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WO2024173714A1 - Regimens and compositions useful for alleviating pain - Google Patents

Regimens and compositions useful for alleviating pain Download PDF

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Publication number
WO2024173714A1
WO2024173714A1 PCT/US2024/016027 US2024016027W WO2024173714A1 WO 2024173714 A1 WO2024173714 A1 WO 2024173714A1 US 2024016027 W US2024016027 W US 2024016027W WO 2024173714 A1 WO2024173714 A1 WO 2024173714A1
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WO
WIPO (PCT)
Prior art keywords
cebranopadol
pain
composition
dose
opioid
Prior art date
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PCT/US2024/016027
Other languages
French (fr)
Inventor
James HACKWORTH
Marc LESNICK
Antonio PARDO
Joseph GRIECO
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Park Therapeutics, Inc.
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Publication date
Priority claimed from PCT/US2023/083697 external-priority patent/WO2024129782A1/en
Application filed by Park Therapeutics, Inc. filed Critical Park Therapeutics, Inc.
Publication of WO2024173714A1 publication Critical patent/WO2024173714A1/en

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • Opioid agonists provide analgesic effects by acting on opioid receptors in the central and peripheral nervous systems that block the sensation of pain from signaling to the brain.
  • Opioid agonists are available in different dosage forms.
  • Opioid agonists may be characterized as full agonist opioids or partial agonist opioids.
  • undesirable common side effects of opioid administration include euphoria, abuseability, sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression.
  • Opioid Use Disorder is a chronic, relapsing condition associated with overdoses and deaths, as well as legal, interpersonal, and employment problems (Opioids. National Institute of Drug Abuse (2022)). Although opioids are recognized as necessary and legitimate therapeutics to treat pain, the risk of developing OUD is significant (Webster, L.R. Risk Factors for Opioid- Use Disorder and Overdose. Anesth Analg 125, 1741-1748 (2017)). Recent studies estimate that among opioid-treated patients with chronic pain, misuse averaged between 21%-29%, and OUD averaged between 8%-12% (Vowles, K.E., et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis.
  • MOP mu opioid peptide
  • methadone is a full MOP receptor agonist which produces dose-dependent analgesia, sedation, cardiotoxicity, and risk of respiratory depression in overdose (Inturrisi, C.E. Pharmacology of methadone and its isomers. Minerva anestesiologica 71, 435-437 (2005)).
  • Buprenorphine is a partial MOP receptor agonist with a high affinity for MOP; at low doses it produces typical MOP receptor agonist effects that at higher doses tend to decline (i.e., analgesia).
  • Naltrexone a MOP receptor antagonist, blocks the effects of opioids and can precipitate withdrawal if administered to an opioid-dependent patient (Bell, J. & Strang, J. Medication Treatment of Opioid Use Disorder. Biological psychiatry 87, 82-88 (2020)).
  • Methadone is used orally; buprenorphine is available in transmucosal preparations alone or in combination with naloxone and longer-acting implantable or injectable formulations; and naltrexone is available in both oral and long-acting injectable formulations. All of these products have significant limitations. Methadone has significant abuse potential and risk of overdose and is thus only administered in health-care settings, causing substantial burden on patients as they must travel to a clinic daily to receive their medication which results in poor adherence to treatment. Buprenorphine can trigger withdrawal when initiated with opioid- dependent patients, and naltrexone requires full detoxification before initiation.
  • Cebranopadol (trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane- 1,1′-(3′H)-pyrano[3,4-b]indol]-4-amine) is an analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist (WO 2004/043967, WO 2008/040481, WO 2012/016703, WO 2012/016699, WO 2012/016695, WO 2012/016698, WO 2012/016697, WO 2013/007361).
  • NOP nociceptin/orphanin FQ peptide
  • opioid receptor agonist WO 2004/043967, WO 2008/040481, WO 2012/016703, WO 2012/016699, WO 2012/016695, WO 2012/016698, WO 2012/016697, WO 2013/007361.
  • Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain with ED50 values of 0.5-5.6 ⁇ g/kg after intravenous and 25.1 ⁇ g/kg after oral administration. In comparison with selective mu ( ⁇ )-opioid receptor (MOP) agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol displays broad activity in various pain states and is highly potent and efficacious in animal models of acute nociceptive, inflammatory, cancer, and, especially, chronic neuropathic pain.
  • MOP selective mu
  • Cebranopadol displays broad activity in various pain states and is highly potent and efficacious in animal models of acute nociceptive, inflammatory, cancer, and, especially, chronic neuropathic pain.
