 1.25 mg, or less than about 1.2 mg, or less than about 1.15 mg, or less than about 1.1 mg, or less than about 1.05 mg, or less than about 1 mg, or less than about 0.95 mg, or less than about 0.9 mg, or less than about 0.85 mg, or less than about 0.8 mg, or less than about 0.75 mg, or less than about 0.7 mg, or less than about 0.65 mg, or less than about 0.6 mg, or less than about 0.55 mg, or less than about 0.5 mg, or less than about 0.475 mg, or less than about 0.45 mg, or less than about 0.425 mg, or less than about 0.4 mg, or less than about 0.375, or less than about 0.35 mg, or less than about 0.325 mg, or less than about 0.3 mg, or less than about 0.275 mg, or less than about 0.25 mg, or less than about 0.225 mg, or less than about 0.2 mg, or less than about 0.175 mg, or less than about 0.15 mg, or less than about 0.125 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg.
[00398] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan adult dose of the invention (i.e., the adult SAD dose of the racemorphan by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.83 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or is less than about 0.34 mg, or less than 0.33 mg, or less than 0.32 mg, or less than about 0.31 mg, or less than 0.3 mg, or less than 0.29 mg, or less than about 0.28 mg, or less than 0.27 mg, or less than 0.26 mg, or less than about 0.27 mg, or less than 0.26 mg, or less than 0.25 mg, or less than about 0.24 mg, or less than 0.23 mg, or less than 0.22 mg, or less than about 0.21 mg, or less than 0.2 mg, or less than 0.19 mg, or less than about 0.18 mg, or less than 0.17 mg, or less than 0.16 mg, or less than about 0.15 mg, or less than 0.14 mg, or less than 0.13 mg, or less than about 0.12 mg, or less than 0.11 mg, or less than 0.1 mg, or less than about 0.09 mg, or less than 0.08 mg, or less than 0.07 mg, or less than about 0.06 mg, or less than 0.05 mg, or less than 0.04 mg, or less than about 0.03 mg, or less than 0.02 mg, or less - -
than 0.01 mg, or less than about 0.009 mg, or less than 0.008 mg, or less than 0.007 mg, or less than about 0.006 mg, or less than 0.005 mg, or less than 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg.
[00399] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan dose of the invention (i.e., the SAD dose of the racemorphan by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.071 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.035 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.0142 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg.
[00400] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural racemorphan dose of the invention (i.e., the SAD dose of the racemorphan by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg.
[00401] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] racemorphan adult dose of the invention (i.e., the adult SAD dose of the racemorphan by the PCA [i.e., intravenous PCA route]) is less than about 1 mg, or less than 0.9 mg, or less than 0.8 mg, or less than 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.4 mg, or less than 0.39 mg, or less than 0.38 mg, or less than about 0.37 mg, or less than 0.36 mg, or less than 0.35 mg, or less than about 0.34 mg, or less than 0.33 mg, or less than 0.32 mg, or less than about 0.31 mg, or less than 0.3 mg, or less than 0.29 mg, or less than about 0.28 mg, or less than 0.27 mg, or less than 0.26 mg, or less than about 0.27 mg, or less than 0.26 mg, or less than 0.25 mg, or less than about 0.24 mg, or less than 0.23 mg, or less than 0.22 mg, or less than about 0.21 mg, or less than 0.2 mg, or less than 0.19 mg, or less than about 0.18 mg, or less than 0.17 mg, or less than 0.16 mg, or less than about 0.15 mg, or less than 0.14 mg, or less than 0.13 mg, or less than about 0.12 mg, or less than 0.11 mg, or less than 0.1 mg, or less than about 0.09 mg, or less than 0.08 mg, or less than 0.07 mg, or less than about 0.06 mg, or less than 0.05 mg, or less than 0.04 mg, or less than about 0.03 mg, or less than 0.02 mg, or less than 0.01 mg, or less than about 0.009 mg, or less than 0.008 mg, or less than 0.007 mg, or less than about 0.006 mg, or less than 0.005 mg, or less than 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg.
[00402] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] racemorphan dose of the invention (i.e., the SAD dose of the racemorphan by the -1 -
PCA [i.e., intravenous PCA route]) is less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than 0.0045 mg/kg, or less than about 0.00428 mg/kg, or less than about 0.0042, or less than about 0.004 mg/kg, or less than about 0.0038 mg/kg, or less than about 0.0036 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00005, or less than about 0.000025 mg/kg.
[00403] In certain preferred embodiments of the invention, the intrathecal racemorphan adult dose of the invention (i.e., the adult SAD dose of the racemorphan by the intrathecal route) is less than about 0.4 mg, or less than about 0.38 mg, or less than about 0.4 mg, or less than about 0.38 mg, or less than about 0.36 mg, or less than about 0.34 mg, or less than about 0.32 mg, or less than about 0.3 mg, or less than about 0.28 mg, or less than about 0.26 mg, or less than about 0.24 mg, or less than about 0.22 mg, or less than about 0.21 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg, or less than about 0.00004 mg, or less than about 0.00003 mg, or less than about 0.00002 mg, or less than about 0.00001 mg, or less than about 0.000009 mg, or less than about 0.000008 mg, or less than about 0.000007 mg, or less than about 0.000006 mg, or less than about 0.000005 mg, or less than about 0.000004 mg, or less than about 0.000003 mg, or less than about 0.000002 mg, or less than about 0.000001 mg.
[00404] In certain preferred embodiments of the invention, the intrathecal racemorphan dose of the invention (i.e., the SAD dose of the racemorphan by the intrathecal route) is less than about 0.0057 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0057 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0029 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0027 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0025 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0023 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.0021 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.000007 mg/kg, or less than about 0.000005 mg/kg, or less than about 0.000003 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000005 mg/kg. - -
[00405] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone adult dose of the invention (i.e., the adult SAD dose of the oxycodone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5.75 mg, or less than about 5.5 mg, or less than about 5.25 mg, or less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg.
[00406] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone adult dose of the invention (i.e., the adult SAD dose of the oxycodone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg.
[00407] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone dose of the invention (i.e., the SAD dose of the oxycodone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.142 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.086 mg/kg, or less than about 0.085 mg/kg, or less than about 0.08 mg/kg, or less than about 0.0775 mg/kg, or less than about 0.075 mg/kg, or less than about 0.0725 mg/kg, or less than about 0.07 mg/kg, or less than about 0.0675 mg/kg, or less than about 0.065 mg/kg, or less than about 0.0625 mg/kg, or less than about 0.06 mg/kg, or less than about 0.0575 mg/kg, or less than about 0.05 mg/kg, or less than about 0.0525 mg/kg, or less than about 0.05 mg/kg, or less than about 0.0475 mg/kg, or less than about 0.045 mg/kg, or less than about 0.0425 mg/kg, or less than about 0.04 mg/kg, or less than about 0.0375 mg/kg, or less than about 0.035 mg/kg, or less than about 0.0325 mg/kg, or less than about 0.03 mg/kg, or less than about 0.0275 mg/kg, or less than about 0.025 mg/kg, or less than about 0.0225 mg/kg, or less than about 0.02 mg/kg, or less than about 0.0175 mg/kg, or less than about 0.015 mg/kg, or less than about 0.0125 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg. [00408] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural oxycodone dose of the invention (i.e., the SAD dose of the oxycodone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg or less than about 0.020 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg.
[00409] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] oxycodone adult dose of the invention (i.e., the adult SAD dose of the oxycodone by the PCA [i.e., intravenous PCA route]) is less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 4 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1.1 mg, or less than about less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than 0.01 mg, or less than about - -
0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg.
[00410] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] oxycodone dose of the invention (i.e., the SAD dose of the oxycodone by the PCA [i.e., intravenous PCA route]) is less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00002 mg/kg.
[00411] In certain preferred embodiments of the invention, the intrathecal oxycodone adult dose of the invention (i.e., the adult SAD dose of the oxycodone by the intrathecal route) is less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.4 mg, or less than about 0.35 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, - -
or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg, or less than about 0.00004 mg, or less than about 0.00003 mg, or less than about 0.00002 mg, or less than about 0.00001 mg, or less than about 0.000009 mg, or less than about 0.000008 mg, or less than about 0.000007 mg, or less than about 0.000006 mg, or less than about 0.000005 mg, or less than about 0.000004 mg, or less than about 0.000003 mg, or less than about 0.000002 mg, or less than about 0.000001 mg.
[00412] In certain preferred embodiments of the invention, the intrathecal oxycodone dose of the invention (i.e., the SAD dose of the oxycodone by the intrathecal route) is less than about 0.0072 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0033 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001425 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or - -
less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.000007 mg/kg, or less than about 0.000005 mg/kg, or less than about 0.000003 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000005 mg/kg.
[00413] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone adult dose of the invention (i.e., the adult SAD dose of the methadone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5.75 mg, or less than about 5.5 mg, or less than about 5.25 mg, or less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg.
[00414] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone adult dose of the invention (i.e., the adult SAD dose of the methadone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less - -
than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg.
[00415] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone dose of the invention (i.e., the SAD dose of the methadone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.142 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.086 mg/kg, or less than about 0.085 mg/kg, or less than about 0.08 mg/kg, or less than about 0.0775 mg/kg, or less than about 0.075 mg/kg, or less than about 0.0725 mg/kg, or less than about 0.07 mg/kg, or less than about 0.0675 mg/kg, or less than about 0.065 mg/kg, or less than about 0.0625 mg/kg, or less than about 0.06 mg/kg, or less than about 0.0575 mg/kg, or less than about 0.05 mg/kg, or less than about 0.0525 mg/kg, or less than about 0.05 mg/kg, or less than about 0.0475 mg/kg, or less than about 0.045 mg/kg, or less than about 0.0425 mg/kg, or less than about 0.04 mg/kg, or less than about 0.0375 mg/kg, or less than about 0.035 mg/kg, or less than about 0.0325 mg/kg, or less than about 0.03 mg/kg, or less than about 0.0275 mg/kg, or less than about 0.025 mg/kg, or less than about 0.0225 mg/kg, or less than about 0.02 mg/kg, or less than about 0.0175 mg/kg, or less than about 0.015 mg/kg, or less than about 0.0125 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about - -
0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg.
[00416] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural methadone dose of the invention (i.e., the SAD dose of the methadone by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg or less than about 0.020 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg.
[00417] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] methadone adult dose of the invention (i.e., the adult SAD dose of the methadone by the PCA [i.e., intravenous PCA route]) is less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 4 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1.1 mg, or less than about less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less - -
than about 0.4 mg, or less than 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08 mg, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg.
[00418] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] methadone dose of the invention (i.e., the SAD dose of the methadone by the PCA [i.e., intravenous PCA route]) is less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or less than about 0.026 mg/kg, or less than about 0.025 mg/kg, or less than about 0.024 mg/kg, or less than about 0.023 mg/kg, or less than about 0.022 mg/kg, or less than about 0.021 mg/kg, or less than about 0.02 mg/kg, or less than about 0.019 mg/kg, or less than about 0.018 mg/kg, or less than about 0.017 mg/kg, or less than about 0.016 mg/kg, or less than about 0.015 mg/kg, or less than about 0.014 mg/kg, or less than about 0.013 mg/kg, or less than about 0.012 mg/kg, or less than about 0.011 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg, or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00002 mg/kg.
[00419] In certain preferred embodiments of the invention, the intrathecal methadone adult dose of the invention (i.e., the adult SAD dose of the methadone by the intrathecal route) is less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.5 mg, or less than about 0.45 mg, or less than about 0.4 mg, or less than about 0.35 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.19 mg, or less than about 0.18 mg, or less than about 0.17 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg, or less than about 0.00004 mg, or less than about 0.00003 mg, or less than about 0.00002 mg, or less than about 0.00001 mg, or less than about 0.000009 mg, or less than about 0.000008 mg, or less than about 0.000007 mg, or less than about 0.000006 mg, or less than about 0.000005 mg, or less than about 0.000004 mg, or less than about 0.000003 mg, or less than about 0.000002 mg, or less than about 0.000001 mg.
[00420] In certain preferred embodiments of the invention, the intrathecal methadone dose of the invention (i.e., the SAD dose of the methadone by the intrathecal route) is less than about 0.0072 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0033 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001425 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg, or less than about 0.0000009 mg/kg, or less than about 0.000007 mg/kg, or less than about 0.000005 mg/kg, or less than about 0.000003 mg/kg, or less than about 0.000001 mg/kg, or less than about 0.0000008 mg/kg, or less than about 0.0000005 mg/kg.
[00421] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol adult dose of the invention (i.e., the adult SAD dose of the tramadol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 24 mg, or less than about 22 mg, or less than about 20, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg, or less than about 0.25 mg.
[00422] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol adult dose of the invention (i.e., the adult SAD dose of the tramadol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about 2 mg, or less than about 1.75 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.75 mg, or less than about 0.5 mg, or less than about 0.25 mg.
[00423] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol dose of the invention (i.e., the SAD dose of the tramadol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.42 mg/kg, or less than about 0.40 mg/kg, or less than about 0.38 mg/kg, or less than about 0.36 mg/kg, or less than about 0.34 mg/kg, or less than about 0.32 mg/kg, or less than about 0.3 mg/kg, or less than about 0.28 mg/kg, or less than about 0.26 mg/kg, or less than about 0.24 mg/kg, or less than about 0.22 mg/kg, or less than about 0.210 mg/kg, or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.05 mg/kg, or less than about 0.04 mg/kg, or less than about 0.03 mg/kg, or less than about 0.02 mg/kg, or less than about 0.01 mg/kg, or less than about 0.0075 mg/kg, or less than about 0.005 mg/kg, or less than about 0.025 mg/kg.
[00424] In certain preferred embodiments of the invention, the intravenous [excluding
PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tramadol dose of the invention (i.e., the SAD dose of the tramadol by the intravenous [excluding PCA], intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for each hour of the intended duration of effect is less than about 0.07 mg/kg, or less than about 0.0675 mg/kg, or less than about 0.065 mg/kg, or less than about 0.0625 mg/kg or less than about 0.06 mg/kg, or less than about 0.0575 mg/kg, or less than about 0.055 mg/kg or less than about 0.0525 mg/kg, or less than about 0.05 mg/kg, or less than about 0.0475 mg/kg or less than about 0.045 mg/kg, or less than about 0.0425 mg/kg, or less than about 0.04 mg/kg or less than about 0.0375 mg/kg, or less than about 0.035 mg/kg, or less than about 0.0325 mg/kg or less than about 0.03 mg/kg, or less than about 0.0275 mg/kg, or less than about 0.025 mg/kg or less than - -
about 0.02 mg/kg, or less than about 0.0175 mg/kg, or less than about 0.015 mg/kg, or less than about 0.0125 mg/kg or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg or less than about 0.007 mg/kg, or less than about 0.006 mg/kg, or less than about 0.005 mg/kg or less than about 0.004 mg/kg, or less than about 0.003 mg/kg, or less than about 0.002 mg/kg or less than about 0.001 mg/kg, or less than about 0.0005 mg/kg.
[00425] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] tramadol adult dose of the invention (i.e., the adult SAD dose of the tramadol by the PCA [i.e., intravenous PCA route]) is less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, less than about 6 mg, or less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.5 mg, or less than about 3.25 mg, or less than about 3 mg, or less than about 2.75 mg, or less than about 2.5 mg, or less than about 2.25 mg, or less than about less than about 2 mg, or less than about 1.75 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than 0.75, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.4 mg, or less than about 0.3 mg, or less than about 0.25 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.05 mg, or less than about 0.025 mg.
[00426] In certain preferred embodiments of the invention, the PCA [i.e., intravenous
PCA] tramadol dose of the invention (i.e., the SAD dose of the tramadol by the PCA [i.e., intravenous PCA route]) is less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.10 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or less than about 0.072 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.066 mg/kg, or less than about 0.064 mg/kg, or less than about 0.062 mg/kg, or less than about 0.060 mg/kg, or less than about 0.058 mg/kg, or less than about 0.056 mg/kg, or less than about 0.069 mg/kg, or less than about 0.054 mg/kg, or less than about 0.052 mg/kg, or less than about 0.050 mg/kg, or less than about 0.048 mg/kg, or less than about 0.046 mg/kg, or less than about 0.044 mg/kg, or less than about 0.042 mg/kg, or less than about 0.040 mg/kg, or less than about 0.038 mg/kg, or less than about 0.036 mg/kg, or less than about 0.034 mg/kg, or less than about 0.032 mg/kg, or less than about 0.030 mg/kg, or less than about 0.028 mg/kg, or less than about 0.026 mg/kg, or less than about 0.024 mg/kg, or less than about 0.022 mg/kg, or less than about 0.020 mg/kg, or less than about 0.018 mg/kg, or less than about 0.016 mg/kg, or less than about 0.014 mg/kg, or less than about 0.012 mg/kg, or less than about 0.01 mg/kg, or less than about 0.008 mg/kg, or less than about 0.006 mg/kg, or less than about 0.004 mg/kg, or less than about 0.002 mg/kg, or less than about 0.001 mg/kg, or less than about 0.00075 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.00025 mg/kg.
[00427] In certain preferred embodiments of the invention, the intrathecal tramadol adult dose of the invention (i.e., the adult SAD dose of the tramadol by the intrathecal route) is less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1.25 mg, or less than about 1 mg, or less than about 0.9 mg, or less than about 0.8 mg, or less than about 0.7 mg, or less than about 0.6 mg, or less than about 0.5 mg, or less than about 0.3 mg, or less than about 0.2 mg, or less than about 0.1 mg, or less than about 0.16 mg, or less than about 0.15 mg, or less than about 0.14 mg, or less than about 0.13 mg, or less than about 0.12 mg, or less than about 0.11 mg, or less than about 0.1 mg, or less than about 0.09 mg, or less than about 0.08, or less than about 0.07 mg, or less than about 0.06 mg, or less than about 0.05 mg, or less than about 0.04 mg, or less than about 0.03 mg, or less than about 0.02 mg, or less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg, or less than about 0.0008 mg, or less than about 0.0007 mg, or less than about 0.0006 mg, or less than about 0.0005 mg, or less than about 0.0004 mg, or less than about 0.0003 mg, or less than about 0.0002 mg, or less than about 0.0001 mg, or less than about 0.00009 mg, or less than about 0.00008 mg, or less than about 0.00007 mg, or less than about 0.00006 mg, or less than about 0.00005 mg.
[00428] In certain preferred embodiments of the invention, the intrathecal tramadol dose of the invention (i.e., the SAD dose of the tramadol by the intrathecal route) is less than about 0.072 mg/kg, or less than about 0.071 mg/kg, or less than about 0.07 mg/kg, or less than about 0.065 mg/kg, or less than about 0.06 mg/kg, or less than about 0.055 mg/kg, or - -
less than about 0.05 mg/kg, or less than about 0.045 mg/kg, or less than about 0.04 mg/kg, or less than about 0.035 mg/kg, or less than about 0.03 mg/kg, or less than about 0.03 mg/kg, or less than about 0.025 mg/kg, or less than about 0.02 mg/kg, or less than about 0.015 mg/kg, or less than about 0.01 mg/kg, or less than about 0.009 mg/kg, or less than about 0.008 mg/kg, or less than about 0.0072 mg/kg, or less than about 0.0071 mg/kg, or less than about 0.007 mg/kg, or less than about 0.0065 mg/kg, or less than about 0.006 mg/kg, or less than about 0.0055 mg/kg, or less than about 0.005 mg/kg, or less than about 0.0045 mg/kg, or less than about 0.004 mg/kg, or less than about 0.0035 mg/kg, or less than about 0.0034 mg/kg, or less than about 0.0033 mg/kg, or less than about 0.0032 mg/kg, or less than about 0.003 mg/kg, or less than about 0.0028 mg/kg, or less than about 0.0026 mg/kg, or less than about 0.0024 mg/kg, or less than about 0.0022 mg/kg, or less than about 0.002 mg/kg, or less than about 0.0019 mg/kg, or less than about 0.0018 mg/kg, or less than about 0.0017 mg/kg, or less than about 0.0016 mg/kg, or less than about 0.0015 mg/kg, or less than about 0.001425 mg/kg, or less than about 0.0014 mg/kg, or less than about 0.0013 mg/kg, or less than about 0.0012 mg/kg, or less than about 0.0011 mg/kg, or less than about 0.001 mg/kg, or less than about 0.0009 mg/kg, or less than about 0.0008 mg/kg, or less than about 0.0007 mg/kg, or less than about 0.0006 mg/kg, or less than about 0.0005 mg/kg, or less than about 0.0004 mg/kg, or less than about 0.0003 mg/kg, or less than about 0.0002 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less than about 0.00004 mg/kg, or less than about 0.00003 mg/kg, or less than about 0.00002 mg/kg, or less than about 0.00001 mg/kg.
[00429] In certain preferred embodiments, the aforementioned parenteral SAD doses of selected combination analgesic chosen from the among dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam, lornoxicam, levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan, tramadol, acetaminophen, propacetamol and nitroparacetamol are for the treatment of: (i) pain of mild intensity; or (ii) pain of moderate intensity; (iii) or pain of moderate or greater intensity; or (iv) pain of moderately severe intensity; or (v) pain of severe intensity or (vi) for the treatment of pain in children, in which case the aforementioned dose is multiplied by the weight of the child (in kilograms) and then divided by 70 kilograms to provide the dose for the child in milligrams (e.g., if the adult dose in a particular embodiment is 5 mg and the child weighs 35 kg, then the dose for the child for the said embodiments is 2.5 mg).