  • cebranopadol In contrast to opioids such as morphine, cebranopadol displays higher analgesic potency in chronic pain, especially of neuropathic origin, than in acute nociceptive pain. In addition, even after doses higher than those required for inducing analgesia, cebranopadol affects neither motor coordination nor respiratory function and thus displays a better tolerability profile than opioids. As a result, there is a broader therapeutic window for cebranopadol than for morphine (K. Linz et al., J. Pharmacol. Exp. Ther.2014535-548). There remains a need for improved therapies for alleviating pain in patients. Further, there is an urgent need for an improved therapeutic for the treatment and/or prevention of OUD.
  • FIG.1 shows results of a single-dose, randomized, double-blind, placebo- and active- controlled crossover trial of oral human-abuse potential study, graphed as a difference in maximum Drug Liking (VAS) scores in modified completer population.
  • FIG.2 provides shows results of a single-dose, randomized, double-blind, placebo- and active-controlled crossover trial of oral human-abuse potential study, graphed as a difference in maximum Drug Liking (VAS) scores in completer population.
  • FIG.3 shows 600 mcg cebranopadol-induced respiratory depression in healthy volunteers.
  • FIG.4 shows mean drug liking time course profile.
  • FIG.5A shows cebranopadol effect on rat heroin self-administration.
  • FIG.5B shows cebranopadol effect on rat heroin self-administration.
  • FIG.6A shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase. Modified Completer Population. TEmax and TEmin are reported in hours.
  • FIG.6B shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase. Modified Completer Population. T Emax and T Emin are reported in hours.
  • FIG.7A shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase. Completer Population. T Emax and T Emin are reported in hours.
  • FIG.7B shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase.
  • FIG.8 shows drug Liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • the hypothesis tested are as follows: Testing h0: ⁇ C1 - ⁇ P ⁇ 15 vs ha: ⁇ C1 - ⁇ P > 15, where ⁇ C1 is the mean for oxycodone IR and ⁇ P is mean for placebo; Testing h0: ⁇ C2 - ⁇ P ⁇ 15 vs ha: ⁇ C2 - ⁇ P > 15, where ⁇ C2 is the mean for tramadol IR and ⁇ P is mean for placebo; Testing h0: ⁇ C1 - ⁇ T ⁇ 0 vs ha: ⁇ C1 - ⁇ T > 0, where ⁇ C1 is the mean for oxycodone IR and ⁇ T is mean for cebranopadol; Testing h
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.9 shows drug Liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.10 shows drug Liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.11 shows drug liking (at this moment) VAS – analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.12 shows drug liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.13 shows drug liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.14 shows drug liking (at this moment) VAS – analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.15 shows drug liking (at this moment) VAS – analysis results. Modified Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.16 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.17 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.18 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.19 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • FIG.20 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • the hypothesis tested are as follows: Testing h0: ⁇ C1 - ⁇ P ⁇ 15 vs ha: ⁇ C1 - ⁇ P > 15, where ⁇ C1 is the mean for oxycodone IR and ⁇ P is mean for placebo; Testing h0: ⁇ C2 - ⁇ P ⁇ 15 vs ha: ⁇ C2 - ⁇ P > 15, where ⁇ C2 is the mean for tramadol IR and ⁇ P is mean for placebo; Testing h0: ⁇ C1 - ⁇ T ⁇ 0 vs ha: ⁇ C1 - ⁇ T > 0, where ⁇ C1 is the mean for oxycodone IR and ⁇ T is mean for cebranopadol; Testing h0: ⁇ C2 ⁇ C2
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.21 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.22 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means.
  • FIG.23 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values ⁇ 0.05 are bolded.
  • FIG.24 shows overall summary of treatment emergent adverse events (TEAEs).
  • TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination (See, Example 1).
  • FIG.25 shows summary of treatment emergent adverse events, by system organ class and preferred term.
  • a TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination.
  • At each level of summarization System Organ Class or Preferred Term
  • subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1.
  • MedDRA Medical Dictionary for Regulatory Activities
  • FIG.26 shows summary of treatment emergent adverse events, by system organ class and preferred term.
  • a TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination.
  • MedDRA Medical Dictionary for Regulatory Activities
  • System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population.
  • FIG.27 shows summary of treatment emergent adverse events, by system organ class and preferred term. Safety Population.
  • TEAE treatment emergent adverse event.
  • a TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination.
  • MedDRA Medical Dictionary for Regulatory Activities
  • System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population.
  • FIG.28 shows summary of treatment emergent adverse events, by system organ class and preferred term.
  • a TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination.
  • System Organ Class or Preferred Term subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1.
  • MedDRA Medical Dictionary for Regulatory Activities
  • System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population.
  • FIG.29 shows summary of treatment emergent adverse events, by system organ class and preferred term.
  • a TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination.
  • System Organ Class or Preferred Term At each level of summarization (System Organ Class or Preferred Term), subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1. System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population.