[00430J The pharmaceutical composition can be administered in varying amounts, volumes and doses, depending on the method of administration, route of administration and patient characteristics (for example, IV bolus; IV slow injection; IV brief infusion; IV prolonged infusion; IV continuous infusion; subcutaneous [SC]) injection; SC infusion; continuous SC infusion; PCA administration; PCEA administration; intrathecal and epidural injections; intrathecal and epidural infusions; IM injection; cerebrospinal fluid [CSF] volume; age, weight, and fluid status of patient; body mass; general health and nutrition; cachexia; pharmacokinetics; pharmacodynamics; nature and severity of pain, fever and/or inflammation; nature of surgical procedure; use of concomitant medications, including other analgesics; co-morbidities; availability of venous access; availability of skilled medical personnel; availability of sterile conditions, etc).
[00431] All volumes of administration of the selected combination analgesic given as a
SAD of the selected combination analgesic compatible with acceptable medical practice are contemplated by the invention.
[00432] In a preferred embodiment, the bolus IV injection volume of a single therapeutic injection dose (excluding slow IV injection, brief or continuous IV infusions) does not exceed about 100 mL, or about 75 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL. In a particularly preferred embodiment, the aforementioned volume does not exceed about 10 mL, or about 5 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
[00433] In a preferred embodiment, the slow IV injection, brief or continuous IV infusions hourly volume does not exceed about 1000 mL, or about 500 mL, or about 250 mL, or about 200 mL, or about 150 mL, or about 100 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL. In a particularly preferred embodiments, the aforementioned volume - -
does not exceed about 250 mL, or about 200 mL, or about 150 mL, or about 100 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL.
[00434] In a preferred embodiment, the SC injection volume of a single therapeutic injection dose (excluding brief or continuous subcutaneous infusion) does not exceed about 5 mL or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
[00435] In a particularly preferred embodiment, the SC injection volume of a single therapeutic injection dose (excluding brief or continuous subcutaneous infusion) does not exceed about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL. In a particularly preferred embodiments, the aforementioned volume does not exceed about 100 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
[00436] In a particularly preferred embodiment, the brief or continuous SC infusion hourly volume does not exceed about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
[00437] In a preferred embodiment, the IM injection volume of a single therapeutic dose does not exceed about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL. In particularly preferred embodiments, the aforementioned volume does not exceed about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
[00438] In a preferred embodiment, the intrathecal volume (excluding intrathecal infusions) of a single therapeutic dose does not exceed about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL. In a particularly preferred embodiments, the aforementioned volume does not exceed about 0 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
[00439] In a preferred embodiment, the hourly intrathecal infusion volume does not exceed about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.4 mL, or about 0.3 mL, or about 0.2 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL. In a particularly preferred embodiments, the aforementioned volume does not exceed about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.4 mL, or about 0.3 mL, or about 0.2 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
[00440] In a preferred embodiment, the epidural volume (excluding epidural infusions) of a single therapeutic dose does not exceed about 100 mL, or about 80 mL, or about 60 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL. In a particularly preferred embodiments, the aforementioned volume does not exceed about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
[00441] In a preferred embodiment, the hourly epidural infusion volume does not exceed about 30 mL, or about 20 mL, or about 15 mL, or about 12 mL, or about 10 mL, or about 8 mL, or about 6 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL. In a particularly preferred embodiments, the aforementioned volume does not exceed about 15 mL, or about 12 mL, or about 10 mL, or about 8 mL, or about 6 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
[00442] In certain preferred embodiments, when the combination analgesic of the invention includes ethylenediamine and/or piperazine, the invention specifically excludes one of more NSAIDS selected from the group of compounds comprising ketoprofen, dexketoprofen, piroxicam and tenoxicam. - -
[00443] In certain preferred embodiments, the invention specifically excludes one of more
NSAIDS selected from the group of compounds comprising dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof.
[00444] In certain preferred embodiments, the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof.
[00445] In certain preferred embodiments, the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with hydroxypropyl-beta-cylcodextrin.
[00446] In certain preferred embodiments, the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with beta-cylcodextrin.
[00447] In certain preferred embodiments, the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with cylcodextrins.
[00448] In certain preferred embodiments, the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with hydroxypropyl-beta- cylcodextrin.
[00449] In certain preferred embodiments, the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with beta-cylcodextrin.
[00450] In certain preferred embodiments, the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with cylcodextrins.
[00451] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with hydroxypropyl- beta-cylcodextrin. [00452] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with beta- cylcodextrin.
[00453] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with cylcodextrins.
[00454] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said SAD of the combination analgesics is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
[00455] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said SAD of combination analgesics is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) and preceded by a loading dose of the one or more combination analgesics by the same route of administration, said loading dose administered using at least the minimum approved or recommended dose of said combination analgesics by said route.
[00456] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said combination analgesics is not given by bolus injection.
[00457] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the combination analgesics dosage form is devoid of ethylenediamine.
[00458] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, - -
enantiomeric excess, and mixtures thereof when the combination analgesics dosage form is devoid of piperazine.
[00459] In certain preferred embodiments, the invention specifically excludes combination analgesics or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the combination analgesics dosage form is devoid of glycine.
[00460] In certain preferred embodiments, the invention specifically excludes NSAIDS and acetaminophen or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said NSAIDS or acetaminophen is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
[00461] In certain preferred embodiments, the invention specifically excludes NSAIDS and acetaminophen or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said NSAIDS or acetaminophen is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) and preceded by a loading dose of the said NSAID or acetaminophen by the same route of administration, said loading dose administered using at least the minimum approved or recommended dose of said combination analgesics by said route.
[00462] In certain preferred embodiments, the invention specifically excludes NSAIDS and acetaminophen or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said NSAIDS and acetaminophen is not given by bolus injection.
[00463] In certain preferred embodiments, the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAID dosage form is devoid of ethylenediamine.
[00464] In certain preferred embodiments, the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAIDS dosage form is devoid of piperazine. - -
[00465] In certain preferred embodiments, the invention specifically excludes NSAIDS or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAIDS dosage form is devoid of glycine.
[00466] In certain preferred embodiments of the invention, some or all of the embodiments, specifications and claims applicable to NSAIDS selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof are applicable or also applicable to other NSAIDS (ie., COX-2 and/or COX-I inhibitors), including, without limitation, compounds selected from the group comprising aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, celecoxib, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, flufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen, indomethacin, isonixin, isoxicam, ketorolac, ketoprofen, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, mofebutazone, nabumetone, naproxen, nifenazone, niflumic acid, nimesulide, oxaprozin, parecoxib, piketoprofen, piroxicam, pirprofen, pranoprofen, proquazone, rofecoxib, salicylic acid, salsalate, sulindac, suprofen, tenidap, tetridamine, tiaprofenic acid, tenoxicam, tolfenamic acid, tolmetin, valdecoxib and zaltoprofen, in racemic, enatiomeric or enantiomeric excess, pharmaceutically acceptable salts thereof of mixture thereof, where in the ULD of the NSAID is given at a dose not to exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose or daily dose of the NSAID by the same route of administration or by the oral route of administration.
[00467] In certain preferred embodiments of the invention, some or all of the embodiments, specifications and claims applicable to opioids selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof, in - -
racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof are applicable or also applicable to other opioids, including, without limitation, compounds selected from the group comprising opioid receptor agonists (i.e., mu (μ), delta (δ), kappa (K) and /or nociceptin/orphanin FQ (N/OFQ) opioid receptors), their subtypes and splice variants, including alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, brifentanil, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levoφhanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmoφhine, metopon, mirfentanil, moφhine, moφhine-6-glucuronide (M6G), myrophine, nalbuphine, narceine, nicomoφhine, norlevoφhanol, normethadone, naloφhine, nociceptin/oφhanin FQ (N/OFQ), normoφhine, noφipanone, ohmefentanyl, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, pholcodine, piminodine, piritramide, propheptazine, promedol, profadol, properidine, propiram, propoxyphene, racemoφhan, remifentanil, sufentanil, tapentadol, tramadol, trefentanil, tilidine, nalbuphine, or an opioid agonist having the same pentacyclic nucleus as nalmefene, naltrexone, buprenoφhine, levoφhanol, meptazinol, pentazocine, dezocine, any opioid having agonist activity at an opioid receptor belonging to the phenanthrene, moφhinan, benzomoφhan, methadone, phenylpiperidine, propionanilide 4- anilidopiperidine, 4-aryl piperidines, and 4-Heteroarylpiperidines class, any opioid having agonist activity at an opioid receptor having the same pentacyclic nucleus as nalmefene, naltrexone, buprenoφhine, levoφhanol, meptazinol, pentazocine and dezocine, and nitric-oxide donating opioids in racemic, enatiomeric or enantiomeric excess, pharmaceutically acceptable salts thereof of mixture thereof. In certain preferred embodiments, the invention includes a method and pharmaceutical compositions for treating or preventing pain, inflammation, and/or fever in a subject in need of such treatment, comprising administering a pharmaceutical composition comprising: (i) a - -
subanalgesic dose (SAD) of the selected combination analgesics comprising at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (ii) an aforementioned intravenous, IV PCA, intramuscular, subcutaneous, intra-articular, local tissue infiltration, epidural or intrathecal SAD dose of the invention; and (iii) a dosage form suitable for intravenous, IV PCA, intramuscular, subcutaneous, intra-articular, local tissue infiltration, epidural or intrathecal administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved after first administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved after multiple dose administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved after intravenous, IV PCA, intramuscular, subcutaneous, intra-articular, local tissue infiltration, epidural or intrathecal administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of moderate intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of at least moderate intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of moderately severe intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of severe intensity. In certain preferred embodiments, some or all of - -
the specifications and claims of the invention are achieved in patients with acute pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with breakthrough pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with acute exacerbations of chronic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with cancer pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with chronic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with neuropathic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with fever. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with inflammation.
[00469] In certain preferred embodiments of the invention, the selected combination analgesic given as a SAD of the selected combination analgesic is administered only by patient controlled (intravenous) analgesia (PCA) or patient controlled epidural analgesia (PCEA).
[00470] The methods and compositions described herein are useful for treating a wide range of specific types of pain including acute pain, subacute pain, chronic pain, cancer pain, breakthrough pain, neuropathic pain, nociceptive pain, visceral pain, idiopathic pain, inflammatory pain, non-inflammatory pain. Nonlimiting examples of acute pain include peri-operative pain, postsurgical pain, headache, acute low back pain, fractures, strains and sprains, ligament pain, cystitis, post-traumatic pain, burn pain, procedure related pain, and renal colic. Nonlimiting examples of chronic pain include cancer pain, osteoarthritis, fibromyalgia, low back pain, idiopathic pain, rheumatoid arthritis, bursitis, myofascial pain and the like. Nonlimiting examples of neuropathic pain include postherpetic neuralgia, trigeminal neuralgia, painful diabetic neuropathy, pain HIV associated neuropathy, painful polyneuropathy, phantom limb pain, stump pain, spinal cord injury pain, post-stroke pain, central pain and the like.
[00471] In some particularly preferred embodiments of the invention, the SAD of the selected combination analgesic chosen is for the treatment of fever, acute pain (e.g., - -
postsurgical pain, procedure related pain, renal colic, posttraumatic pain, headache), breakthrough pain and acute exacerbations of chronic pain.
[00472] In some particularly preferred embodiments of the invention, the SAD of the selected combination analgesic chosen is for use in patients who are generally expected to have an established venous access through a catheter.
[00473] In some particularly preferred embodiments of the invention, the SAD of the selected combination analgesic chosen is for use in the treatment of pain, inflammation and fever in patients for whom standard of care generally requires hospitalization or retention in a medically supervised facility during the period of treatment with the pharmaceutical composition and methods of the invention.
[00474] The term "analgesic effectiveness" is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, along with a tolerable level of side effects, as determined by the human patient.
[00475] The term "therapeutic effectiveness" is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, fever and/or inflammation, along with a tolerable level of side effects, as determined by the human patient.
[00476] The term "effectiveness" is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, fever and/or inflammation, along with a tolerable level of side effects, as determined by the human patient.
[00477] The pharmaceutical composition can be administered in varying amounts and volumes. Thus, for example, the method of the invention may comprise administering, to a subject in need of an analgesic, anti-inflammatory or anti-pyretic treatment, a subanalgesic dose (SAD) of the selected combination analgesic comprising: (i) a pharmaceutical composition of at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group comprising levorphanol, methadone, - -
moφhine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; plus (ii) as required, water for injection, saline, glucose solutions, ringer's lactate, pH adjustment agents, additional excipients, buffers, surfactants, preservatives and the like.
[00478] Administration of the two or more SAD of the composition can be via different parenteral routes.
[00479] The two or more SAD of the composition may be administered as a single pharmaceutical composition. That is, the two or more SAD of the composition may be formulated together so that both active agents are contained in one pharmaceutical compositions. For example, the two or more SAD of the composition may be formulated into a single vial, ampoule or prefilled syringe, mixed together into a parenteral delivery system (e.g., a cassette, cartridge, volume control set, minibag, large volume parenteral, bottle, etc) or into a unit dosage form. Alternatively, the two or more SAD of the composition may be administered separately (for example through the same vein but separate containers, or through different veins or through different parenteral routes of administration. The two or more SAD of the composition may be administered sequentially, simultaneously, contemporaneously, or using a different dosing frequency and dosing schedule for each, provided that are the two or more SAD of the composition are present in systemic circulation at quantifiable levels for at least part of the dosing period or treatment period.
[00480] In some embodiments, the subanalgesic dose (SAD) of the two or more compounds of the invention are able to independently exert analgesia, despite their subanalgesic doses.
[00481] In some embodiments, one , or more or all of the embodiments and specifications of the invention referring to SAD are applicable to analgesic doses.
[00482] Preferably the two or more SAD of the selected analgesics are administered by the same route of administration. It is further understood that the various embodiments of the method of the present invention may utilize each of the various composition embodiments described herein. - -
Common Parenteral Routes of Administration
[00483] Administration of the present invention can be via any parenteral route of administration. Non-limiting examples of suitable parenteral routes of administration are described in general terms as follows. Each of the following routes of administration can be used in the present invention, in particular in each of the specific embodiments described.
[00484] IM Administration. Once a popular method of drug administration, the intramuscular (IM) route is used considerably less frequently today due to improved availability of oral drugs and due to the ease of intravenous administration. This method of drug administration involves injecting drug directly into muscle mass, from where drug will gradually be absorbed systemically. For drugs that are not irritating when given by the IM route which require only a single injection, the IM route is still a viable route of administration, particularly in the outpatient setting or where strict aseptic conditions cannot be assured. When repeated administration is required or a rapid and reliable onset is desired, the intravenous route is preferred as repeated IM administration can be painful and inconvenient. Commonly the deltoid, gluteus maximus and vastus lateralis are sites for IM injection. The tolerability of IM administration is partly a function of the dose and the injection volume, both of which are reduced by SAD selected combination analgesics of the invention. Additionally, IM administration is particularly attractive in the ambulatory care/out-patient setting, where venous access is lacking or impractical, and in settings where sterility cannot be absolutely assured. The reduced dose and volume of the SAD of the invention particularly facilitate deltoid injections which are more convenient, more socially acceptable and provide more reliable pharmacokinetics and clinical effects that injection into the gluteus maximus.
[00485] Subcutaneous Administration involves injection into the subcutaneous fatty tissue under the skin. It can be used for the intermittent administration and self-administration of insulin and other medicines. In a small number of patients, particularly outpatients, this route is also used for the continuous or intermittent administration of drugs, usually with a programmable subcutaneous infusion device.
[00486] Epidural and Intrathecal Administration. Epidural and intrathecal infusions can provide effective analgesia, but require skilled personnel (usually an anesthetist) to put the systems in place. Catheters can be placed at any level of the spinal cord, although - -
most commonly these techniques are used for pain in the lower part of the body. Epidural and intrathecal routes of administration are advantageous for difficult abdominal or pelvic pain. For short term use, epidural catheters can be placed percutaneously, and fixed either by secure taping or subcutaneous tunnelling. The drugs can then be delivered through a small pump or a syringe driver. Subjects can be ambulant and managed at home with these systems. However the treatment team must have the necessary training, knowledge and support. In patients with a longer prognosis, but who have a continuing source of pain, intrathecal systems, which can be fully implantable, have many advantages. These offer great freedom to the patient, as there is no external equipment and the pump only needs to be refilled every few weeks. Some of the pumps are programmable and offer great flexibility. In some preferred embodiments, epidural and especially intrathecal doses of selected combination analgesics can be lower than intravenous doses. Epidural and intrathecal administration of selected combination analgesics can be also be used in conjunction with intravenous selected combination analgesics to provide additive or synergistic analgesia. Patient-controlled epidural analgesia is abbreviated "PCEA".
[00487] Intraarticular Administration. This method of administration can be used to provide analgesic and anti-inflammatory drugs directly into affected joints to relieve pain and inflammation, usually due to surgery, osteoarthritis or joint trauma.
[00488] Surgical site or open wound. This method of administration can be used when localized attenuation of pain or inflammation is deemed desirable and is achieved by topical, dermal administration or infiltration of a dose to a surgical site or open wound. The term "infiltration", "local infiltration", "tissue infiltration" and "local tissue infiltration" shall mean administration into a discrete surgical site, open wound or at the location of pain in a human or animal.
Common Methods of Intravenous Administration
[00489] IV Drug Administration. The mode of IV drug administration depends on the particular selected combination analgesics used, the patient's condition, and the desired clinical effects of the selected combination analgesics. The four primary modes of IV drug administration are continuous infusion, intermittent infusion, direct injection, and patient-controlled analgesia. - -
[00490] Continuous infusion typically refers to the admixture of a drug in a large volume of solution that is infused continuously over several hours to several days. The solution container is connected to an administration set, and the solubilized drug is infused through the venous access. The infusion may be administered by gravity feed or by use of electronic infusion control pump to deliver the drug accurately. Typically, continuous infusions can be used when the drug is highly diluted and constant plasma drug concentration should be maintained. Alternatively, continuous infusion can be used where large volumes of fluids and electrolytes need to be replenished along with the administration of the selected combination analgesics. Among the disadvantages with continuous infusion are possible fluid overload and potential incompatibilities between the infusion and other IV drugs administered through the same venous access device. Patient comfort may be compromised and patient mobility restricted.
[00491] Intermittent infusion refers to the administration of the drug as a small volume of fluid, typically 25 to 250 mL, and infused over, for example, 15 to 120 minutes at periodic intervals. Among the advantages of the intermittent method are the ability of the drug to produce higher peak blood concentrations at periodic intervals (compared with a continuous infusion), decreased risk of fluid overload, and greater convenience for the patient. Intermittent infusions may be given in a number of ways, including "piggyback" infusions through the established pathway of a primary infusion solution. Although the primary infusion is interrupted during the piggyback infusion, the drug from the intermittent infusion container mixes with the primary solution below the piggyback injection level. Thus, if this method is used, the drug and the primary solution must be compatible.
[00492] A second method to administer intermittent infusions is as a simultaneous infusion, where the drug is administered as a secondary infusion concurrently with the primary infusion. Instead of connecting the intermittent infusion at the piggyback port, it is attached to a lower secondary port. One potential disadvantage of this method is the tendency for blood to back up into the tubing once the secondary infusion has been completed, potentially occluding the venous access device. This generally does not occur with the piggyback method because the hydrostatic pressure closes the back check valve once the intermittent infusion is completed. [00493] A third method is the use of a volume control set. Although it was originally designed to control the fluid volume delivered to the patient, a drug may be added to a small amount of solution in the volume control set and infused at the desired rate. It is still used in some pediatric settings because it limits the amount of fluid the child receives.
[00494] A fourth method for administering intermittent infusions is directly into the venous access device. The device is generally intended for intermittent administration, such as a peripheral heparin lock. The drug is added to a minibag or minibottle and infused intermittently. Between doses, the drug container and tubing are discarded.
[00495] Technological advances have produced alternatives for providing intermittent IV doses, including drug powders that are attached between the primary solution and the infusion set. Once the drug vial is attached, the solution flows from the primary container through the drug vial and to the patient. Another innovation involves intermittent doses of drugs that are activated only at the time of use. Rather than preparing and refrigerating the drug before administration, the pharmacy simply dispenses the drug vial attached to a small container of solution. Immediately before administering the drug, the nurse activates the system by removing the barrier between the drug and the solution and agitating the container to achieve solubilization.
[00496] Direct injection, also known as IV push, IV bolus, or slow IV injection, is the administration of a drug directly into the venous access device or through the proximal port of a continuous infusion set. A purpose is to achieve rapid plasma concentrations while avoiding costly and time consuming use of infusion devices. Instead of regulating drug administration by the infusion rate, a direct injection requires only the time it takes to push the syringe plunger. Since the drug may be incompatible with the infusing solution or heparin may be present in the intermittent device, the vascular access device can be flushed with normal saline before and after injecting the drug. Direct injections may require that the drug be drawn into a syringe before administration or that the drug be available in a prefilled syringe. A needle 1 inch or shorter should be used to administer the medication because longer needles may puncture the IV tubing or the vascular access device. Another alternative is a needleless system, which also prevents inadvertent puncture of the tubing or device. [00497] Patient-controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) is the fourth method of administration of drug administration which promotes patient comfort through the self- administration of analgesic agents. With this method, generally an automated pump (PCA pump) is programmed to administer a small bolus of the drug when activated by the patient. The bolus amount (demand dose) and the time between doses (lock-out interval) are predetermined and programmed into the pump. Most commonly, it refers to intravenous, epidural, intrathecal or subcutaneous administration of an analgesic via a pumping device with the patient having some ability to control the timing and quantity of drug delivery. See, for example, U.S. Patent No. 6,010,483. Pumps currently used for patient controlled analgesia generally give the clinician two to four parameters to set when prescribing a given drug for a patient. These include (1) a demand dose or bolus amount of drug administered whenever the patient presses a button; (2) a lockout interval which determines how soon after a bolus is administered a second bolus will be delivered if the patient pushes the button again; and optionally (3) a daily or 24 hour maximum dose or a daily or 24 hour maximum number of demand doses; and (4) override doses, said override doses administered by or under the supervision of a qualified care giver or health care worker . If a patient presses the button before the lockout interval has elapsed, the pump simply ignores the request. The dose and lockout are generally programmed into the pump for an individual patient and drug combination. The dose is prescribed based on the clinician's assessment of the patient's opioid requirement (depending on weight, habituation, or other factors). The lockout interval is generally set depending on the time to onset of clinical effect of a given drug. The lockout interval is used to prevent a patient from giving himself or herself another bolus before the previous bolus has had a chance to take effect. Except when otherwise specified, for the purposes of this invention, PCA refers to patient controlled analgesia by the intravenous route and PCEA refers patient controlled analgesia by the epidural route.
[00498] The treatment of pain inflammation and/or fever is frequently multimodal and involves the use of multiple drugs to provide optimal efficacy and safety. It is contemplated that the present invention may be used alone or co-administered with other drugs to provide additive, superadditive, complementary, or synergistic therapeutic effects. A co-administered drug (in the same or different dosage form, by any route of administration) may include other NSAIDs, NO-NSAIDs, COX-2 selective inhibitors, acetaminophen, nitroparacentamol, tramadol, local anesthetics, antidepressants, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, cannabinoid agonists, opioid receptor agonists, NO-opioids, NMDA receptor antagonists, gabapentin, pregabalin, gabapentinoids, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers, serotonin 5-HT(lB/lD) receptor agonists superoxide dismutase mimetics, p38 MAP kinase inhibitors, triptans, TRPVl agonists, dextromethorphan, dextrorphan, ketamine, glycine receptor antagonists, antiepileptics, and any other drugs that can be shown by a person proficient in the art to prevent or treat pain.
[00499] Other therapeutically active agents from various therapeutic classes may also be used in combination with the present invention. They include, but are not limited to decongestants, analgesics, analgesic adjuvants, antidepressants, antipsychotics, anxiolytics, hypnotics, sedatives, drugs to treat urinary incontinence, antihistamines, expectorants, antitussives, diuretics, anti-inflammatory agents, antipyretics, antirheumatics, antioxidants, laxatives, local anesthetics, proton pump inhibitors, motility modifying agents, vasodilators, inotropes, beta blockers, beta adrenergic agonists, drugs to treat asthma and COPD, antiinfectives, anti-migraine agents, antihypertensives, antianginal agents, gastric acid reducing agents, anti-ulcer agents, anticoagulants, lipid and cholesterol lowering drugs, anti-diabetic drugs, anti-epileptics, hormones, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids, biological peptides and drugs to treat various infectious, immunologic disorders, cardiovascular, pulmonary, gastrointestinal, hepatic, biliary, nutritional, metabolic, endocrine, hematologic, oncologic, musculoskeletal, neurologic, psychiatric, genitourinary, gynecologic, obstetric, pediatric, otolaryngogologic, ophthalmic, dermatologic, dental, oral, and genetic disorders, diseases and maladies. The drug being used in combination therapy with the present invention can be administered by any route, including parenterally, orally, topically, transdermally, sublingually, and the like.
[00500] Some preferred combination therapies comprise the use of a composition of the present invention in combination with a therapeutic and effective dose of one or more compounds selected from the group consisting of acemetacin, ε-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, iS-adenosyhnethionine, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), alvimopan, amfenac, amino chlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4- picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, anileridine, antrafenine, apazone, balsalazide, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmnorphine, berberine, bermoprofen, bezitramide, p- bromoacetanilide, bromosaligenin, bucetin, bucloxic acid, bucolome, bufexamac, bumadizon, bupivacaine, buprenorphine, butacetin, butibufen, sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, dihydroergotamine, butorphanol, carbamazepine, carbiphene, carsalam, chlorobutanol, chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin, clopirac, codeine, cropropamide, crotethamide, desomorphine, dexoxadrol, dextromoramide, dezocine, diampromide, difenamizole, difenpiramide, dihydrocodeine, dihydrocodeinone dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, dipyrocetyl, dipyrone, ditazol, droxicam, emorfazone, enfenamnic acid, epirizole, eptazocine, etanercept, etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etofenamate, etonitazene, eugenol, felbinac, fenclozic acid, fendosal, fentanyl, fentiazac, fepradinol, feprazone, floctafenine, flunoxaprofen, fluoresone, flupirtine, fluproquazone, fosfosal, gabapentin, gentisic acid, glafenine, glucametacin, guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuproxam, imidazole salicylate, indomethacin, indoprofen, infliximab, interleukin-10, isofezolac, isoladol, isomethadone, isonixin, isoxepac, ketobemidone, p-lactophenetide, lefetamine, levoφhanol, lidocaine, lexipafant, lofentanil, lonazolac, meperidine, meptazinol, mesalamine, metazocine, methadone, methotrimeprazine, methylnaltrexone, metiazinic acid, metofoline, metopon, mofebutazone, mofezolac, morazone, morphine, morphine-6- glucuronide, morpholine salicylate, myrophine, nabumetone, nalbuphine, nalorphine, nefopam, nicomorphine, nifenazone, nimesulide, nitroparacetamol, 5'-nitro-2'- propoxyacetanilide, norlevoφhanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozim, oxycodone, oxymorphone, papaveretum, paranyline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, - -
phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone, pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamnide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, salverine, simetride, sodium salicylate, sufentanil, sulfasalazine, superoxide dismutase, suprofen, suxibuzone, tapentadol, tenoxicam, talniflumate, tapentadol, terofenamate, tetrandrine, thiazolinobutazone, tiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol, tropesin, viminol, xenbucin, ximoprofen, zaltoprofen, sumatriptan, rizatriptan, naratriptan, frovatriptan, eletriptan, dihydroergotamine, ergotamine tartrate, zolmitriptan, divalproex sodium, topiramate, almotriptan, propranolol, metoprolol, timolol, levetiracetam, flunarizine, cannabinoid agonists, gabapentin, lamotrigine, oxcarbazepine, zonisamide, gabapentin, pregabalin, botulinum toxin, amitriptyline, nortriptyline, doxepin, valproic acid, lacosamide, metoclopramide, morphine-6-gucuronide, nitric-oxide donors, nitric-oxide donor-linked analgesics, nitric- oxide donor-linked opioids, opioid agonists, and ziconotide.
[00501] Particularly preferred combination therapies comprise the use of a composition of the present invention in combination with drugs that possess analgesic, anti-inflammatory, antipyretic and antimicrobial properties.
[00502] The drug being used in combination therapy with the present invention can be administered by any route, including parenterally, orally, topically, transdermally, inhalationally, and the like.
[00503] Another aspect of the present invention is directed to a composition comprising a subanalgesic dose (SAD) of the selected combination analgesics with at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (V) one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemoφhan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof.
[00504] Another aspect of the present invention is directed to a composition comprising:
(i) subanalgesic dose (SAD) of the selected combination analgesics with at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemoφhan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and (ii) a compound selected from ethylenediamine, piperazine, and mixtures thereof, wherein the ratio of the subanalgesic dose (SAD) of the selected combination analgesics to ethylenediamine, piperazine, and mixtures thereof is from about 500;l to 1:500, or from about 100:1 to about 1:100, or from about 50:1 to 1:50, or from about 20;l to 1:20, or from about 10:1 to 1:10, 1:5, 0.99:1, 1:0.99, 1:0.9, 0.9:1, 1:0.8, or 0.8:1..
[00505] The concentration of the selected combination analgesic may vary as needed, e.g., from about 0.000001 to about 1000 mg/mL, preferably from about 0.0001 to about 200 mg/mL, based on weight or potency of the NSAID. Other suitable values include about 0.001, 0.01, 0.1, 1, 5, 10, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 500, 550, 600, 650, 700, 800, 900 or 1000 mg/mL.
[00506] The selected combination analgesic can be a parenteral drug formulation prepared, e.g., as a solid, liquid, semi-solid, or emulsion. The most common forms include solid, - -
e.g., dry powder, crystalline, amorphous, lyophilized, and liquid formulations. Solid compositions can be reconstituted with a liquid vehicle just prior to administration. However, in many situations, it is particularly advantageous to provide a liquid formulation, more especially a ready-to-use or dilutable formulation. The formulation may optionally contain one or more additives, adjuvants, excipients, auxiliary agents or enabling agents, such as buffers, stabilizing agents, tonicity agents, antioxidant, anesthetics or bulking agent.
[00507] In some embodiments the dosage form of the invention is devoid of one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds know in the art.
[00508] In some embodiments the dosage form of the invention contains one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds known in the art.
[00509] In certain preferred embodiments, the pharmaceutical composition is devoid of one or more salts or complexes such as any of the inorganic cation salts (e.g., sodium, potassium, lithium, magnesium, calcium, cesium, ammonia, ferrous, zinc, manganous, aluminum, ferric, and manganic), organic salts (e.g., tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, tris-(hydroxymethyl)aminomethane, N- methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins).
[00510] In certain preferred embodiments, the pharmaceutical composition is devoid of one or more salts or complexes such as inorganic cation salts, organic salts such primary, secondary, tertiary and quaternary amines include substituted amines.
[00511] In certain preferred embodiments, the pharmaceutical composition is devoid of one or more salts or complexes of aminoalcohols chosen from the group consisting of ethanolamine, 3-amino-l-propanol, (R)-I -amino-2-propanol, (S)-I -amino-2- propanol, 2-amino-l,3-propandiol, N-(2-hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, and N-methylglucosamine
[00512] In certain preferred embodiments, the pharmaceutical composition is devoid of one or more salts or complexes of alkali and alkaline earth metals and salts of an organic nature, such as the salts of basic amino acids.
[00513] In certain preferred embodiments, the pharmaceutical composition is devoid of one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds know in the art.
[00514] The invention contemplates all possible pharmaceutically acceptable salts and complexes of the SAD of the selected combination analgesic.
[00515] The pharmaceutical composition contains the SAD of the selected combination analgesic may be in unsalified form or as a salt or complex. Nonlimiting examples of salts is provided below.
[00516] In some preferred embodiments, the pharmaceutical composition contains the
SAD of the selected combination analgesic as a salt or complex of inorganic cation salts, organic salts such primary, secondary, tertiary and quaternary amines include substituted amines Examples of suitable pharmaceutically acceptable salts of selected combination analgesics include any of the inorganic cation salts such as sodium, - -
potassium, lithium, magnesium, calcium, cesium, ammonia, ferrous, zinc, manganous, aluminum, ferric, and manganic; organic salts with primary, secondary, tertiary and quaternary amines, or mixtures thereof. Examples of such primary, secondary, tertiary and quaternary amines include substituted amines including but not limited to naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and mixtures thereof. More specifically, suitable amines include but are not limited to tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2- diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N- ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, tris- (hydroxymethyl)aminomethane, Ν-methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins and the like, and mixtures thereof.
[00517] In some preferred embodiments, the pharmaceutical composition contains the
SAD of the selected combination analgesic as a salt or complex of aminoalcohols chosen from the group consisting of ethanolamine, 3-amino-l-propanol, (K)-I -amino-2- propanol, (S)-I -amino-2-propanol, 2-amino-l,3-propandiol, N-(2- hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, and N- methylglucosamine.
[00518] In some preferred embodiments, the pharmaceutical composition contains the
SAD of the selected combination analgesic as a salt or complex of alkali and alkaline earth metals and salts of an organic nature, such as the salts of basic amino acids.
[00519] In some preferred embodiments, the pharmaceutical composition contains the
SAD of the selected combination analgesic as a salt. Examples of suitable pharmaceutically acceptable salts of selected combination analgesics include hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, citrates, tartrates, bitartrates, phosphates, malates, maleates, napsylates, fumarates, succinates, acetates, terephlhalates, pamoates and pectinates.
[00520] In some preferred embodiments, the pharmaceutical composition contains, in addition to the SAD of the selected combination analgesic, one or more cyclodextrins (e.g., beta-hydroxypropyl- cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutylether cyclodextrin, gamma-cyclodextrin).
[00521] In some preferred embodiments, the pharmaceutical composition contains, in addition to the SAD of the selected combination analgesic, ethanol, benzyl alcohol, - -
propylene glycol, polyethylene glycol (PEG)-600, PEG-400, PEG-200, propylene glycol, glycerol, hydrotropes, sodium benzoate, sodium hydroxybenzoate and methyl-p- hydroxybenzoate sodium, sodium metabisulfite, EDTA.
[00522] In some preferred embodiments, the pharmaceutical composition contains, in addition to the SAD of the selected combination analgesic is micronized or prepared as a nanoparticulate composition.
[00523] In some preferred embodiments, the pharmaceutical composition contains the
SAD of the selected combination analgesic is free of preservatives.
[00524] In some preferred embodiments, the pharmaceutical composition contains the
SAD of the selected combination analgesic is free of pharmaceutical excipients.
[00525] The preparation of parenteral pharmaceutical composition is well known in the art
- see Niazi, S. Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products, (Volume 6), CRC Press, 2004; Remington: The Science of Pharmacy Practice, 21st Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, MD; Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRC Press, 2001; Pharmaceutical Dosage Forms: Parenteral Medications, Volume I. Avis KE, Lieberman HA, and Lachman L (eds), Marcel Dekker; 2nd revised and expanded edition (1992); Pharmaceutical Dosage Forms Parenteral Medications, Lieberman HA, Marcel Dekker Inc (1992); Development of Biopharmaceutical Parenteral Dosage Forms, Bontempo CJ, Informa Healthcare (1997) (all of which are hereby incorporated by reference).
[00526] Liquid carriers and excipients are known in the art. See, e.g., Remington's.
Suitable liquid carriers and excipients include, but are not limited to, water, saline, ethanol, benzyl alcohol, etc., and mixtures thereof.
[00527] In one embodiment, a preferred carrier is water, in particular water for injection
(WFI).
[00528] The pharmaceutical composition may contain a buffer. The term "buffer" refers to a pharmaceutically acceptable excipient that helps to maintain the pH of the solution within a particular range specific to the buffering system. The buffer is present for example at a concentration in the range from about 0.03% to about 5.0% w/v, or about 0.1% to about 2.0% w/v. Non-limiting illustrative examples of pharmaceutically acceptable buffering agents include phosphates, 2-amino-2-(hydroxymethyl)-l,3- - o -
propanediol ("tris"), ascorbate, acetates, citrates, tartrates, lactates, succinates, amino acids and maleates and the like. Buffers are known in the art. See, e.g., Remington's.
[00529] The pH of a liquid formulation of the present invention in preferred embodiments is generally from about 5 to about 9, preferably from about 6 to about 8. In other embodiments, the pH of the liquid formulation is about 5, 6, 7, 8, or 9. Alternatively, the pH of the liquid formulation is about 7.5. Alternatively, the pH of the liquid formulation may be selected from the following ranges: 6.0 to 6.9; 6.5 to 6.9; 7 to 7.5; 7.6 to 8.0; 7.6 to 8.5; and 7.6 to 9.0.
[00530] The concentration and dosage of the selected combination analgesic in the liquid parenteral formulation can vary as needed. For example, the SAD of the selected combination analgesic can be in an amount of about from about 0.000001 to about 1000 mg/mL, alternatively from about 0.001 mg/mL to about 200 mg/mL, based for example on the mass of the selected combination analgesic, its solubility, the route of administration, the choice of dose, patient characteristics and the purpose of drug administration. Furthermore, the liquid formulation may be packaged in any suitable container, for example, a vial, ampoule, bag, bottle, prefilled syringe, and the like. Preferably, the liquid formulation comprises a physiologically compatible fluid, such as sterile, buffered saline.
[00531] The liquid carrier used in preferred embodiments is preferably injection-quality water, by itself or preferably with the addition of conventional, physiologically tolerated solvents and/or solubilizing agents, e.g., propylene glycol, polyols such as glycerol, polyoxyalkylenes, e.g., poly(oxyethylene)-poly(oxypropylene) polymers, glycerol-formal, benzyl alcohol, or butanediol. The addition of solubilizing agents produces a composition which is stable at low temperatures and minimizes or prevents partial crystallization of the selected combination analgesic, in spite of the high concentration NSAID that may be present.
[00532] In each of the embodiments described herein, the liquid pharmaceutical formulation may be characterized in terms of its osmolality. In certain preferred embodiments, the osmolality of the pharmaceutical formulation is from about 50 to about 1000 mOsm/L, preferably about 100 to about 500 mOsm/L. In other embodiments, the pharmaceutical compositions of the present invention are prepared such that the osmolality is about 200 to about 300 mOsm/L, about 250 to about 350 mOsm/L, about 270 to about 330 mOsm/L, about 270 to about 290 mOsm/L, or about 280 to about 300 mOsm/L, or is 270, 280, 290, 300, or 310 mOsm/L. Alternative preferred embodiments include compositions which have a lower osmolality than physiological osmolality.
[00533] For therapeutic use, the injection preparations according to the invention can be sterilized by conventional methods or filled under sterile conditions.
[00534] The concentration of the selected combination analgesic in the liquid pharmaceutical composition can vary and may depend on the intended use. In certain preferred embodiments, the injection solutions according to the invention contain from about 0.0001 to about 90% of the selected combination analgesic.
[00535] According to the invention, liquid formulations of invention may employ one or more stabilizing agents. A stabilizing agent may slow, delay, reduce, or prevent the precipitation of one or more analgesics. It will be understood that the effectiveness of such means for stabilizing the analgesic salt, illustrative examples of which are individually described in further detail below, depend on, inter alia, composition of the particular solvent liquid, selection and amount of analgesic salt, and desired final presentation of the composition.
[00536] One class of suitable salt stabilizing means, particularly for a PEG-containing composition of the invention, is a means for limiting effective exposure of the composition to oxygen. The term "limiting effective exposure of the composition to oxygen" includes placing the composition in contact with an oxygen-limited microatmosphere and/or including in the composition one or more excipients or agents that mitigate potential deleterious effects of oxygen. Limiting the effective exposure of the composition to oxygen can be accomplished by one or more of the illustrative, nonlimiting means described more fully immediately below.
[00537] One means for limiting effective exposure of the composition to oxygen is to place the composition in contact with an oxygen-limited microatmosphere in a sealed container. Such a container can have a substantial internal headspace occupied by a microatmosphere having low oxygen pressure. Alternatively, the container can have very little or no headspace, in which case effective exposure of the composition to oxygen is limited largely by the barrier effect provided by the sealed container itself. Any suitable pharmaceutical container can be used to prepare an article of manufacture according to this embodiment. The container can be a multi-dose container, enclosing an - oZ-
amount of the composition preferably corresponding to 2 to about 30, for example about 4 to about 20, unit doses. Alternatively, the container encloses an amount of the composition corresponding to a single unit dose. Such a single-dose article of manufacture has the further advantage of eliminating a measuring step before administration of the composition. Since compositions of the invention are desirable for parenteral administration, the container preferably is sufficient to maintain sterility of a composition contained therein. The container can also be used to facilitate direct administration (without need for transfer to another vessel or container) of a composition of the invention, e.g., a syringe. Non-limiting examples of suitable containers for an article of manufacture of this invention include vials of any shape and/or size, ampoules, syringes, packets, pouches, auto-injectors, etc. In one embodiment, the container further comprises means to protect the composition from exposure to light, e.g., amber glass walls.
[00538] A composition of the invention can be sealed in a container in any suitable manner including but not limited to frictionally- and/or hermetically-induced seals. Such a seal can illustratively be provided by a stopper made of rubber or other polymeric material. A preferred seal comprises an inert coating, for example a coating of a fluoropolymer such as polytetrafluoroethylene, e.g., Teflon , to prevent chemical interaction between the composition and the seal. The seal can illustratively be secured by a metal over-cap and/or an external cover, e.g., plastic, until use. Optionally, the seal can comprise at least one septum or thinner area of sealing material through which a needle can be inserted to extract the composition without cracking or breaking any glass or plastic portion of container wall. Regardless of what form of seal is used, such a seal should substantially inhibit movement of gas into or out of the container until the seal is penetrated for use of the composition present in the container.