  • FIG.30 shows that in the two hours patients post-administration of an immediate release cebranopadol composition at 600 microgram (mcg or ⁇ g), 800 mcg, or 1000 mcg), cebranopadol patients have less respiratory depression and a slower onset of respiratory depression than patients receiving oxycodone at two hours post-administration (placebo (13% reduction VE55 at 1 hour); cebranopadol 600 mgc (13% VE55 reduction after 1 hour) cebranopadol 800 mcg (15% VE55 reduction after 1 hour), cebranopadol 1000 mcg (16% VE55 reduction after 1 hour).
  • FIG.31 shows results from a generated PK/PD model to quantify respiratory depression following doses of 600 mcg, 800 mcg, 1000 mcg of cebranopadol and .
  • a PK/PD model predicts the amount of respiratory depression for a given level of analgesic effect of Cebranopadol and Oxycodone.
  • FIG.32 shows respiratory AEs (respiratory depression and oxygen saturation decrease), plotted as %, at supratherapeutic doses of Cebranopadol in comparison to Oxycodone (60 mg).
  • FIG.33 shows mean (SD, standard deviation) O 2 saturation peripheral pharmacodynamic analysis population, plotted as percent of O2 saturation peripheral.
  • FIG.34 shows mean (SD, standard deviation) O 2 saturation peripheral change from baseline (CFB) pharmacodynamic analysis, plotted as percent O2 saturation peripheral CFB.
  • Cebranopadol has demonstrated significantly lower abuse potential compared to both Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Standard Deviation is represented by error bars. Ceb – Cebranopadol; Oxy – Oxycodone; Tram – Tramadol; PBO – Placebo.
  • Cebranopadol has demonstrated significantly lower abuse potential compared to both Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Standard Deviation is represented by error bars. Ceb – Cebranopadol; Oxy – Oxycodone; Tram – Tramadol; PBO – Placebo. SUMMARY OF THE INVENTION
  • a method for preventing and/or treating opioid use disorder (OUD) in a subject, said method comprising treating a dosing a subject being treated for pain with a pharmaceutical composition comprising at least one cebranopadol or a pharmaceutically acceptable salt thereof.
  • the composition provides an immediate release profile for the cebranopadol or pharmaceutically acceptable salt thereof, hydrate, or salt hydrate.
  • the composition comprises cebranopadol in its free base form. In certain embodiments, at least 80% of the cebranopadol is in crystal form A.
  • the composition is delivered once daily. In certain embodiments, the composition is delivered no more than once a day for three to 14 days.
  • a composition useful in treating a subject being treated for pain and having or susceptible to opioid use disorder is provided. In certain embodiments, the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, administrable to the subject.
  • the composition is administered daily at a dose in an amount of about 10 ⁇ g to about 2000 ⁇ g cebranopadol.
  • the cebranopadol is a free base.
  • at least 80% of the cebranopadol is in crystal form A.
  • use of cebranopadol in treating a subject having opioid use disorder is provided.
  • at least 80% of the cebranopadol is in crystal form A.
  • the subject is being treated for pain.
  • the pain is chronic, acute, central, peripheral, neuropathic, and/or nociceptive pain.
  • the pain is visceral pain, skeletal pain, and/or nervous pain.
  • a method for reducing the risk of apnea and/or oxygen desaturation in a patient in need of pain treatment comprises administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol.
  • an immediate release cebranopadol composition for use in reducing the risk of apnea and/or oxygen desaturation in a patient in need of pain treatment said method comprising administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol.
  • cebranopadol in preparing a medicament for use in reducing the risk of apnea and/or oxygen desaturation in a patient receiving pain treatment.
  • the method comprises administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol.
  • a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol.
  • the patient has asthma, chronic obstructive pulmonary disease (COPD), pneumonia, chronic or acute bronchitis, emphysema, cystic fibrosis, interstitial lung disease (ILD), pulmonary embolism, pleural effusion, mesothelioma, tuberculosis, acute respiratory distress syndrome (ARDS), neuromuscular disorders, obesity hypoventilation syndrome, or lung cancer.
  • COPD chronic obstructive pulmonary disease
  • ILD interstitial lung disease
  • pulmonary embolism pleural effusion
  • mesothelioma tuberculosis
  • ARDS acute respiratory distress syndrome
  • a method, composition or use is provided, wherein cebranopadol prevents apnea and/or oxygen desaturation in a patient receiving pain treatment in the first two hours post-dosing of an immediate release composition independent of dose.
  • the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate.
  • the composition is administered daily at a dose in an amount of about 10 ⁇ g to about 2000 ⁇ g cebranopadol.
  • the cebranopadol is a free base.
  • at least 80% of the cebranopadol is in crystal form A. Still other aspects and advantages of the invention will be apparent from the following detailed description of the invention. DETAILED DESCRIPTION OF THE INVENTION
  • methods, compositions, and uses are provided for treating and/or preventing opioid use disorder using cebranopadol.