[00539] Even where the composition is enclosed in a sealed container with an oxygen limited micro atmosphere, effective exposure of the composition to oxygen can be further limited by one or more of the following means: 1) a container size and/or shape that substantially maximizes fill volume and/or substantially minimizes headspace volume; 2) low oxygen pressure in the headspace; 3) use in the solvent liquid of water which has been purged of molecular oxygen; and 4) use of a grade of PEG having a low peroxide content, for example not greater than about 1.5 meq/kg and preferably not greater than about 1.0 meq/kg.
[00540] The term "headspace" or "headspace volume" with respect to an article of manufacture of the invention refers to any interior volume of the container that is not occupied by, but is in contact with, the composition. Generally, the headspace volume is occupied by a gaseous medium. The term "fill volume" with respect to an article of manufacture of the invention refers to any interior volume of the container that is occupied by the composition.
[00541] The term "total volume" refers to the entire interior volume of the container and may also be referred to elsewhere as overflow volume; total volume generally equals the sum of the fill and headspace volumes.
[00542] Yet another suitable means for limiting effective exposure of a composition, particularly a PEG-containing composition, of the invention to oxygen, and thereby providing said analgesic salt stabilizing means, comprises one or more pharmaceutically acceptable antioxidants, preferably free-radical scavenging antioxidants, as a component of the solvent liquid. Non-limiting illustrative examples of suitable antioxidants include α-tocopherol (vitamin E), ascorbic acid (vitamin C) and salts thereof including sodium ascorbate and ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cystein, cysteinate HCl, dithionite sodium, ethylenediamine tetraacetic acid, fumaric acid, gentisic acid and salts thereof, hypophosphorous acid, malic acid, methionine, monothioglycerol, N-acetyl-cysteine, alkyl gallates, for example propyl gallate, octyl gallate and lauryl gallate, sodium sulfite, sodium bisulfite, sodium and potassium metabisulfite, thioglycolate sodium, ethanolamine, glutamate monosodium, formaldehyde, sulfoxylate sodium and monothioglycerol. Preferred free radical-scavenging antioxidants are alkyl gallates, vitamin E, BHA, BHT, ascorbate and methionine, more especially BHA, ascorbate and methionine. Preferably, an antioxidant is selected that is substantially soluble in the particular solvent liquid employed and does not result in changes to the composition which are detectable by unaided sensory organs (e.g., color or odor changes). BHA is an illustrative preferred antioxidant for use in a composition of the invention. If included, one or more antioxidants are preferably present in a composition of the invention in a - -
total antioxidant amount of about 0.001% to about 5%, preferably about 0.001% to about 2.5%, and still more preferably about 0.001% to about 1%, by weight.
[00543] When freeze dried, the formulations may optionally contain a bulking agent. The term "bulking agent" refers to a pharmaceutically acceptable excipient that adds bulk to a formulation which results in a well-formed cake upon freeze drying. The bulking agent is for example present in a formulation at a concentration in the range from about 1% to about 60% w/v, or about 3% to about 50% w/v. Nonlimiting examples of suitable bulking agents include mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin.
[00544] The solid composition also may include a tonicity agent. Suitable tonicity agents include, but are not limited to, glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, and sorbitol.
[00545] Non-limiting examples of suitable nonaqueous solubilizers that can be present in the solvent liquid include polyethylene glycol (PEG), ethanol, dimethylacetamide (DMAC), propylene glycol, and mixtures thereof. It is preferred that the solvent liquid comprise at least one of PEG, DMAC, and ethanol.
[00546] Yet another means for stabilizing the formulation in a PEG-containing composition is a metal sequestering agent or chelating agent. Non-limiting examples of suitable sequestering agents include ethylenediamine tetraacetic acid (EDTA), potassium polyphosphate, sodium polyphosphate, potassium metaphosphate, sodium metaphosphate, dimethylglyoxirne, 8-hydroxyquinoline, nitrilotriacetic acid, dihydroxyethylglycine, gluconic acid, citric acid and tartaric acid.
[00547] The composition of the present invention can optionally contain a surfactant.
Non-limiting examples of suitable surfactants include cetrimide, docusate sodium, glyceryl monooleate, sodium lauryl sulfate, or sorbitan esters. The surfactant may optionally be a polyoxyethylenesorbitan fatty acid ester. Polyoxyethylenesorbitan fatty acid esters are also referred to as polysorbates, e.g., polysorbate 80 (polyoxyethylene sorbitan monooleate, Tween 80), polysorbate 40 and polysorbate 20.
[00548] The composition of the present invention can optionally be manufactured in glass- lined or a "greater than or equal to 316 temper-grade" steel tank.
[00549] Oxygen pressure in a container headspace of an article of manufacture of the invention can be limited in any suitable manner, illustratively by placing nitrogen and/or a — —
noble gas (collectively referred to herein as "inert gases") in the container headspace. In this embodiment, the headspace volume preferably comprises one or more inert gases selected from the group consisting of nitrogen, helium, neon and argon. One way to ensure low oxygen pressure in the headspace is to prepare, fill and seal the container under an atmosphere of inert gas and/or to flush the container headspace with inert gas after filling, illustratively using parallel in-line flushing. An inert gas atmosphere can illustratively be provided using a zero oxygen tunnel commercially available from Modified Atmosphere Packaging Systems of Des Plaines, 111., or by using a nitrogen or noble gas atmosphere glove bag.
[00550] Various polymorphs of this invention may be prepared by crystallization under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray data or such other techniques.
[00551] Pharmaceutically acceptable solvates of the invention may be prepared by conventional methods such as dissolving the compounds in solvents such as water, methanol, ethanol etc., and recrystallizing by using different crystallization techniques.
[00552] In an additional embodiment, the composition of the present invention comprises:
(i) subanalgesic dose (SAD) of the selected combination analgesics comprising a pharmaceutical composition of at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts - oo-
thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (ii) sterile water; (iii) optionally one or more pharmaceutically acceptable buffers; (iv) optionally one or more pharmaceutically acceptable antioxidants; (v) optionally one or more pharmaceutically acceptable tonicity adjusters; (vi) optionally one or more pharmaceutically acceptable solubility enhancers; and (vi) optionally one or more pharmaceutically acceptable preservatives; and wherein: (a) the pH is preferably from about 6.5 to about 8.5, more preferably from about 7.0 to about 8.0; and/or (b) the concentration of said selected combination analgesic is about 0.00001 mg/mL to about 1000 mg/mL, preferably about 0.001, 0.01, 0.1, 1, 5, 10, 20, 25, 40, 50, 60, 75, 100, 200, 300 or 400 mg/mL; and/or (c) the composition shows no substantial visible signs of crystallization and/or significant deviation, e.g., less than or equal to 10% of original value, in pH and/or osmolality, and/or contains 100% ± 10% original content of the selected combination analgesic; and/or (d) the composition is substantially free of a surfactant; and/or (e) wherein said composition is substantially free of a benzyl alcohol; and/or (f) said composition is substantially free of a polyethylene glycol (PEG); and/or (g) said composition is substantially free of a N-methylglucamine; and/or (h) said composition is substantially free of lysine, arginine and/or glycine or derivatives thereof; and/or (i) said composition is substantially free of one or more of, or all of, alkylammonium salts, i.e., tromethamine, dropopizine, 3-(4-phenyl-l-piperazinyl)-l,2- propanediols, and derivatives thereof; or (j) said composition is substantially free of pharmaceutical excipients; and/or (k) said composition is substantially free of preservatives, and/or antioxidants and/or buffers and/or tonicity adjusters; and/or organic solvents and/or bulking agents; and/or (1) said composition is substantially free of citric acid and/or glycerol or derivatives thereof; and/or (m) wherein one or more analgesics are in the form of a solvate, polymorph, hydrate, conjugate, ester or prodrug in racemic, enatiomeric excess or enantiomeric form, or mixture thereof.
[00553] In some preferred embodiments, the composition is contained in a sealed glass vial or a prefilled syringe.
[00554] In another embodiment, the present invention is directed to a composition comprising the SAD of selected combination analgesics with ethylenediamine and/or piperazine having an aqueous solubility of greater than about 50 mg/mL, greater than about 100 mg/mL, greater than about 200 mg/mL, greater than about 350 mg/mL, greater than about 400 mg/mL, greater than about 450 mg/mL, or greater than about 500 mg/mL.] Additionally, the present invention is directed to sealed syringe comprising a sterile solution comprising one of more selected combination analgesic subanalgesic doses (SAD) comprising at least one compound each selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof. For example, a solution comprising water, e.g., purified by reverse osmosis, piperazine, and one of more selected combination analgesic and optionally sorbitol, and adjusted to a pH from about 6.5 to about 8.5 is added to presterilized syringes under nitrogen atmosphere and aseptic conditions. The solution is optionally first filtered through a filter, e.g., a 0.45 micron filter, and deoxygenated with nitrogen or deoxygenated and finally passed through 0.22 micron membrane filter into presterilized syringes under nitrogen atmosphere and aseptic conditions. The syringes are sealed under an inert atmosphere, e.g., nitrogen. The sealed syringe containing the selected combination analgesic can be used in accordance with the methods described herein. In preferred embodiments, the solutions in the sealed syringe show no visible signs of crystallization or significant deviation in pH and osmolality and contain 100% ± 15% original NSAID content when stored for 12 weeks at 50C, 25°C/60% RH, 30°C/60% RH, 40°C/75% RH as determined by HPLC. - -
[00556] In some embodiments, the osmolality of the solution in the sealed syringe may be from about 200 to about 400, preferably from about 280 to about 300 mOsm/L.
[00557] Additionally, it is understood that each of the various embodiments of the pharmaceutical compositions described herein may be used with each of the various embodiments of the described method of the present invention as described herein.
Preparing the Compositions
[00558] In certain preferred embodiments, the compositions of the present invention can be prepared by direct salification or complexation between the selected combination analgesic in unsalified form and a pharmaceutically acceptable salt, complexing agent or solubility enabling agent.
[00559] The precise procedure and process form manufacture, including the order of mixing and choice and quantity of pharmaceutical excipients, adjuvants, auxiliary agents and enabling agents (e.g., buffers, stabilizing agents, tonicity agents, antioxidants, preservatives, solubilizing agents, stabilizing agents, diluents or bulking agent) will vary depending on the dose, route of administration and choice of the selected combination analgesics selected from at least two of the three groups (i.e., a, b, c), i.e., (a) one or more compounds selected from the group comprising celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) one or more compounds selected from the group comprising levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (c) one or more compounds selected from the group comprising acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof. The preparation of parenteral pharmaceutical composition is well known in the art - see Niazi, S. Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products, (Volume 6), CRC Press, 2004; Remington: The Science of Pharmacy Practice, 21st Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, MD; Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRC Press, 2001; Pharmaceutical Dosage Forms: Parenteral Medications, Volume I. Avis KE, Lieberman HA, and Lachman L (eds), Marcel Dekker; 2nd revised and expanded edition (1992); Pharmaceutical Dosage Forms Parenteral Medications, Lieberman HA, Marcel Dekker Inc (1992); Development of Biopharmaceutical Parenteral Dosage Forms, Bontempo CJ, Informa Healthcare (1997) (all of which are hereby incorporated by reference).
[00560] To practice the invention, it is not necessary to incorporate all of the selected combination analgesics within a single container. In some embodiments, preferably the selected combination analgesics are in the form of a solid, semisolid, suspension emulsion or solution within a single container (e.g., ampoule, vial, prefϊlled-syringe, or minibag). In some embodiments, the one or more of the analgesics that form the selected combination analgesics of the invention may be in separate containers. This may be preferred in some embodiments when there is physical or chemical incompatible with between the selected combination analgesics. In some embodiments, the selected combination analgesics are mixed just prior to parenteral administration. In some embodiments, the one or more of the analgesics that form the selected combination analgesics of the invention may be in separate containers. To practice the invention, it is not necessary to administer all of the selected combination analgesics at the same time. In some embodiments, the one or more of the analgesics that form the selected combination analgesics may be administered separately (e.g., sequentially, consecutively, contemporaneously or temporally related, e.g., seconds, minutes or hours apart).
[00561] Kits for use in treating or preventing pain, comprising: (i) a dosage form of the invention in an ampoule, vial, prefilled syringe, minibag, autoinjector or sterile container; (ii) a container or packaging for the dosage form; and optionally, any of (iii) to (ix): (iii) syringe; (iv) alcohol swab; (v) sterile absorbent gauze; (vi) sterile occlusive dressing to cover the injection site which is optionally adhesive (e.g., bandage, adhesive bandage, clear bandage, Liquid Bandage™, Band Aid™, Elastoplast™, Tegaderm™, etc); (vii) educational instructions in any media about various medical conditions, their etiology, pathophysiology, consequences and treatment, including information on the proper use and disposal of the medication; (viii) containers or bags for the safe disposal of any used or remaining unused dosage form and needles, preferably child proof, needle stick safe and flushable; (ix) tamper evident and child proof packaging for the kit and its contents.
Determination of Analgesic Activity
[00562] The analgesic effects of the compositions of the present invention can be evaluated in one or more of the tests described below:
Rat Tail Flick Test
[00563] The tail flick test was first described by D 'Amour and Smith (1941), and remains essentially unchanged in application. (See generally D'Amour, F.E. and Smith, D.L., "A method for determining loss of pain sensation", J. Pharmacol. Exp. Therap., 72:1 A- 79(1941); Dewey, D.L. and Harris, L.S., The Tail-flick test. In: S. Ehrenpreis and A. Neidle (Eds.), Methods in Narcotic Research, Marcel Dekker, Inc., New York, 1975, pp. 101-109; and Dubner, R. and Ren, K., "Assessing transient and persistent pain in animals." In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain, Churchill Livingstone, London, 1999, pp. 359-369). Quite simply, the tail of a rat or mouse is exposed to radiant heat, and the latency to withdraw is determined. The basal heat intensity is set so that naive rats withdraw their tails within 2 to 3 sec. A cut-off latency of 10 sec {i.e., 3 to 4 times basal control value) is commonly employed to prevent tissue damage. An alternative to using radiant heat is to dip the tail into a water bath maintained at a fixed temperature, usually in the moderately noxious range of about 520C or 55°C. One advantage of a water bath is that the temperature is kept constant.
[00564] The tail-flick test is considered to be very robust in that weak analgesic agents are not detected by this test. In contrast, it is considered highly selective. There is a high degree of correlation between drugs that are identified as antinociceptive in the tail-flick test and clinically active analgesic agents. It is especially predictive of rank-order of potency of opioid-type analgesic agents, and the clinically effective dose of a novel opioid may be predicted by the relative potency of the drug to a known substance, such as morphine, based on this assay. Importantly, agents that are sedating and may produce a positive response in the writhing test or hot plate test do not show antinociceptive activity in the tail-flick test. It is even possible to perform the tail-flick test in lightly anesthetized animals. [00565] Data obtained from the rat tail-flick test conform to a graded dose-response curve.
The raw tail withdrawal latencies are converted to a %MPE (% maximal possible effect) by the formula:
[00566] % MPE = 100 x (test latency - basal latency)/(cut-off - basal latency).
[00567] This formula constrains the data to fit between 0% MPE and 100 % MPE. This allows the generation of dose-response curves and the calculation of ED50 values (50% effective doses) with attendant confidence intervals. These calculations then allow for the determination of relative potencies of different drugs and allow for the isobolographic determination of possible synergistic effects. Instances where the test latency is less than the basal latency produces a negative % MPE, which is meaningless unless one is measuring hyperalgesia. By convention, these values are set to 0% MPE when the expected drug effect is antinociception or no activity.
Kim and Chung Model
[00568] Dose-response curve against tactile hyperesthesia and thermal hyperalgesia caused by peripheral nerve injury are generated. The peripheral nerve injury is established by tight ligation of the L5 and L6 spinal nerves, according to the techniques established by Chung and colleagues (Kim and Chung Pain, 1992: 50, 355-363.). Spinal nerve ligation (SNL) reliably produces tactile hyperesthesia and thermal hyperalgesia in rats. Tactile hyperesthesia is widely accepted as a model of allodynia to light touch often reported by patients with nerve injury. Thermal hyperalgesia represents a model of enhanced sensitivity to pain. The standard protocol for the evaluation of tactile hyperesthesia is to determine the paw withdrawal threshold of the hindpaw of the rats in response to probing with von Frey filaments. Thermal hyperalgesia is indicated by a significant reduction in paw withdrawal latency to noxious radiant heat projected onto the plantar aspect of the hindpaw of the rat. Tests are conducted with systemic (SC) and intrathecal (IT) administration. In order to properly conduct this study, sham-operated animals are also required. Since sham-operated rats do not develop tactile hyperesthesia, only responses to thermal stimuli are tested. Testing of sham-operated rats requires an additional 48 animals. Approximately 26 rats are be used for initial dose-finding experiments. Animals are tested within 7 to 10 days of SNL. Surgery and testing may be staggered to optimize testing efficiency. The intrathecal drug administration studies require implantation of catheters 7 days prior to the SNL surgery, and testing at 10 days after SNL surgery. Carrageenan-Induced Inflamed Paw Model
[00569] Models of inflammation that produce more persistent pain include the injection of carrageenan into the footpad of the limb; the potential analgesic and/or anti-inflammatory properties of putative analgesics substances can be evaluated in this model. See generally Bhalla T.N. & Tangri, K.K. "The time course of the carrageenan-induced oedema of the paw of the rat." J. Pharm. Pharmacol. 22:721 (1970); Randall, L.O. & Selitto, J.J., "A method for measurement of analgesic activity on inflamed tissue," Arch. Int. Pharmacodyn. Ther. 777:409-419 (1957); Hargreaves, K., et al. "A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia." Pain 52:77-88 (1988).
[00570] Typically, rats are handled and acclimatized to the behavioral testing equipment over a minimum of 2 days prior to testing. Behavioral tests are performed on all rats on the day prior to dosing to establish baseline values, and the animals are randomized into treatment groups based on these pre-dose responses. An assessment of the inflammatory agent (carrageenan) is performed prior to the main study, using the chosen behavioral tests. On the day of dosing, an inflammatory response is induced in the left hind paw of each rat by an intraplantar injection (approx. 0.05 mL) of carrageenan (0.6% w/v), under brief anesthesia. The test substance, reference substance, or vehicle is generally administered 30 minutes prior to carrageenan administration for oral dosing.
[00571] The following tests may be performed. A minimum period of 5 minutes is allowed between each type of test (or repeat challenges to the same paw) to reduce the risk of sensitization.
[00572] Paw Volume: Each animal is gently restrained, their hind limb extended, and the paw placed in the pre-filled chamber of a Digital Plethysmometer. The paw volume is then calculated based on the volume of liquid displaced in the chamber, for both the ipsilateral and contralateral hind paws.
[00573] Mechanical hyperalgesia test: Each rat is gently restrained, their hind limb extended, and the paw placed lightly on the Randall-Selitto device. A progressively increasing pressure is then applied to the dorsal surface of the paw via a blunt peg attached to a weight level, and the withdrawal threshold calculated for both the ipsilateral and contralateral hind paws. The maximum pressure applied is about 250 g. The withdrawal threshold is defined as the minimum force (in grams) required to elicit a - -
reflex withdrawal response. Typical end points are a struggle response, paw withdrawal or a squeak response.
[00574] Thermal hyperalgesia test: Rats are placed in clear plastic chambers with a glass floor and allowed a short period to acclimatize to their environment prior to testing (approximately 2-5 minutes). The animals are then challenged with a radiant infrared heat source, directed at the plantar surface of their hind paw from below, and the withdrawal latency calculated for both the ipsilateral and contralateral hind paw
[00575] Standard statistical methods are employed to evaluate test substance related effects. Data are analyzed for homogeneity and either parametric or non-parametric methods applied.
Third Molar Extraction Model
[00576] Male and female patients with acute postsurgical pain following the removal of one or more bony impacted third molars are participants. Within 4 to 6 hours after completion of surgery, patients who are experiencing moderate or severe pain, as measured by a visual analog pain intensity scale (VAS > 50 mm) and by a categorical pain intensity scale (moderate or severe pain descriptor), and who meet all other inclusion/exclusion criteria are admitted to the study. Patients are randomly assigned to receive drug or placebo. Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at the various time points: Baseline (0 hour - pain intensity only), 15, 30 and 45 minutes, and at 1, 1.5, 2, 3, 4, 5, 6, 7, 8 and 12 hours after administration of study medication, and immediately prior to the first rescue dose. Time to onset of perceptible and meaningful pain relief is evaluated using the two stopwatch method. Patients record their global evaluation of study medication at the completion of the 8-hour assessment or at the time of first rescue medication use. Efficacy endpoints include Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and Sum of Pain Relief Intensity Difference (SPRID) at various time points, Time to First Rescue, Time Specific Pain Intensity Difference (PID), Time Specific Pain Relief (PR), Peak Pain Intensity Difference (PPID), Peak Pain Relief (PPR), Time to Confirmed Perceptible Pain Relief (stopwatch) and Time to Meaningful Pain Relief (stopwatch) and Patient Global Evaluation.
Bunionectomy Surgery Model - -
[00577] Male or female patients requiring primary unilateral first metatarsal bunionectomy surgery alone or with ipsilateral hammertoe repair (without additional collateral procedures) under regional anesthesia (Mayo block) are participants.
[00578] Patients who experience moderate or severe pain on a categorical scale (moderate or severe descriptor) and on a visual analog pain intensity scale (VAS; >50 mm) within 6 hours following completion of bunionectomy surgery are randomly assigned to receive study drugs or placebo. Patients are encouraged to wait at least 60 minutes before requesting remedication for pain. At the completion of the single-dose phase (8 hours) or at first request for remedication (whichever is earlier), patients enter into a multiple-dose phase lasting approximately 72 hours. During the multiple dose phase, patients receive study medication or placebo at a fixed dose interval (e.g., every 8, 12 or 24 hours). Once the multiple dose phase of the study has begun, patients experiencing pain between scheduled doses of study medication are provided access to supplemental open-label (rescue) analgesia. Patients whose pain cannot be adequately managed on a combination of study medication and rescue medication or who develop unacceptable side effects during the study are discontinued from further study participation and their pain managed conventionally.
[00579] Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at representative time points, e.g., Baseline (pain intensity only), 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours after administration of study medication and immediately prior to the first remedication. Time to onset of perceptible and meaningful pain relief is evaluated using the double-stopwatch method. Patients complete a global evaluation of study medication at the completion of the 8-hour assessment or just prior to the first remedication. Following completion of the single- dose phase (8 hours or just prior to first remedication, if < 8 hours), patients begin the multiple dose phase of the study. During the multiple dose phase, patients record their overall pain intensity since the previous scheduled dose, their current pain intensity and a patient global, immediately prior to each scheduled dose of study medication and at early termination.
[00580] Measures of efficacy in the single-dose phase include Sum of Pain Intensity
Difference (SPID), Total Pain Relief (TOTPAR), Sum of Pain Relief Intensity Difference (SPRID), Time to First Remedication, Time Specific Pain Intensity Difference (PID), Time Specific Pain Relief (PR), Peak Pain Intensity Difference (PPID), Peak Pain Relief (PPR), Time to Confirmed Perceptible Pain Relief (stopwatch) and Time to Meaningful Pain Relief (stopwatch) and Patient Global Evaluation. Measures of efficacy in the multiple-dose phase include the time specific overall pain intensity, current pain intensity and patient global at the time of scheduled remedication, the average of overall pain intensity, current pain intensity and patient global over 0-24, 24-48 and 48-72 and number of doses of rescue analgesic over 0-24, 24-48 and 48-72 and 0-72 hours.
Chronic Pain of Osteoarthritis
[00581] The increased therapeutic benefits associated with the administration of a composition of the invention may, in some preferred embodiments, be demonstrated in repeated dose randomized, double-blind, controlled studies comparing subanalgesic and analgesic doses of the invention. Typically, patients who meet the American College of Rheumatology criteria for knee and/or hip OA are washed off their analgesics for 2 to 7 days to allow for pain of moderate to severe intensity to return. Once a stable baseline pain score is established, patients are randomized to treatment, usually for a period of one to 12 weeks. Pain, joint stiffness and physical function can be measured with a multidimensional instrument, such as the WOMAC, quality of life with the SF- 12 or SF-36 and adverse events with a non-directed questionnaire at baseline and at post- baseline return visits. Response to pain, stiffness, physical function, quality of life and adverse events are calculated as change from baseline and compared between treatments. Sample sizes in the studies are sufficient to demonstrate the increased therapeutic benefit of the invention.
Migraine
[00582] The increased therapeutic benefits associated with the administration of a composition of the invention may, In some preferred embodiments, be demonstrated in patients with migraine headaches, typically in a prospective, randomized, double-blind, parallel group, single-dose, placebo-controlled, study. Crossover studies are also possible. The study population consists of male and non-pregnant female subjects, 18 to 65 years of age with a primary headache diagnosis of either migraine attack without aura or migraine attack with aura, as diagnosed according to the International Classification of Headache Disorders-2 criteria. To qualify, the subject must typically have a history, on average, of at least one migraine attack per month, but an average of no more than 6 migraine attacks each month during the past year. Using a headache diary subjects are instructed to treat and evaluate the headache pain and symptoms associated with one eligible migraine attack, with or without aura, with at least moderate headache pain intensity. Eligible subjects are randomly assigned to receive the test drug or placebo to treat one migraine attack, with or without aura, with headache pain of at least moderate pain intensity as determined by them migraine questionnaire they are asked to take a single dose of study drug, according to their randomized treatment assignment. Headache pain intensity, nausea, photophobia, phonophobia, vomiting, and ability to function are assessed at baseline, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 16 and 24 hours post-dose. In addition, the recurrence of pain and use of any rescue mediation is documented. Primary efficacy variables typically consist of the percent of subjects who are without: (i) pain; (ii) nausea; (iii) photophobia and, (iv) phonophobia, each at 2 hours post-dosing. Secondary efficacy variables typically consist of headache pain intensity and associated symptoms at each evaluation time point, incidence of vomiting, patient function, sum of pain intensity difference at each evaluation time (SPID), percent of subjects who experience headache recurrence up to 24 hours, and the median time to recurrence. Recurrence is defined as the reduction in pain from moderate or severe pain to none at 2 hours after taking study drug, followed by: (i) an increase to mild, moderate or severe pain within 24 hours after taking the study drug, or (ii) consuming a rescue medication within 24 hours after taking the study drug.
[00583] The included examples are illustrative but not limiting of the methods and composition of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention.
Definitions
[00584] "Drug," "pharmacological agent," "pharmaceutical agent," "active agent," and
"agent" are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial effect. In general, this includes therapeutic agents in all of the major therapeutic areas, also including proteins, peptides, oligonucleotides, and carbohydrates as well as inorganic ions, such as calcium ion, lanthanum ion, potassium ion, magnesium ion, phosphate ion, and chloride ion.
[00585] "Pharmaceutically or therapeutically acceptable excipient or carrier" refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the hosts, which may be either humans or animals, to which it is administered. Pharmaceutically or therapeutically acceptable excipients or carriers are well known in the art. "Pharmaceutically or therapeutically acceptable excipient or carrier" or "excipient" may include compounds found on the FDA EAFUS database (http://vm.cfsan.fda.gov/~dms/eafus.html); FDA Food Additives Status List (http://www.cfsan.fda.gov/~dms/opa-appa.html); FDAGRAS list and database; FDA Color Additive Status List (http://www.cfsan.fda.gov/~dms/opa-appc.html); FDA Inactive Ingredients Database (http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm); Rowe, Sheskey and Owen, Handbook of Pharmaceutical Excipients, APhA Publications; 5th edition (2006); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker, eds, 1 lth ed., McGraw Hill (2005); Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); Martindale: The Complete Drug Reference, 35th Edition, Pharmaceutical Press (2007); United States Pharmacopeia-National Formulary (USP-NF), (USP 30 - NF 25, 2007), the International Programme on Chemical Safety (http://www.inchem.org/), Health Canada's List of Acceptable Non-medicinal Ingredients (http://www.hc-sc.gc.ca/dhp- mps/prodnatur/legislation/docs/nmi-imn_listl_e.html) and Ash, Michael (ed and compiler), Pharmaceutical Additives Electronic Handbook, Synapse Information Resources, Inc.; 3 Cdr edition (February 19, 2007), all hereby incorporated by reference in their entirety.
[00586] The term "complex" as used herein means any physical combination of two or more discrete chemical compounds. A complex includes, but is not limited to, a salt, a physical mixture, a chelate, and the like. For example, as used herein, a complex includes a salt; a physical mixture; a solid wherein two or more discrete chemical compounds are associated by hydrogen bonding; a solid wherein two or more discrete chemical compounds are associated by hydrophobic bonding; a solid wherein two or more discrete chemical compounds are associated by ionic bonding; a solid wherein two or more discrete chemical compounds are associated by hydrogen, ionic, and or hydrophobic bonding; a co-crystal containing two or more discrete chemical compounds. The complex can be constructed through several modes of molecular recognition including hydrogen- bonding, pi-stacking, guest-host complexation, and Van-Der-Waals interactions. The term "subanalgesic dose", "subanalgesic doses", "subanalgesic dosage" and
"SAD", as used herein refers to a dosage of compounds chosen from the group of compounds defined herein as selected combination analgesics, which when given alone (i.e., individually or in the absence of the combination) do not result in the production of meaningful analgesia when administered to a human or antinociception when administered to non-human subjects requiring alleviation of pain. Dosage ranges and the lower threshold of doses required to produce meaningful analgesia when administered to a human or antinociception when administered to non-human subjects are well known in the art (e.g., in Gilman et al., eds., Goodman And Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill (2001); Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); and Martindale: The Complete Drug Reference, 34th Edition, Pharmaceutical Press (2004); Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No. 02-E002, October 2001; Carr et al. J Nat Cancer Inst Monograph 2004;32:23-31; Agency for Health Care Policy and Research Clinical Practice Guidelines for Cancer Pain Management, Guideline No. 9, AHCPR Publication No. 94-0592, March 1994; Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005, Physicians Desk Reference, 2006, Thomson Publications, each of which is herein incorporated by reference) or can be readily determined using methods known in the art and those described herein. Accordingly, the term "subanalgesic dosage" includes within its scope dosages falling below such lower thresholds. This term will also cover direct administration of each compound from the list of selected combination analgesics, as well as administration which includes controlled-release, sustained release, modified release or extended release by parenteral routes of administration. Of course it will be appreciated that a subanalgesic dosage from the list of selected combination analgesics in accordance with the invention will be dependent upon the mode or route of administration thereof (e.g., intravenous vs. intrathecal). - -
[00588] "Therapeutically effective amount" refers to the amount of an active agent or combination sufficient to induce a desired biological result. That result may be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
[00589] The term "effective amount" means the quantity of a compound or combination of compounds according to the invention necessary to prevent, to cure, or at least partially arrest a symptom of local pain or discomfort in a subject. A subject is any animal, preferably any mammal, more preferably a human. Amounts effective for creating a substantially local therapeutic effect will, of course, depend on the severity of the disease causing the painful condition, and the weight and general state of the subject. Typically, animal models, such as those described in the Background and Examples herein, may be used to determine suitable dosages to be used. In addition, various general considerations taken into account in determining the "therapeutically effective amount" are known to those of skill in the art and are described, e.g., in Gilman et al, eds., Goodman And Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill (2001); Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); and Martindale: The Complete Drug Reference, 34th Edition, Pharmaceutical Press (2004); Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No. 02-E002, October 2001; Carr et al. J Nat Cancer Inst Monograph 2004;32:23-31; Agency for Health Care Policy and Research Clinical Practice Guidelines for Cancer Pain Management, Guideline No. 9, AHCPR Publication No. 94-0592, March 1994; Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005, Physicians Desk Reference, 2006, Thomson Publications, each of which is herein incorporated by reference.
[00590] The term "parenteral" and "parenteral administration" herein encompasses administration of a composition by means other than through the gastrointestinal tract such as into or through the skin of a subject, and includes intradermal, subcutaneous, intramuscular, intravenous, intramedullary, intra-articular, intrasynovial, intraspinal, epidural, intrathecal and intracardiac administration. The term "parenteral" and "parenteral administration" herein also encompasses infiltration or topical application to a surgical site, open wound and local site of pain or inflammation. Any known device or delivery system useful for parenteral injection or infusion of drugs can be used to effect such administration. . In some embodiments, particularly preferred parenteral routes of administration include intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration, epidural or intrathecal route. In some embodiments, particularly preferred method of administration include PCA and PCEA.
[00591] The term "subject" for purposes of treatment includes any animal subject who has any one of the known forms of pain. The subject is preferably a mammal and more preferably is a human. The subject can of course include other non-human animals, preferably horses, livestock, cattle, domesticated animals, cats, dogs, and the like.
[00592] All types of pain are contemplated by this invention. Preferably, the pain is acute pain or acute exacerbation of chronic pain.
[00593] As used herein, the term "pain", also referred to as "analgesia" or "analgesic" includes: (i) peripheral neuropathic pain, e.g., acute and chronic inflammatory demeyelinating polyradiculopathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome (CRPS) Type I and Type II, entrapment neuropathies (e.g., carpal tunnel syndrome), HIV sensory neuropathy, iatrogenic neuralgias (e.g., postthoracotomy pain, postmastectomy pain), idiopathic sensory neuropathy, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, radiculopathy (e.g., cervical thoracic, lumbosacral), sciatica, acute herpes zoster pain, temporomandibular joint disorder pain and postradiation plexopathy; and (ii) central neuropathic pain, e.g., compressive myelopathy from spinal stenosis, HIV myelopathy, multiple sclerosis pain, Parkinson's disease pain, postischemic myelopathy, post postradiation myelopathy, poststroke pain, posttraumatic spinal cord injury and syringomyelia; and (iii) cancer associated neuropathic pain, e.g., chemotherapy induced polyneuropathy, neuropathy secondary to tumor infiltration or nerve compression, phantom breast pain, postmastectomy pain, postradiation plexopathy and myelopathy; (iv) chronic pain, e.g., back pain, rheumatoid arthritis, osteoarthritis, inflammatory pain, non-inflammatory pain, myofascial pain, fibromyalgia, cancer pain, visceral pain, somatic pain, pelvic pain, musculoskeletal pain, post-traumatic pain, bone pain and idiopathic pain; (v) acute pain, e.g, acute postsurgical pain (including laparoscopic, laparatomy, gynecologic, urologic, cardiothoracic, arthroscopic, gastrointestinal, neurologic, orthopedic, oncologic, maxillofacial, ophthalmic, otolaryngologic, soft tissue, plastic, cosmetic, vascular and podiatric surgery, including abdominal surgery, abdominoplasty, adenoidectomy, amputation, angioplasty, appendectomy, arthrodesis, arthroplasty, arthroscopy, bilateral cingulotomy, biopsy, brain surgery, breast biopsy, cauterization, cesarean section, cholecystectomy, circumcision, commissurotomy, cordotomy, corneal transplantation, cricothoracotomy, discectomy, diverticulectomy, episiotomy, endarterectomy, endoscopic thoracic sympathectomy, foreskin restoration, fistulotomy, frenectomy, frontalis lift, fundectomy, gastrectomy, grafting, heart transplantation, hemicorporectomy, hemorrhoidectomy, hepatectomy, hernia repair, hypnosurgery, hysterectomy, kidney transplantation, laminectomy, laparoscopy, laparotomy, laryngectomy, lithotripsy, lobotomy, lumpectomy, lung transplantation, mammectomy, mammoplasty, mastectomy, mastoidectomy, mentoplasty, myotomy, mryingotomy, nephrectomy, nissen fundoplication, oophorectomy, orchidectomy, parathyroidectomy, penectomy, phalloplasty, pneumotomy, pneumonectomy, prostatectomy, psychosurgery, radiosurgery, ritidoplasty, rotationplasty, sigmoidostomy, sphincterotomy, splenectomy, stapedectomy, thoracotomy, thrombectomy, thymectomy, thyroidectomy, tonsillectomy, tracheotomy, tracheostomy, tubal ligation, ulnar collateral ligament reconstruction, ureterosigmoidostomy, vaginectomy, vasectomy, vulvectomy; renal colic; incisional pain; inflammatory incisional pain; nociceptive incisional pain; acute neuropathic incisional pain following surgery), renal colic, trauma, acute back pain, burn pain, burn dressing change pain, migraine pain, tension headache pain, acute musculoskeletal pain, acute exacerbation or flare of chronic back pain, acute exacerbation or flare of osteoarthritis, acute exacerbation or flare of chronic pain, breakthrough chronic non-cancer pain, breakthrough cancer pain, acute exacerbation or flare of fibromylagia, acute exacerbation or flare of rheumatoid arthritis, acute exacerbation or flare of myofacsial pain, acute exacerbation or flare of chronic idiopathic pain, acute exacerbation or flare of neuropathic pain, procedure related pain (e.g., arthroscopy, laparoscopy, endoscopy, intubation, bone marrow biopsy, soft tissue biopsy, catheterization), and other self-limiting pain states. As used herein, the term "acute pain" refers to self-limiting pain that subsides over time and usually lasting less that about 30 days and more preferably lasting less than about 21 days. Acute pain does not include chronic conditions such as chronic neuropathy, chronic neuropathic pain and chronic cancer and non-cancer pain. [00595] As used herein, "neuropathic pain" is pain initiated or caused by a primary lesion or dysfunction of the nervous system and includes (i) peripheral neuropathic pain and (ii) central neuropathic pain.
[00596] As used herein, the term "chronic pain" includes all non-neuropathic pain lasting more than 30 days, including inflammatory pain, non-inflammatory pain, muscle pain, joint pain, fascia pain, visceral pain, bone pain and idiopathic pain.
[00597] As used herein, the term "antipyretic", "anti-fever" or "fever reducing" refers to pharmaceutical agents that prevent or reduce fever by lowering the body temperature from a raised state.
[00598] As used herein, "Perceptible Pain Relief, "Confirmed Perceptible Pain Relief and "Meaningful Pain Relief are assessed and defined as follows: At the time of dosing with the study medication, a trained member of study staff starts two stopwatches for each patient. The patient is instructed to stop the first stopwatch at the time of perceptible pain relief and the second stopwatch at the time when they first experience meaningful pain relief. The usual definitions of the perceptible and meaningful pain relief are as follows: Perceptible Pain Relief is when the patient begins to feel any pain relieving effect from the drug. The patient is typically instructed as follows: "I would like you to stop the first stopwatch when you first feel any pain relief whatsoever. This does not mean you feel completely better, although you might, but when you first feel any difference in the pain that you have had". Meaningful Pain Relief is when the patient feels their pain relief is meaningful to them. The patient is typically instructed as follows: "I would like you to stop the second stopwatch when you have meaningful pain relief. That is, when the relief from the pain is meaningful to you". Confirmed Perceptible Pain Relief is Perceptible Pain Relief in those patients who go on to also have Meaningful Pain Relief.
[00599] As used herein, "NNT" or "the number needed to treat" is the number of patients who need to be treated in order for one patient to obtain > 50% pain relief or > 50% reduction in pain intensity at a specified timepoint.
[00600] As used herein, Responded/,, is the number of patients who have a 30% postbaseline reduction in pain at a specified timepoint.
[00601] For the purposes of in vivo testing, unless specified otherwise, pain intensity is measured on a VAS or categorical scale. On the categorical scale, the patient is asked "My pain at this time is: None = 0, Mild = 1, Moderate = 2, Severe = 3. On the VAS, the patient is asked "My pain at this time is" (with VAS anchors: "No Pain" and "Extreme Pain").
[00602] For the purposes of in vivo testing, unless specified otherwise, pain relief is measured on a categorical scale. The patient is asked "My relief from starting pain is: None = 0, A little = 1 , Some = 2, A lot = 3, Complete = 4.
[00603] As used herein, the term "Fever" (also known as "pyrexia", or a "febrile response" refers to an increase in internal body temperature to levels that are above normal (i.e., above 370C or 98.6°F). Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, usually by about 1-2°C. When a patient has or is suspected of having a fever, that person's body temperature is measured using a thermometer. Fever may be present if: (i) the rectal temperature is at, or higher than 38°C (100.40F); (ii) the oral temperature is at, or higher than 37.50C (99.5°F); or (iii) axillary temperature is at, or higher than 37.2°C (99°F). Fever is usually classified as: (i) low- grade: 38 - 39°C (100.4 - 102.20F); (iii) moderate: 39 - 40 0C (102.2 - 104 0F); (iii) high- grade: > 40 0C (> 104 0F) or (iv) hyperpyrexia: > 42 0C (> 107.6 0F). Hyperpyrexia is a medical emergency because it approaches the upper limit compatible with human life. Fever is a common symptom of many medical conditions, including infectious diseases, immune response, tissue destruction, malignancies, metabolic disorders, thromboembolic processes, drug induced and idiopathic
[00604] As used herein, "equianalgesic doses," also referred to as "analgesic equivalence," is a term used by practitioners of the art to refer to approximately comparable doses of analgesics required to provide a similar magnitude of analgesia. There are established standards to allow practitioners of the art to convert the dose of one analgesic, given by any route of administration, to an approximately equivalent dose of another analgesic, given by any route of administration. These analgesic conversion tables provide what in the art is called "analgesic equivalence" or "equianalgesic doses" (Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, Fourth Edition, 5th ed, American, Pain Society (2003); Gutstein HB & Akil H. Opioid Analgesics. In: Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 10th Ed., Hardman JG & Limbird LE (Eds), p 569-619, McGraw-Hill, New York, NY); ; Roberts U & Morrow JD. Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the - -
Treatment of Gout. In: Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 10th Ed., Hardman JG & Limbird LE (Eds), p 687-731, McGraw-Hill, New York, NY; Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No. 02-E002, October 2001; Carr et al. J Nat Cancer Inst Monograph 2004;32:23-31; Agency for Health Care Policy and Research Clinical Practice Guidelines for Cancer Pain Management, Guideline No. 9, AHCPR Publication No. 94-0592, March 1994; Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005). The availability of analgesic equivalence tables allows practitioners of the art to convert patients from one analgesic to another without a protracted titration period on the new analgesic.
EXAMPLES
[00605] Non-limiting examples are set forth below. Examples 1 to 11 involve complexes of ketoprofen, dexketoprofen and piroxicam with ethylenediamine and/or piroxicam. These examples demonstrate, among other things, the feasibility of preparing complexes of selected NSAIDS with ethylenediamine and/or piroxicam to enhance solubilization, to facilitate small volume delivery, to facilitate bolus injections of selected NSAIDS (compared to the generally administered slow IV infusions) and to administer the dosage forms rapidly with decreased injection site pain, injection site inflammation, injection site irritation, phlebitis and thrombophlebitis.
[00606] Example 12 is a randomized double-blind clinical trial of a selected NSAID, ketoprofen in patients following surgery. The ketoprofen was administered as a bolus IV injection at two dose levels, the minimum approved intravenous dose (100 mg) and at 50% of the minimum approved dose (50 mg). Results are presented comparing the efficacy on standardized pain measures to the maximum recommended bolus IV morphine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg) and 150% of the maximum approved IV bolus dose of tramadol (150 mg). Ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) provided almost identical efficacy on all tested parameters, when compared with the minimum approved IV dose (100 mg) of ketoprofen. Both ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) and ketoprofen at the minimum approved IV dose (100 mg) provided far superior - -
efficacy when compared with the maximum recommended bolus IV morphine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg), and 150% of the maximum approved IV bolus dose of tramadol (150 mg), P <0.001.
[00607] These observations and other embodiments and aspects of the invention, including the SAD administration of one or more non-opioids of the invention by patient controlled analgesia and the use of one or more loading doses of non-opioids provide for the therapeutically effective use of SAD of the combination analgesic given parenterally; said SAD of each drug in the combination not to exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose or daily dose of the said analgesic by the same route of administration or by the oral route of administration.
Example 1 Ketoprofen-Piperazine (1:2) Complex
[00608] The solubility of ketoprofen is 51 mg/1000 mL or 0.051 mg/mL. An aqueous mixture of 0.5 M of ketoprofen and 1.0 M and piperazine was sonicated until a clear solution was obtained. The solution was then filtered with a 0.45 μm syringe filter (pH about 10.00 for filtered aliquot). Small aliquots (about 0.250 mL) were placed in a 12- depression spot ceramic plate. The physical mixture precipitated out at ambient temperature over several days (2-3 days).
[00609] The ketoprofen-piperazine complex was formed as a semisolid (physical mixture) having an aqueous solubility of greater than 360 mg/mL and a pH of about 9.4 (for a saturated solution).
Example 2 Ketoprofen-Ethylenediamine (1:2) Complex
[00610] The solubility of ketoprofen is 51 mg/1000 mL or 0.051 mg/mL. A mixture of 0.5
M of ketoprofen and 1.0 M and ethylenediamine was sonicated until a clear solution was obtained. The solution was then filtered with a 0.45 μm syringe filter (pH about 10.00 for - -
filtered aliquot). Small aliquots (about 0.250 mL) were placed in a 12-depression spot ceramic plate. The physical mixture precipitated out at ambient temperature over several days (2-3 days).
[00611] The ketoprofen-ethylenediamine complex was formed as a semisolid having an aqueous solubility of greater than 500 mg/mL and a pH of about 7.3 (for a saturated solution).
Example 3 Static Dilution Test of a Ketoprofen-Ethylenediamine Composition
[00612] A 500 mg ketoprofen solution was serially diluted in normal saline (NS) and isotonic Sorensen phosphate buffer pH 7.4 (ISPB) separately. Dilutions were made by adding respective volumes of the solutions to NS or ISPB such that a range of 4-2560 fold dilution was covered. Thus, for the first dilution 1 part of solution was added to 3 parts of NS or ISPB resulting in a 4-fold dilution. Subsequent dilutions were made serially resulting in a final 8-, 16-, 32-, 64-, 128-, 256-, and 2560-fold dilution. After every dilution, vials were vortexed and allowed to stand for 1 minute. Presence of precipitation in the form of turbidity or cloudiness was tested visually using Laser Diffraction (Tyndall Effect). The pH was measured after every dilution. Vials were rechecked for the presence of precipitation after 24 hours.
[00613] Ketoprofen-ethylenediamine passed the static dilution test. No precipitation or turbidity was observed visually upon passing laser beam for the entire range of dilution (4-2560 fold) both after 1 minute as well as 24 hours following dilution.
Results of Static Dilution Studies
Figure imgf000207_0001
- -
Figure imgf000208_0001
Example 4 Static Dilution Test of a Ketoprofen-Piperazine Composition
[00614] A 50 mg ketoprofen solution was serially diluted in normal saline (NS) and isotonic Sorensen phosphate buffer pH 7.45 (ISPB) separately. Dilutions were made by adding respective volumes of the solutions to NS or ISPB such that a range of 2-3200 fold dilution was covered. Thus, for the first dilution 1 part of solution was added to 1 parts of NS or ISPB resulting in a 2-fold dilution. Subsequent dilutions were made serially resulting in a final 4-, 8-, 16-, 32-, 320-, 3200-fold dilution. After every dilution vials were vortexed and allowed to stand for 1 minute. Presence of precipitation in the form of turbidity or cloudiness was tested visually using Laser Diffraction (Tyndall Effect). The pH was measured after every dilution. Vials were rechecked for the presence of precipitation after 24 hours.
[00615] Ketoprofen-piperazine passed the static dilution test, i.e., no precipitation or turbidity was observed visually upon passing laser beam for the entire range of dilution (4-3200 fold) both after 1 minute as well as 24 hours following dilution.
Results of Static Dilution Studies
Figure imgf000208_0002
- -
Figure imgf000209_0001
Example 5 Dynamic Dilution Test
[00616] Two 50 mg/mL ketoprofen formulations (ketoprofen-ethylenediamine and ketoprofen-piperazine) were tested and compared for the occurrence of precipitation upon dynamic dilution in ISPB using a validated standard dynamic injection apparatus with high predictive value for phlebitis. (See Yalkowsky, S.H. et al., J. Pharma. ScL 72:1014- 19 (1983); Johnson et al., J. Pharm. ScL 92:1574-81 (2003)). Each solution at a flow rate of 5 mL/min was introduced to ISPB flowing at a rate of 5 mL/min in a tube for 30 seconds and passed through a flowcell. Absorbance was measured at 540 nm using a UV spectrophotometer. The wavelength 540 nm was chosen since all the formulations had no or very small absorbance at that wavelength. The results of the tests are shown in the Figures.
[00617] The results indicate that there was no substantial precipitation of the formulations in this test. The solutions, tested at 50 mg/mL, both passed the dynamic precipitation test, i.e., no significant change in absorbance was observed at 540 nm. The minor absorbance (< 0.1) was neglected as this was considered to result from the schlieren pattern developed during mixing due to difference in viscosity of the solution and ISPB. Phenytoin solution, which is known to produce phlebitis, was used as a positive control in this test. Note also that the sharp spikes observed for the test formulations are the result of schlieren patterns that result from density differences between the formulation and the diluent and are not due to precipitation.
Example 6 Relative Viscosity of Ketoprofen-Ethylenediamine Formulation
[00618] The relative viscosity of the ketoprofen-ethylenediamine solutions (50 and 500 mg/mL) and ketoprofen-piperazine solutions (12.7 mg/mL and 50 mg/mL) were determined by the capillary method using an Ostwald-Cannon-Fenske viscometer. The time required for each solution to pass between two marks on the viscometer was used to determine the relative velocity. Density was measured separately for the solutions. Water was used as reference liquid (viscosity of water at 20° C is 1.002 cP). The following equation was used to calculate the viscosity: i\ \ lΑi = Pl t. / p2 t2 where: r|l is the viscosity of test solution r\2 is the viscosity of water at 20° C
Pj is the density of test solution
P2 is the density of water tj is the time taken by test solution to pass between two marks in the viscometer t2 is the time taken by water to pass between two marks in the viscometer
[00619] The viscosities of ketoprofen-ethylenediamine 50 mg/mL and 500 mg/mL, as determined by the Ostwald-Cannon-Fenske viscometer were 1.2 and 26 cP, respectively.
[00620] The viscosities of ketoprofen-piperazine solutions 12.7 and 50 mg/Ml were 1.12
Cp and 1.25 cP, respectively. - -
Example 7 Ionic Strength of Ethyl enediamine and Piperazine Salts of Ketoprofen
[00621] The ionic strength for ketoprofen-ethylenediamine 50 and 500 mg/mL and ketoprofen-piperazine 12.7 and 50 mg/mL solutions were calculated using following equation: μ = 0.5 Σci(Zi)2 where: μ is the ionic strength of the solution
Cj is the concentration of the ionic species
Zj is the charge on the ionic species [00622] The ionic strength of ketoprofen-ethylenediamine 50 and 500 mg/mL was 0.295 and 2.95, respectively. [00623] The ionic strength of ketoprofen-piperazine 12.7 and 50 mg/mL solutions was
0.225 and 0.5, respectively
Example 8
[00624] The purpose of this study was to evaluate the thrombophlebitis potential of unsalified ketoprofen relative to its ethylenediamine and piperazine salts, using a dynamic injection model of phelebitis. Unsalified ketoprofen 50 mg/mL was prepared in 0.1 N NaOH. The sample was sonicated for approximately 20 minutes and the resulting suspension of pH 6.50 was filtered with a 0.45 μm syringe filter and tested for the occurrence of precipitation upon dynamic dilution in ISPB using a validated standard dynamic injection apparatus with high predictive value for phlebitis. Ketoprofen at a flow rate of 5 mL/min was introduced to ISPB flowing at a rate of 5 mL/min in a tube for 30 seconds and passed through a flowcell. Absorbance was measured at 540 run using a UV spectrophotometer. The wavelength 540 nm was chosen since all the formulations had no or very small absorbance at that wavelength. The results were compared with ketoprofen- ethylenediamine and ketoprofen-piperazine (without any pH adjustment or additives). - -
[00625] The absorbance from the unsalified pH adjusted ketoprofen was a 83 -fold and
445-fold greater than the relative absorbencies of ethylenediamine and piperazine salts, respectively, at a wavelength of 540 nm. Max UV-Absorbance (540 nm)
Sample lnjection-1 Injection-2 Injection-3
Ketoprofen 50mg/mL suspension pH-6.50 2.7763 3.1730 3.1730 Ketoprofen-Ethylenediamine 50 mg/mL 0.0413 0.0295 0.0383 Ketoprofen-Piperazine 50 mg/mL (1:2 mix) 0.0152 0.0030 0.0023
Example 9
[00626] The purpose of this study was to test the stability of ethylenediamine and piperazine salts of ketoprofen. Ketoprofen as the ethylenediamine salt (0.1 M) at an initial concentration of 50 mg/mL and ketoprofen as the piperazine crystalline salt at an initial concentration of 10 mg/mL were retested after 3 months storage at room temperature using an HPLC analytical method. There was no significant degradation of ketoprofen. The detected concentration of ketoprofen after three months was 49.4 mg/mL (98.8%) and 9.94 mg/mL (99.4%) for ketoprofen-ethylenediamine and ketoprofen-piperazine, respectively, which is within the range of experimental error.
Example 10
[00627] The purpose of this study was to assess the acute irritative potential of two dose levels of unsalified ketoprofen using a validated in vivo model for assessment of venous irritation and thrombophlebitis. Ketoprofen solution at a concentration of 50 mg/mL was prepared in 0.1 N NaOH. The pH was gradually increased over 4 hours in order to avoid the presence of excess sodium hydroxide. The pH was increased using solid sodium hydroxide. The final pH of the solution was 8.72 (constant over 12 hours). The solution was filtered with a 0.45 μm syringe filter into a sterile evacuated vial.
[00628] Two male, purpose-bred New Zealand White rabbits (age 22 weeks, weight 2.8 to
3.2 kilograms) were used for this study. Animals were individually housed, with a 12 hours light/12 hours dark cycle. All animals had access to Harlan Teklad Hi-Fiber Rabbit Diet. Tap water was available ad libitum. Study animals were acclimated to their housing for a minimum of 5 days prior to dosing. Prior to injection, the hair surrounding - -
all injection sites was clipped and the sites were swabbed with 70% ethanol or isopropyl alcohol. One rabbit each was administered test article, Treatment A (Ketoprofen 5 mg/0.1 mL or Treatment B (Ketoprofen 15 mg/0.3 mL) intravenously into a marginal vein of each ear, over one minute (i.e., Ketoprofen 5 mg/0.1 mL over one minute or Ketoprofen 15 mg/0.3 mL over one minute). All animals were treated on Day 1 of the study. The test sites were identified with indelible marker. Intravenous sites were marked with an indelible marker at the area of entry of the needle, approximately at the end of its progress and approximately 1 cm from that point.
[00629] Clinical observations for any pharmacotoxicological signs were recorded and irritation at injection sites was scored, using the Draize evaluation score.
[00630] The intravenous administration of Treatment A (Ketoprofen: 5mg/0.1 mL) resulted in well defined erythema and slight edema were observed at the 24 hour observation period. The intravenous administration of Treatment B (Ketoprofen: 15mg/0.3 mL) resulted in very slight to moderate to severe erythema and very slight edema at the 24 hour observation period.
[00631] Under the conditions of this study, intravenous administration of Treatment A
(Ketoprofen: 5 mg/0.1 mL) and Treatment B (Ketoprofen: 15 mg/0.3 mL) produced irritation in the ear veins of rabbits. The irritation was progressive over time and displayed the potential for a dose related response.
Example 11
[00632] The purpose of this study was to assess the acute irritative potential of unsalified
NSAIDs versus their respective ethylenediamine and piperazine salts when administered intravenously to rabbits, using a validated model for assessment of venous irritation and thrombophlebitis and a randomized design.
[00633] Purpose-bred New Zealand White rabbits (age 8-24 weeks, weight 2.0 to 3.5 kilograms) were used for this study. Animals were individually housed, with a 12 hours light/ 12 hours dark cycle. All animals had access to Harlan Teklad Hi-Fiber Rabbit Diet. Tap water was available ad libitum. Study animals were acclimated to their housing for a minimum of 5 days prior to dosing. Prior to injection, the hair surrounding all injection sites was clipped and the sites were swabbed with 70% ethanol or isopropyl alcohol. - -
[00634] Test articles consisted of unsalified ketoprofen, unsalified dexketoprofen, unsalified piroxicam, ketoprofen-ethylenediamine, dexketoprofen-ethylenediamine, piroxicam-ethylenediamine, ketoprofen-piperazine, and dexketoprofen-piperazine. Eight rabbits each were allocated to each group as follows:
Figure imgf000214_0001
[00635] Eight rabbits per group were anesthetized prior to test article administration with a combination of ketamine and xylazine to reduce possible injection site trauma. Puralube Vet ointment was placed in each eye after subcutaneous anesthesia was administered. All rabbits were administered the respective test article intravenously into a marginal vein of each ear, over one minute. Intravenous sites were marked with an indelible marker at the area of entry of the needle, approximately at the end of its progress and approximately 1 cm from that point, at the time of injection and as needed throughout the duration of the study. Clinical observations were recorded at 1, 4, and 24 hours. Irritation at injection sites was scored at 1 and 24 hours, using the Draize evaluation score. Injection sites underwent histopathological evaluation. Treatment differences in erythema and edema scores following treatment were compared for the unsalified NSAID with their respective ethylenediamine and piperazine salts using the Wilcoxon Signed-Ranks test.
[00636] The injection site erythema and edema scores for unsalified ketoprofen, dexketoprofen and piroxicam were compared with their respective ethlyenediamine and piperazine salts (ethylenediamine salt only for piroxicam).
[00637] Piroxicam vs. Piroxicam-Ethylenediamine: At the 1-hour post-infusion time point, piroxicam-ethylenediamine was not statistically different from unsalified piroxicam on the erythema (p<0.38) and edema (p < 0.38) scores. At the 24-hour post-infusion time - -
point, piroxicam-ethylenediamine produced significantly lower erythema (p < 0.0001) and edema (p < 0.00006) scores than unsalified piroxicam.
[00638] Ketoprofen vs. Ketoprofen-Ethylenediamine: At the 1-hour post-infusion time point, ketoprofen-ethylenediamine produced significantly lower erythema (p < 0.0002) and edema (p < 0.0002) scores than unsalified ketoprofen. Similarly, at the 24-hour post- infusion time point, ketoprofen-ethylenediamine produced significantly lower erythema (p < 0.0002) and edema (p < 0.0008) scores than unsalified ketoprofen.
[00639] Ketoprofen vs. Ketoprofen-Piperazine: At the 1-hour post-infusion time point, ketoprofen-piperazine produced significantly lower erythema (p < 0.0002) and edema (p < 0.0003) scores than unsalified ketoprofen. Similarly, at the 24-hour post-infusion time point, ketoprofen piperazine produced significantly lower erythema (p < 0.0003) and edema (p < 0.0001) scores than unsalified ketoprofen.
[00640] Dexketoprofen vs. Dexketoprofen-Ethylenediamine: At the 1-hour post- infusion time point, dexketoprofen-ethylenediamine produced significantly lower erythema (p < 0.0001) and edema (p < 0.0003) scores than unsalified dexketoprofen. Similarly, at the 24-hour post-infusion time point, dexketoprofen-ethylenediamine produced significantly lower erythema (p < 0.0006) and edema (p < 0.021) scores than unsalified dexketoprofen.
[00641] Dexketoprofen vs. Dexketoprofen-Piperazine: At the 1-hour post-infusion time point, dexketoprofen-piperazine produced significantly lower erythema (p < 0.0019) and edema (p < 0.0019) scores than unsalified dexketoprofen. Similarly, at the 24-hour post- infusion time point, dexketoprofen-piperazine produced significantly lower erythema (p < 0.0002) and edema (p < 0.0024) scores than unsalified dexketoprofen.
[00642] The mean injection site erythema and edema scores for unsalified NSAID and their respective piperazine and/or ethlyenediamine salts at 1 and 24 hours post infusion are presented in the Table below.
Mean Injection Site Erythema and Edema Score (Draize Score)
Figure imgf000215_0001
- -
Figure imgf000216_0001
ER = Erythema; ED = Edema
[00643] Microscopic observations of injection sites included congestion, edema, hemorrhage, inflammatory cell infiltrate, necrosis/loss of cellular detail (vessel and regional), thrombosis, necrosis/exudative scabs of the epithelium and occasional incidental observations of keratin cyst, acanthosis, dermal fibrosis or chronic dermal inflammation. Thrombosis was recorded for amorphous aggregates of fibrin like material within vascular lumens and variably adherent to vessel walls. These aggregates consistently lacked organization. Necrosis/exudative scabs at the epithelial surface were generally only recorded when they were proximal to the ear vein and hence likely to be representative of the needle point of entry through the epidermis.
[00644] Piroxicam vs. Piroxicam-Ethylenediamine: Piroxicam-ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified piroxicam, which had an intermediate incidence. Similarly, piroxicam-ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified piroxicam which had an intermediate incidence.
[00645] Ketoprofen vs. Ketoprofen-Ethylenediamine: Ketoprofen-ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified ketoprofen, which had a high incidence. Similarly, ketoprofen ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified ketoprofen which had a high incidence.
[00646] Ketoprofen vs. Ketoprofen-Piperazine: Ketoprofen-piperazine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified ketoprofen, which had a high incidence. Similarly, ketoprofen-piperazine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified ketoprofen which had a high incidence.
[00647] Dexketoprofen vs. Dexketoprofen-Ethylenediamine: Dexketoprofen- ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified dexketoprofen, which had an intermediate incidence. Similarly, dexketoprofen-ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified dexketoprofen which had an intermediate incidence.
[00648] Dexketoprofen vs. Dexketoprofen-Piperazine: Dexketoprofen-piperazine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified. dexketoprofen, which had an intermediate incidence. Similarly, dexketoprofen piperazine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified dexketoprofen which had an intermediate incidence.
[00649] Under the conditions of this study, injection site erythema and edema scores for unsalified ketoprofen, dexketoprofen, and piroxicam were higher than their respective piperazine and/or ethlyenediamine salts. Similarly, histopathologic examination revealed that the incidence of inflammatory cell infiltrates and the intensity of edema and infiltrates for unsalified ketoprofen, dexketoprofen, and piroxicam were higher than their respective piperazine and/or ethlyenediamine salts.
Example 12
[00650] Study Design: The study was a randomized, double blind controlled clinical trial in patients with moderate to severe postsurgical pain after removal of bony impacted third molars.
[00651] Treatments: The study included the following treatments administered by IV bolus injection, ketoprofen 100 mg (the minimum approved dose of IV ketoprofen); ketoprofen 50 mg (50% of the minimum approved dose of IV ketoprofen); tramadol 150 mg (150% of the maximum approved dose of bolus IV tramadol; tramadol 100 mg (the maximum approved dose of bolus IV tramadol); and morphine 4 mg (the maximum recommended bolus dose of IV morphine). - -
[00652] Study Objectives: The objective of the study was to compare the efficacy and safety of the treatments in patients with moderate to severe postsurgical pain.
[00653] Methodology: This was a randomized, double-blind, single-dose, parallel group, positive comparator study in patients requiring removal of 2 or more third molars (one of which was a mandibular, bony impacted third molar). Patients were randomly assigned to receive a single dose of each treatment. Pain was assessed by each patient at Baseline (0 hour); 15, 30, and 45 minutes; and at 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours after administration of study medication using self-rating scales. At each time period, levels of pain intensity (PI) (categorical and visual analog scale [VAS]) and pain relief (PR) were evaluated. Time to onset of perceptible and time to meaningful pain relief were evaluated using the 2 stopwatch method. Patients were encouraged to wait at least 60 minutes from the time of study medication administration to use of rescue medication; however, patients could have received rescue medication at any time during the study. Immediately before the first dose of rescue medication, the patients completed final pain assessments. Efficacy assessments were terminated upon administration of rescue medication. Rescue analgesic consisted of oral ibuprofen 400 mg or acetaminophen (acetaminophen) 1000 mg per dose, given every 4 to 6 hours as needed (PRN), up to a maximum dose of 2400 mg of ibuprofen or 4 g of acetaminophen per day. In the event that ibuprofen and/or acetaminophen did not provide satisfactory analgesia, one or 2 doses of oral codeine 30 mg plus acetaminophen 500 mg every 4 hours PRN could have been administered, if absolutely necessary. A patient global evaluation of study medication was completed at 8 hours after study drug administration or immediately before administration of rescue medication.
[00654] Safety was assessed by routine laboratory analyses (chemistry, hematology and urinalysis) and physical examination performed prior to surgery and 5 to 10 days post- treatment. Vital signs (heart rate, respiration rate, and blood pressure) were recorded at baseline; 15 and 30 minutes; and 1, 4, 6, and 8 hours post-dosing. Vital signs were collected only after pain assessments at corresponding time points were collected. Female patients of childbearing potential had a urine pregnancy test at Screening, within 24 hours prior to surgery, and at the Follow-up visit. Adverse events (AEs) were monitored during the course of the study. [00655] Diagnosis and main criteria for inclusion: Male and female patients, 18 to 40 years of age (inclusive), and with a body weight of 50 kg to 115 kg (inclusive) who had surgical extraction of 2 or more third molars were eligible provided that one was a bony impacted mandibular third molar, and if only 2 third molars were extracted, they were ipsilateral. Qualified patients had moderate or severe pain within 6 hours of completion of surgery as measured by the categorical PI scale and a VAS measurement for PI of > 50 mm at Baseline. Patients provided written informed consent prior to participation in the study, were in good health as determined by the Investigator, and demonstrated the ability to properly complete the pain assessments, to understand the English language, and to cooperate with study procedures. Female patients of childbearing potential were non- lactating, had a negative urine pregnancy test within 24 hours before surgery, and practiced abstinence or a medically acceptable form of contraception.
[00656] Criteria for evaluation:
[00657] Efficacy: The primary efficacy measure was total pain relief (TOTPAR) over the
0-4 hour interval. Secondary efficacy measures were TOTPAR over the 0-2, 0-6, and 0-8 hour intervals; summary of pain intensity difference (SPID) over the 0-2, 0-4, 0-6, and 0- 8 hour intervals; sum of PR and pain intensity difference (SPRID) over the 0-2, 0-4, 0-6, and 0-8 hour intervals; time from study medication administration to first rescue medication; time-specific pain intensity difference (PID) on the VAS and categorical scales; time-specific PR; time-specific PR and PID (PRID), peak PID; peak PR; time to pain half gone; time to first change from the baseline assessment in PID (categorical scale) of > 1; time from study medication to perceptible pain relief; time from study medication administration to confirmed perceptible pain relief (stopwatch); time from study medication administration to meaningful pain relief (stopwatch); and patient global evaluation.
[00658] Safety: Safety was assessed by incidence of AEs, changes in clinical laboratory testing, vital signs (heart rate, respiration rate, blood pressure), and physical examinations.
[00659]
[00660] Statistical methods: All efficacy analyses were performed on the Intent-to-Treat
(ITT) population, defined as all randomized patients who received study medication and had at least one post baseline PI or PR measurement. Patients who took rescue -21 -
medication within 60 minutes after dosing were included in the ITT population. Each efficacy variable had multiple comparisons performed using Fisher's protected least significance (PLSD) in order to control for the comparison-wise error rate. If a variable was measured over multiple intervals, this was done for each interval. The overall 2- sided test (i.e., F, or log-rank) was first assessed for significance (p < 0.05). If it was significant, all 2-sided pair-wise treatment comparisons were performed and a given comparison was declared significant if its p-value was < 0.05. TOTPAR, SPID, SPRID, and time-specific PID, PR, and PRID were analyzed using an analysis of variance (ANOVA) model with effects for treatment and baseline pain stratification.
[00661] The time to perceptible pain relief was the time recorded by the first stopwatch, and the time to meaningful pain relief was the time recorded by the second stopwatch. Time to confirmed perceptible pain relief was defined as the time to perceptible pain relief only if both perceptible and meaningful pain relief were experienced. Time to perceptible pain relief, confirmed perceptible, meaningful pain relief; time to re- medication; time to first change from the Baseline assessment in PID (categorical) of > 1; and time to pain half gone were estimated using Kaplan-Meier method. Summary information including the median time estimates and 95% confidence intervals on the median time for the above time variables was provided using Kaplan-Meier methodology and the method of Simon and Lee, and treatment groups were compared using the log- rank test. Peak PID, peak PR, and the patient global evaluation were analyzed using the stratified rank-sum test, stratified by baseline pain. The proportions of patients with 50% pain gone, with meaningful pain relief, and re-medicated were analyzed using the Chi- square test.
[00662] The safety analyses were conducted on the treated patient population, defined as all randomized patients who received study medication. Safety measures were summarized using descriptive statistics.
[00663] Results and Conclusions:
[00664] This study compared the following treatments administered by IV bolus injection, ketoprofen 100 mg (the minimum approved dose of IV ketoprofen); ketoprofen 50 mg (50% of the minimum approved dose of IV ketoprofen); tramadol 150 mg (150% of the maximum approved dose of bolus IV tramadol; tramadol 100 mg (the maximum approved dose of bolus IV tramadol); and morphine 4 mg (the maximum recommended bolus dose of IV morphine).
[00665] The efficacy results were not significantly different for ketoprofen 50 mg versus ketoprofen 100 mg.
[00666] A single IV dose of ketoprofen 50 mg or 100 mg demonstrated efficacy results that were statistically significantly superior to those of a single IV dose of placebo or morphine 4 mg for all efficacy measures, and significantly superior to a single IV dose of tramadol 100 mg or tramadol 150 mg for almost all efficacy measures.
[00667] A single IV dose of ketoprofen 50 mg or 100 mg received a global evaluation of
Good, Very Good, or Excellent for 88% to 94% of patients, compared with 45% to 49% of patients who received tramadol, 15% of patients who received morphine 4 mg, and 9% of patients who received placebo.
[00668] Administration of a single IV dose of ketoprofen was well tolerated at both the
50 mg and 100 mg dose levels, with an overall incidence of adverse events similar to that for placebo.
[00669] The proportions of patients with at least one adverse event for ketoprofen 50 mg, and ketoprofen 100 mg groups was 60.6%, and 64.5%, respectively. The proportions of patients with at least one adverse event for morphine 4 mg, tramadol 100 mg and tramadol 150 mg was 72.7%, 72.7% and 86.4%, respectively
[00670] The majority of adverse events in the ketoprofen groups were mild or moderate in intensity; only 1/33 patients treated with ketoprofen 50 mg had severe adverse events (dry mouth [dry socket] and postoperative infection), and 2/31 patients treated with ketoprofen 100 mg reported one severe adverse event each (application site swelling and abdominal pain). The majority of adverse events in the tramadol 100 mg group were mild or moderate; whereas, all adverse events in the tramadol 150 mg group were moderate or severe. Five of 33 patients in the 100 mg group and 13/22 patients in the 150 mg group had severe adverse events. Three of 33 patients in the morphine 4 mg group had severe adverse events. Serious adverse events were reported for 3 patients in the tramadol 150 mg group; 2 of these patients experienced convulsions immediately after dosing, and one patient was hospitalized for a postoperative abscess. No patients in any other treatment group experienced a serious adverse event or were discontinued from the study for any reason. There did not appear to be adverse affects on laboratory values or vital signs in any treatment group, with the exception of severe hypotension accompanied by loss of consciousness for one patient in the morphine 4 mg group.
[00671] Ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) provided almost identical efficacy on all tested parameters, when compared with the minimum approved IV dose (100 mg) of ketoprofen. Both ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) and ketoprofen at the minimum approved IV dose (100 mg) provided far superior efficacy when compared with the maximum recommended bolus IV morphine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg), and 150% of the maximum approved IV bolus dose of tramadol (150 mg), P < 0.05 to < 0.001.
[00672] These observations and other embodiments and aspects of the invention, including the dosing of ULD of selected NSAIDS by patient controlled analgesia (until now not recommended) and the use of one or more loading doses preceding the ULD of selected NSAID provides a basis therapeutically effective use of one or more selected NSAID given parenterally at dose not to exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose or daily dose of the NSAID by the same route of administration or by the oral route of administration.
[00673] These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.
[00674] The included examples are illustrative but not limiting of the methods and composition of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention.
[00675] A wide variety of materials can be used for preparing the dosage form according to this invention. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.
[00676] Having now fully described the invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

- - WHAT IS CLAIMED IS:
1. A method of treating pain, fever and/or inflammation in a subject in need of such treatment, said method comprising parenterally administering a dosage form comprising at least one compound each selected from at least two of the three groups (a, b, c) below: (a) celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)- ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and (c) acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; wherein said composition is administered by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route; wherein said dose in adults from group (a) is less than about 20 mg if said compound is dexibuprofen, less than about 20 mg if said compound is dexflurbiprofen, less than about 10 mg if said compound is dexketoprofen, less than about 3.75 mg if said compound is diclofenac, less than about 20 mg if said compound is flurbiprofen, less than about 40 mg if said compound is ibuprofen, less than about 20 mg if said compound is ketoprofen, less than about 5 mg if said compound is ketorolac, less than about 2.5 mg if said compound is S(-)-ketorolac, less than about 100 mg if said compound is naproxen, less than about 5 mg if said compound is piroxicam, less than about 10 mg if said compound is tenoxicam, less than about 2 mg if said compound is lornoxicam, less than about 40 mg if said compound is celecoxib, less than about 40 mg if said compound is lumiracoxib, less than about 10 mg if said compound is parecoxib, and less than about 10 mg if said compound is etoricoxib, or wherein said dose in adults or children is less than about 0.3 mg/kg if said compound is dexibuprofen, less than about 0.3 mg/kg if said compound is dexflurbiprofen, less than about 0.15 mg if said compound is dexketoprofen, less than about 0.053 mg/kg if said compound is diclofenac, less than about 0.3 mg/kg if said compound is flurbiprofen, less than about 0.6 mg/kg if said compound is ibuprofen, less than about 0.3 mg/kg if said compound is ketoprofen, less - -
than about 0.07 mg/kg if said compound is ketorolac, less than about 0.04 mg/kg if said compound is S(-)-ketorolac, less than about 1.4 mg/kg if said compound is naproxen, less than about 0.07 mg/kg if said compound is piroxicam, less than about 0.15 mg/kg if said compound is tenoxicam, less than about 0.03 mg/kg if said compound is lornoxicam, less than about 0.57 mg/kg if said compound is celecoxib, less than about 0.57 mg/kg if said compound is lumiracoxib, less than about 0.14 mg/kg if said compound is parecoxib and less than about 0.14 mg/kg if said compound is etoricoxib; wherein said dose in adults from group (b) is less than about 0.3 mg if said compound is levorphanol, less than about 2 mg if said compound is methadone, less than about 5 mg if said compound is morphine- 6-glucuronide, less than about 2 mg if said compound is oxycodone, less than about 0.3 mg if said compound is oxymorphone, less than about 1 mg if said compound is racemorphan and less than about 10 mg if said compound is tramadol; wherein said dose in adults from group (c) is less than about 200 mg if said compound is acetaminophen, less than about 400 mg if said compound is propacetamol, less than about 300 mg if said compound is nitroparacetamol; said composition substantially free of beta-cyclodextrins.
2. A method of treating pain, fever and/or inflammation in a subject in need of such treatment, said method comprising parenterally administering a dosage form comprising at least one compound each selected from at least two of the three groups (a, b, c) below: (a) celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)- ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and (c) acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof;; wherein said composition is administered by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route; wherein said dose of each drug is less about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual - -
dose and/or daily dose by the same parenteral route of administration, said composition substantially free of beta-cyclodextrins.
3. A method of treating pain, fever and/or inflammation in a subject in need of such treatment, said method comprising administering a dosage form comprising at least one compound each selected from at least two of the three groups (a, b, c) below: (a) celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and (c) acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; wherein said composition is administered by the intrathecal route; wherein said dose from group (a) is less than about 0.00014 mg/kg in adults or children, or less than 0.01 mg in adults; wherein said dose in adults from group (b) is less than about 0.0029 mg/kg in adults or children, or less than 0.2 mg in adults if said compound is levorphanol, less than about 0.0072 mg/kg in adults or children, or less than 0.5 mg in adults if said compound is methadone, less than about 0.001425 mg/kg in adults or children, or less than 0.1 mg in adults if said compound is morphine-6- glucuronide, less than about 0.0072 mg/kg in adults or children, or less than 0.5 mg in adults if said compound is oxycodone, less than about 0.0015 mg/kg in adults or children, or less than 0.1 mg in adults if said compound is oxymorphone, less than about 0.006 mg/kg in adults or children, or less than 0.4 mg in adults if said compound is racemorphan and less than about 0.14 mg/kg in adults or children, or less than 10 mg in adults if said compound is tramadol; wherein said dose in adults from group (c) is less than about 200 mg if said compound is acetaminophen, less than about 400 mg if said compound is propacetamol, and less than about 300 mg if said compound is nitroparacetamol; said composition substantially free of beta-cyclodextrins. - -
4. The method according to claim 1 to claim 3, where in the dose of each compound in the dosage form is a subanalgesic dose.
5. The method according to claim 1 to claim 4, wherein at least the non-opioid is administered by patient controlled analgesia by the intravenous route (PCA), the epidural route (PCEA) or the subcutaneous route, wherein the non-opioid dose is the demand dose.
6. The method according to claim 5, wherein the patient controlled analgesia device has a lockout period of not less than about 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 210, 240, 300 or 360 minutes.
7. The method according to claim 5, wherein the cumulative daily or 24 hour demand dose administered does not exceed about 10, 20, 30, 40, 50, 60 or 70% of the minimum approved or recommended daily dose of each selected analgesic by the same route of administration or by the oral route of administration.
8. The method according to claim 1 to claim 5, where administration of at least the non- opioid is preceded by one or more loading doses of said non-opioid, said loading dose given by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said non-opioid by said route, or at least equal to the minimum approved or recommended oral dose.
9. The method according to claim 1 to claim 5, wherein administration of the subanalgesic dose of each compound is in a volume of less than 0.1, 0.5, 1.0 or 2.0 mL.
10. The method according to claim 1 to claim 5, wherein administration of the subanalgesic dose of each compound is over not more than 10, 30, 60 or 120 seconds.
11. The method according to claim 1 to claim 3, wherein administration of the subanalgesic dose of at least one non-opioid is: (i) preceded by one or more loading doses of the non- opioid given by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said of the non-opioid by said route, or at least equal to the minimum approved or recommended oral dose; (ii) given as a demand dose by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration; (iii) administered not more frequently then the - -
lockout period, said lock-out period not less than about 5, 15, 20, 30, 45, 60, 90 or 120 minutes; (iv) said demand dose cumulatively not to exceed 10, 20, 30, 40, 50, 60 or 70% of the minimum approved or recommended daily dose of said non-opioid for the same route of administration or for the oral route of administration; (v) said demand dose to be given over a period not to exceed 5, 30, 60, 120 or 300 seconds.
12. A claim of claim 1 to claim 11, wherein said administration compared to administration of at least the minimum approved or recommended dose of each of the said analgesics by the same route produces one or more or all of the following:
a. improved local tolerability, improved venous tolerability, reduced local irritation, reduced injection site pain, and/or reduced phlebitis by the intravenous route; or
b. reduced injection site pain, muscular irritation, abscesses, nerve irritation and/or nerve damage by the intramuscular route;
a. reduced joint toxicity by the intra-articular route;
b. reduced subcutaneous toxicity, including injection site pain, subcutaneous irritation, subcutaneous inflammation, injection site redness and/or abscesses by the subcutaneous route;
c. reduced soft tissue toxicity, including injection site pain, discomfort, irritation and redness, by the subcutaneous route;
d. reduced gastrointestinal toxicity, including ulceration, bleeding, perforation, dyspepsia and/or heartburn by any parenteral route;
e. reduced postsurgical wound complications, including wound healing, wound closure, wound infection, edema, abscess, swelling and/or bleeding from or near the site of surgery by any parenteral route;
f. reduced orthopedic surgical complications including non-union, malunion, avascular necrosis by any route;
g. reduced post-surgical bleeding, reduced fluid replacement and/or reduced need for blood transfusion by any route; - -
h. reduced hepatic impairment, including elevations in AST, ALT, ALP, GGT, bilirubin and/or albumin by any route;
i. reduced renal impairment, including elevations in BUN, plasma creatinine and/or plasma electrolytes by any route;
j. reduced nausea, vomiting and/or retching by any route;
k. reduced drowsiness or sedation by any route;
1. reduced constipation or ileus by any route;
m. reduced pruritus by any route;
n. reduced cognitive, motor and psychomotor impairment by any route;
o. reduced cardiovascular impairment, including myocardial infarction, congestive heart failure, elevations in systolic or diastolic blood pressure elevations and/or peripheral edema by any route;
p. reduced cardiovascular impairment in patients at high risk for such impairment (e.g. patients with significant ischemic heart disease, angina, coronary occlusion and stenosis, angioplasty candidates, CABG surgery candidates), including myocardial infarction, congestive heart failure, elevations in systolic or diastolic blood pressure elevations and/or peripheral edema by any route;
q. reduced NSAID-associated side effects by any route;,
r. reduced opioid-associated side effects by any route;.
s. reduced risk of bleeding during concurrent anticoagulation and/or fibrinolytic therapy by any route;
t. reduced pharmacokinetic and/or pharmacodynamic interactions when co-administered with other drugs (drug-drug interactions) by any route; - -
u. reduced intrathecal and epidural toxicity, including injection site pain, injection site irritation, hematoma, abscess, inflammatory mass lesions and/or granulomas by the intrathecal or epidural routes;
v. TOTPAR, SPID and/or SPRID at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose after first administration which is not more than 1.5% lower for every 2% decrease in dose from the said minimum dose;
w. PID and/or PR at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose after first administration which is not more than 1.5% lower for every 2% decrease in dose from the said minimum dose;
x. PPR and/or PPID after first administration which is not more than 1.5% lower for every 2% decrease in dose from the said minimum dose;
y. Number of patients with pain who need to be treated to obtain > 50% pain relief in one patient (NNT) at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose after first administration which is not more than 1.5% lower for every 2% decrease in dose from the said minimum dose;.
z. Percentage of patients who have a > 30% postbaseline reduction in pain (Responder3o%) at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose after first administration which is not more than 1.5% lower for every 2% decrease in dose from the said minimum dose;
aa. Time to confirmed perceptible pain relief using a double stopwatch method after first administration which is not more than 1.5% shorter (i.e., earlier) for every 2% decrease in dose from the said minimum dose;
bb. Time to meaningful pain relief using a double stopwatch method after first administration which is not more than 1.5% shorter (i.e., earlier) for every 2% decrease in dose from the said minimum dose;
cc. Median time to rescue analgesic request or use after first administration which is not more than 1.5% shorter (i.e., earlier) for every 2% decrease in dose from the said minimum dose;
13. A claim of claim 1 to claim 5 wherein the pain is of mild intensity.
14. A claim of claim 1 to claim 5 wherein the pain is of moderate intensity.
15. A claim of claim 1 to claim 5 wherein the pain is of moderately severe intensity.
16. A claim of claim 1 to claim 5 wherein the pain is of severe intensity.
17. A claim of claim 1 to claim 5 wherein the pain is acute pain.
18. A claim of claim 1 to claim 5 wherein the pain is acute postsurgical pain.
19. A claim of claim 1 to claim 5 wherein the pain is acute migraine pain.
20. A claim of claim 1 to claim 5 wherein the pain is acute post-traumatic pain.
21. A claim of claim 1 to claim 5 wherein the pain is acute musculoskeletal pain.
22. A claim of claim 1 to claim 5 wherein the pain is acute renal colic pain.
23. A claim of claim 1 to claim 5 wherein the pain is acute procedure related pain.
24. A claim of claim 1 to claim 5 wherein the pain is burn pain.
25. A claim of claim 1 to claim 5 wherein the pain is acute exacerbation of chronic pain.
26. A claim of claim 1 to claim 5 wherein the pain is chronic pain.
27. A claim of claim 1 to claim 5 wherein the pain is cancer pain.
28. A claim of claim 1 to claim 5 wherein the subject is an adult.
29. A claim of claim 1 to claim 5 wherein the subject is a child.
30. A claim of claim 1 to claim 5 wherein the patient is at risk for NSAID associated side effects.
31. A claim of claim 1 to claim 5 wherein the patient has ischemic heart disease. - -
32. A claim of claim 1 to claim 5 wherein the patient is at risk for postsurgical ileus, bowel obstruction or constipation.
33. A claim of claim 1 to claim 5 wherein the patient is at high risk for or has gastrointestinal ulcer, perforation and/or bleeding.
34. A claim of claim 1 to claim 5 wherein the patient has been or is anticipated to be anticoagulated or receiving fibrinolytic therapy.
35. A claim of claim 1 to claim 5 wherein the patient is over 65 year's age.
36. A claim of claim 1 to claim 5 wherein the patient is over 70 year's age.
37. A claim of claim 1 to claim 5 wherein the patient is over 75 year's age.
38. A claim of claim 1 to claim 5 wherein an onset of effect or time to confirmed perceptible pain relief of less than about 5, 10 or 15 minutes is required.
39. A claim of claim 1 to claim 5 wherein the subject has migraine and said administration also provides relief from phonophobia, photophobia and nausea.
40. A claim of claim 1 to claim 5 wherein the standard of care further requires bolus administration.
41. A claim of claim 1 to claim 5 wherein the subject further has pain, inflammation and/or fever as result of major surgery including gynecologic surgery, gastrointestinal surgery, orthopedic surgery, urologic surgery, oncologic surgery, cardiothoracic surgery, transplant surgery, neurosurgery, vascular surgery, laparotomy, head and neck surgery or pelvic surgery.
42. A claim of claim 1 to claim 5 wherein the subject further has pain, inflammation and/or fever which is not a consequence of third molar extraction, dental surgery, bunionectomy, hammer toe repair, metatarsophalangeal surgery, podiatric surgery, dysmenorrhea, muscle strains, muscle sprains, renal colic, tension headache, muscle contraction headache, sore throat, mucositis, and/or migraine. - -
43. A claim of claim 1 to claim 5 wherein the subject further does not have pain of mild intensity (mild pain), or moderate intensity (moderate pain).
44. A claim of claim 1, claim 2, claim 4 and claim 5 wherein said administration is not intraarticular.
45. A claim of claim 1, claim 2, claim 4 and claim 5 wherein said administration is not by slow IV injection (i.e., 1 to 5 minutes).
46. A claim of claim 1 , claim 2, claim 4 and claim 5 wherein said administration is not by IV infusion (i.e., 5 to 30 minutes).
47. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the dexibuprofen dose in adults is less than about 15 mg, or less than about 10 mg, or less than about 7 mg, or less than about 5 mg, or less than about 3 mg, or less than about 1 mg.
48. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the dexflurbiprofen or flurbiprofen dose in adults is less than about 15 mg, or less than about 10 mg, or less than about 7 mg, or less than about 5 mg, or less than about 3 mg, or less than about 1 mg.
49. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the lornoxicam dose in adults is less than about less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1 mg.
50. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the ketoprofen dose in adults is less than about 15 mg, or less than about 12 mg, or less than about 10 mg, or less than about 7.5 mg, or less than about 5 mg, or less than about 4 mg, or less than about or less than about 3 mg, or less than about 2 mg, or less than about 1 mg.
51. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the dexketoprofen dose in adults is less than about 9.5 mg, or less than about 8.5 mg, or less than about 7.5 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg. - -
52. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the diclofenac dose in adults is less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, 0.5 mg.
53. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the ibuprofen dose in adults is less than about 35 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 12 mg, or less than about 10 mg, or less than about 6 mg, or less than about 5 mg or less than about 3 mg,.
54. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the ketorolac dose in adults is less than about 4.5 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg.
55. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the S(-)-ketorolac dose in adults is less than about 2.2 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.5 mg, or less than about 0.3 mg.
56. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the naproxen dose in adults is less than about 90 mg, or less than about 80 mg, or less than about 70 mg, or less than about 60 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 20 mg.
57. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the piroxicam dose in adults is less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than about 1.5 mg, or less than about 1 mg, or less than about 0.8 mg, or less than about 0.5 mg, or less than about 0.3 mg.
58. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the tenoxicam dose in adults is less than about 9.5 mg, or less than about 7.5 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg, or less than about 3 mg, or less than about 2.5 mg, or less than about 2 mg, or less than - -
about 1.5 mg, or less than about 1 mg, or less than about 0.7 mg, or less than about 0.5 mg,.
59. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the adult celecoxib dose is less than about 35 mg or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 10 mg.
60. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the adult lumiracoxib dose is less than about 35 mg or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 10 mg.
61. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the adult parecoxib dose is less than about 9 mg or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg.
62. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the adult etoricoxib dose is less than about 9 mg or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg.
63. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the acetaminophen dose in adults is less than about 200 mg, or less than about 175 mg, or less than about 150 mg, or less than about 125 mg, or less than about 100 mg, or less than about 50 mg.
64. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the propacetamol dose in adults is less than about 400 mg, or less than about 350 mg, or less than about 300 mg, or less than about 250 mg, or less than about 200 mg, or less than about 100 mg.
65. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the nitroparacetamol dose in adults is less than about 300 mg, or less than about 250, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg.
66. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the dexibuprofen dose is less than about 0.25 mg/kg, or less than about 0.20 mg/kg, or less than about 0.15 mg/kg or less than about 0.1 mg/kg, or less than about 0.07 mg/kg, or less than about 0.04 mg/kg.
67. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the dexflurbiprofen and flurbiprofen dose is less than about 0.25 mg/kg, or less than about 0.20 mg/kg, or less than about 0.15 mg/kg or less than about 0.1 mg/kg, or less than about 0.07 mg/kg, or less than about 0.04 mg/kg.
68. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the lornoxicam dose is less than about 0.25 mg/kg, or less than about 0.024 mg/kg, or less than about 0.022 mg/kg or less than about 0.02 mg/kg, or less than about 0.18 mg/kg, or less than about 0.15 mg/kg.
69. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the ketoprofen dose is less than about 0.25 mg/kg, or less than about 0.20 mg/kg, or less than about 0.15 mg/kg or less than about 0.1 mg/kg, or less than about 0.07 mg/kg, or less than about 0.04 mg/kg.
70. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the dexketoprofen dose is less than about 0.12 mg/kg, or less than about 0.09 mg/kg, or less than about 0.06 mg/kg, or less than about 0.03 mg/kg, or less than about 0.01 mg/kg.
71. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the diclofenac dose is less than about 0.05 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.043 mg/kg, or less than about 0.04 mg/kg, or less than about 0.036 mg/kg, or less than about 0.032 mg/kg, or less than about 0.028 mg/kg, or less than about 0.024 mg/kg, or less than about 0.021 mg/kg, or less than about 0.017 mg/kg.
72. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the ibuprofen dose is less than about 0.056 mg/kg, or less than about 0.052 mg/kg, or less than about 0.048 mg/kg, or less than about 0.044 mg/kg, or less than about 0.036 mg/kg, or less than about 0.026 mg/kg, or less than about 0.018 mg/kg, or less than about 0.012 mg/kg.
73. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the ketorolac dose is less than about 0.066 mg/kg, or less than about 0.062 mg/kg, or less than about 0.058 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.049 mg/kg, or less than about 0.044 mg/kg, or less than about 0.038 mg/kg.
74. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the S(-)-ketorolac dose is less than about 0.037 mg/kg, or less than about 0.034 mg/kg, or less than about 0.03 mg/kg, or - -
less than about 0.025 mg/kg, or less than about 0.02 mg/kg, or less than about 0.015 mg/kg, or less than about 0.01 mg/kg.
75. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the naproxen dose is less than about 1.36 mg/kg, or less than about 1.3 mg/kg, or less than about 1.2 mg/kg, or less than about 1.1 mg/kg, or less than about 1 mg/kg, or less than about 0.75 mg/kg, or less than about 0.55 mg/kg, or less than about 0.4 mg/kg, or less than about 0.25 mg/kg.
76. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the piroxicam dose is less than about 0.065 mg/kg, or less than about 0.06 mg/kg, or less than about 0.055 mg/kg, or less than about 0.05 mg/kg, or less than about 0.045 mg/kg, or less than about 0.04 mg/kg, or less than about 0.039 mg/kg, or less than about 0.032 mg/kg.
77. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the tenoxicam dose is less than about 0.12 mg/kg, or less than about 0.09 mg/kg, or less than about 0.05 mg/kg, or less than about 0.03 mg/kg.
78. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the celecoxib dose is less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg.
79. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the lumiracoxib dose is less than about 0.7 mg/kg, or less than about 0.6 mg/kg, or less than about 0.5 mg/kg, or less than about 0.4 mg/kg, or less than about 0.3 mg/kg, or less than about 0.2 mg/kg, or less than about 0.1 mg/kg.
80. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the parecoxib dose is less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg.
81. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the etoricoxib dose is less than about 0.14 mg/kg, or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg.
82. A claim of claim 1, claim 2, claim 4 and claim 5, wherein the adult celecoxib dose is less than about 35 mg or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 10 mg.
83. A claim of claim 3, wherein the dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam, lornoxicam, celecoxib, lumiracoxib, parecoxib and etoricoxib dose is less than about 0.009 mg, or less than about 0.007 mg, or less than about 0.005 mg, or less than about 0.002 mg.
84. A pharmaceutical composition for treating pain, fever and/or inflammation in a subject in need of such treatment, comprising parenterally administering a dosage form comprising at least one compound each selected from at least two of the three groups (a, b, c) below: (a) celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)- ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and (c) acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; wherein said composition is administered by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route; wherein said dose in adults from group (a) is less than about 20 mg if said compound is dexibuprofen, less than about 20 mg if said compound is dexflurbiprofen, less than about 10 mg if said compound is dexketoprofen, less than about 3.75 mg if said compound is diclofenac, less than about 20 mg if said compound is flurbiprofen, less than about 40 mg if said compound is ibuprofen, less than about 20 mg if said compound is ketoprofen, less than about 5 mg if said compound is ketorolac, less than about 2.5 mg if said compound is S(-)-ketorolac, less than about 100 mg if said - -
compound is naproxen, less than about 5 mg if said compound is piroxicam, less than about 10 mg if said compound is tenoxicam, less than about 2 mg if said compound is lornoxicam, less than about 40 mg if said compound is celecoxib, less than about 40 mg if said compound is lumiracoxib, less than about 10 mg if said compound is parecoxib, and less than about 10 mg if said compound is etoricoxib, or wherein said dose in adults or children is less than about 0.3 mg/kg if said compound is dexibuprofen, less than about 0.3 mg/kg if said compound is dexflurbiprofen, less than about 0.15 mg if said compound is dexketoprofen, less than about 0.053 mg/kg if said compound is diclofenac, less than about 0.3 mg/kg if said compound is flurbiprofen, less than about 0.6 mg/kg if said compound is ibuprofen, less than about 0.3 mg/kg if said compound is ketoprofen, less than about 0.07 mg/kg if said compound is ketorolac, less than about 0.04 mg/kg if said compound is S(-)-ketorolac, less than about 1.4 mg/kg if said compound is naproxen, less than about 0.07 mg/kg if said compound is piroxicam, less than about 0.15 mg/kg if said compound is tenoxicam, less than about 0.03 mg/kg if said compound is lornoxicam, less than about 0.57 mg/kg if said compound is celecoxib, less than about 0.57 mg/kg if said compound is lumiracoxib, less than about 0.14 mg/kg if said compound is parecoxib and less than about 0.14 mg/kg if said compound is etoricoxib; wherein said dose in adults from group (b) is less than about 0.3 mg if said compound is levorphanol, less than about 2 mg if said compound is methadone, less than about 5 mg if said compound is morphine- 6-glucuronide, less than about 2 mg if said compound is oxycodone, less than about 0.3 mg if said compound is oxymorphone, less than about 1 mg if said compound is racemorphan and less than about 10 mg if said compound is tramadol; wherein said dose in adults from group (c) is less than about 200 mg if said compound is acetaminophen, less than about 400 mg if said compound is propacetamol, less than about 300 mg if said compound is nitroparacetamol; said composition substantially free of beta-cyclodextrins.
85. A pharmaceutical composition for treating pain, fever and/or inflammation in a subject in need of such treatment, comprising parenterally administering a dosage form comprising at least one compound each selected from at least two of the three groups (a, b, c) below: (a) celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)- ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically - -
acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and (c) acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof;; wherein said composition is administered by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route; wherein said dose of each drug is less about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose by the same parenteral route of administration, said composition substantially free of beta-cyclodextrins.
A pharmaceutical composition for treating pain, fever and/or inflammation in a subject in need of such treatment, comprising administering a dosage form comprising at least one compound each selected from at least two of the three groups (a, b, c) below: (a) celecoxib, etoricoxib, parecoxib, lumiracoxib, valdecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; (b) levorphanol, methadone, morphine-6-glucuronide, oxycodone, oxymorphone, racemorphan and tramadol in racemic form, enatiomeric form or enantiomeric excess, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; and (c) acetaminophen, propacetamol and nitroparacetamol, pharmaceutically acceptable salts thereof, nitric oxide donors thereof and mixtures thereof; wherein said composition is administered by the intrathecal route; wherein said dose from group (a) is less than about 0.00014 mg/kg in adults or children, or less than 0.01 mg in adults; wherein said dose in adults from group (b) is less than about 0.0029 mg/kg in adults or children, or less than 0.2 mg in adults if said compound is levorphanol, less than about 0.0072 mg/kg in adults or children, or less than 0.5 mg in adults if said compound is methadone, less than about 0.001425 mg/kg in adults or children, or less than 0.1 mg in adults if said compound is morphine-6- glucuronide, less than about 0.0072 mg/kg in adults or children, or less than 0.5 mg in - -
adults if said compound is oxycodone, less than about 0.0015 mg/kg in adults or children, or less than 0.1 mg in adults if said compound is oxymorphone, less than about 0.006 mg/kg in adults or children, or less than 0.4 mg in adults if said compound is racemorphan and less than about 0.14 mg/kg in adults or children, or less than 10 mg in adults if said compound is tramadol; wherein said dose in adults from group (c) is less than about 200 mg if said compound is acetaminophen, less than about 400 mg if said compound is propacetamol, and less than about 300 mg if said compound is nitroparacetamol; said composition substantially free of beta-cyclodextrins.
87. A claim of claim 1 to 5 and claim 84 to claim 86, wherein said dosage form is administered in unsalifϊed or substantially unsalified form.
88. A claim of claim 1 to 5 and claim 84 to claim 86, wherein said dosage form further comprises ethylenediamine and/or piperazine in a molar ratio of 1 :5 to 5: 1.
89. A claim of claim 1 to 5 and claim 84 to claim 86, wherein said compound is manufactured as a ready to use solution (e.g., solution in an ampoule, vial or prefϊlled syringe).
90. A claim of claim 1 to 5 and claim 84 to claim 86, wherein said compound is: (i) administered in unsalifϊed or substantially unsalified form; and (ii) manufactured as a ready to use solution (e.g., solution in an ampoule, vial or prefϊlled syringe).
91. A claim of claim 1 to 5 and claim 84 to claim 86, wherein said compound is: (i) administered in unsalifϊed or substantially unsalifϊed form; (ii) manufactured as a ready to use solution (e.g., solution in an ampoule, vial or prefϊlled syringe); and (iii) has an injection or infusion volume of not more that 1 mL, or not more than 0.5 mL, or not more than 0.25 mL, or not more than 0.1 mL.
92. A claim of claim 1 to 5 and claim 84 to claim 86, wherein said compound is a salt or complex of inorganic cations, organic salts, primary, secondary, tertiary and quaternary amines, alkylammonium salts, substituted amines, aminoalcohols, alkali and alkaline earth metals, basic amino acids, including sodium, potassium, lithium, magnesium, calcium, tromethamine, triethylamine, tripropylamine, dropopizine, 2- dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, tris-(hydroxymethyl)aminomethane, N-methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins, ethanolamine, 3-amino-l-propanol, (R)-l-amino-2-propanol, (S)-I -amino-2-propanol, 2-amino- 1 ,3-propandiol, N-(2-hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D- glucosamine, and N-methylglucosamine.
93. A solid or liquid pharmaceutical composition of claim 1 to claim 93 further comprising one or more ingredients selected from among inorganic cations, organic salts, primary, secondary, tertiary and quaternary amines, alkylammonium salts, substituted amines, aminoalcohols, alkali and alkaline earth metals, basic amino acids.
94. A solid or liquid pharmaceutical composition of claim 1 to claim 93 further comprising one or more compounds selected from the group comprising preservatives, antioxidants, buffers, tonicity adjusters, solvents and bulking agents.
95. A solid or liquid pharmaceutical composition of claim 1 to claim 93 further comprising one or more compounds selected from the group comprising preservatives, antioxidants, buffers, tonicity adjusters, solvents and bulking agents; one or more compounds selected from the group comprising a salt or complex forming agent selected from the group comprising inorganic cations, organic salts, primary, secondary, tertiary and quaternary amines, alkylammonium salts, substituted amines, aminoalcohols, alkali and alkaline earth metals, basic amino acids, sodium, potassium, lithium, magnesium, calcium, tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2- diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N- ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, tris- (hydroxymethyl)aminomethane, N-methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins, ethanolamine, 3-amino-l-propanol, (R)-I- amino-2-propanol, (S)-I -amino-2-propanol, 2-amino-l,3-propandiol, N-(2- hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, and N- methylglucosamine; (vi) a ready to use solution (e.g., solution in an ampoule, vial or prefilled syringe). - -
96. A claim of claim 1 to 95, wherein the composition has an injection or infusion volume of not more that 50 mL, or not more than 10 mL, or not more than 5 mL, or not more than 2 mL, or not more than 1 mL, or not more than 0.5 mL, or not more than 0.1 mL, or not more than 0,01 mL.
97. The composition according to any one of claim 1 to claim 96 with an aqueous solubility of greater than about 100 mg/niL, or of greater than about 150 mg/mL, or of greater than about 200 mg/mL, or of greater than about 300 mg/mL.
98. The composition according to any one of claim 1 to claim 96, further comprising: (i) sterile water; (ii) one or more pharmaceutically acceptable buffers; and (iii) one or more pharmaceutically acceptable preservatives; (iv) one or more pharmaceutically acceptable excipients; and wherein the pH of the composition is from about 5.5 to about 9; and the concentration of said analgesic is about 0.0001 mg/mL to about 1000 mg/mL.
99. The claim 1 to 96, wherein the dosage form also contains one or more analgesics selected from the group consisting of COX-2 selective inhibitors, acetaminophen, nitroparacetamol, nitric oxide donors, tramadol, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, cannabinoid agonists, opioid receptor agonists, NMDA receptor antagonists, gabapentin, pregabalin, gabapentinoids, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers, superoxide dismutase mimetics, p38 MAP kinase inhibitors, TRPVl agonists, dextromethorphan, dextrorphan, ketamine, glycine receptor antagonists and antiepileptics.
100. The claim 1 to 96, wherein the dosage form also contains one or more drugs selected from the group consisting of analgesics, decongestants, analgesic adjuvants, antihistamines, expectorants, antitussives, diuretics, anti-inflammatory agents, antipyretics, antirheumatics, antioxidants, laxatives, proton pump inhibitors, motility modifying agents, vasodilators, inotropes, beta blockers, beta adrenergic agonists, drugs to treat asthma and COPD, anti-migraine agents, antidepressants, anxiolytic agents, antiinfectives, antihypertensives, antianginal agents, anticoagulants, lipid and cholesterol lowering drugs, anti-diabetic drugs, hormones, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids, and biological peptides. A kit for use in treating or preventing the pain, comprising: (i) a dosage form of the ULD NSAID invention in an ampoule, vial, prefilled syringe or autoinjector; (ii) a container for the dosage form; and optionally, any of (iii) to (ix): (iii) syringe; (iv) alcohol swab; (v) sterile absorbent gauze; (vi) sterile occlusive dressing to cover the injection site which is optionally adhesive (e.g., bandage, adhesive bandage, clear bandage, Liquid Bandage™, Band Aid™, Elastoplast™, Tegaderm™, etc); (vii) educational instructions in any media about various medical conditions, their etiology, pathophysiology, consequences and treatment, including information on the proper use and disposal of the medication; (viii) containers or bags for the safe disposal of any used or remaining unused dosage form and needles, preferably child proof, needle stick safe and flushable; (ix) tamper evident and child proof packaging for the kit and its contents.
PCT/US2008/004059 2007-03-26 2008-03-26 Subanalgesic doses of drug combinations WO2008150324A1 (en)

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CN113209109A (en) * 2021-05-08 2021-08-06 贵州省人民医院 Medicine applied to accelerated rehabilitation of pediatric urology surgery

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