  • methods, compositions and uses are provided for treating post-surgical pain by administering a cebranopadol composition, optionally by starting administration of a cebranopadol by administering prior to or during surgery.
  • methods, compositions and uses are provided by for treating and/or preventing apnea in a pain patient having diminished lung capacity.
  • composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered to a subject with impaired lung function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime.
  • impaired lung function is associated with a decreased lung capacity.
  • decreased lung function is associated with an existing lung disease in individuals, including, but not limited to, lung cancer, chronic obstructive pulmonary disease (COPD), pneumonia, septic embolization, noncardiogenic pulmonary edema, foreign body granulomatosis, bullous lung disease, emphysema, interstitial lung disease, pulmonary vascular disease, pneumothorax, pneumomediastinum, pulmonary hypertension, asthma, amyloidosis, chronic pulmonary complications associated with injection cocaine use which lung scarring due to repeated pulmonary infections and pulmonary infarction, and pulmonary arterial hypertension.
  • COPD chronic obstructive pulmonary disease
  • pneumonia septic embolization
  • noncardiogenic pulmonary edema foreign body granulomatosis
  • bullous lung disease emphysema
  • interstitial lung disease pulmonary vascular disease
  • pneumothorax pneumomediastinum
  • pulmonary hypertension asthma
  • amyloidosis chronic pulmonary complications associated with injection cocaine use
  • the composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered at least one of immediately prior to a surgical procedure, intraoperatively, and/or immediately following a surgical procedure or trauma.
  • cebranopadol is used in a pain therapy following a rapid onset opioid, following by discontinuation of the opioid or opioid like drug.
  • cebranopadol may be administered after prior, short-term, treatment with an opioid; treatment with cebranopadol may be continued for a day, days, or weeks following removal of opioid treatment.
  • Cebranopadol provides the activity of a full mu-agonist, while providing less abuse potential than a partial mu-agonist.
  • full agonists bind tightly to the opioid receptor and may undergo conformational changes to produce effect.
  • full agonists may include, e.g., codeine, fentanyl, heroin, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, and oxymorphone.
  • These full agonists are typically classified as opioids as a Class (Schedule II) drug.
  • a full agonist may be on Class (Schedule) III drug (e.g., buprenorphine, codeine when mixed with acetaminophen).
  • Class (Schedule) III drug e.g., buprenorphine, codeine when mixed with acetaminophen.
  • partial mu opioid receptor agonists includes tramadol and other opioid-like compounds, e.g., , butorphanol, typically classified as a Class (Schedule) IV drug. It has surprisingly found that when cebranopadol is administered according to the methods provided herein, particularly crystal form A cebranopadol, subjects are therapeutically treated as effectively as with a full mu agonist, yet the potential for abuse is reduced in relation to partial mu opioids or opioid-like drugs, such as tramadol. This combination of properties is unexpected.
  • the mu-agonist activity is assessed using a visual analog scale (VAS rating) and/or a Multi-Task Test.
  • VAS rating visual analog scale
  • a method, use or composition is provided for treating pain, wherein pain is associated with tissue damage following surgery.
  • a method, use or composition is provided for treating pain, wherein pain is associated with undergoing surgical procedures (e.g., peri-operative, post-operative pain).
  • a method, use or composition is provided for treating pain, wherein pain is trauma pain.
  • a method, use or composition is provided for treating pain, wherein pain is associated with hyperalgesia (i.e., increased sensation of pain on a noxious stimulus, typically associated with inflamed tissue.
  • a method, use or composition for treating pain, wherein pain is associated with opioid-induced hyperalgesia, which may occur in both short and chronic opioid administration.
  • a method for treating pain with reduced risk of abuse is provided in a patient having nociceptive or neuropathic pain, said regimen comprising dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof.
  • the composition is a film- coated tablet.
  • the cebranopadol is in free base form.
  • at least 80% of the cebranopadol in the composition is in crystal form A.
  • “treatment of pain” refers to any amelioration of pain, alleviation of pain or pain relief including the prevention thereof.
  • “Cebranopadol” is intended to include trans-6′-fluoro-4′,9′-dihydro-N,N- dimethyl-4-phenyl-spiro[cyclohexane-1,1′-(3′H)-pyrano[3,4-b]indol]-4-amine (also referred to as (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4- b]indol]-4-amine; free base: CAS Number 86351391-1), its pharmaceutically acceptable salts and solvates thereof: See, e.g., US 7799931, incorporated by reference herein.
  • a free base form of cebranopadol is selected.
  • a cebranopadol API composition comprises at least 50% to 100% of crystal form A, or at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or about 100% crystal form A.
  • the crystal form may be present in a pharmaceutically acceptable salt form, e.g., HCl salt, and/or a hemihydrate, hydrate, solute, or anhydrous form.
  • the cebranopadol is present in the active pharmaceutical ingredient (API) and/or the pharmaceutical composition as a free base and/or in crystal form A. See, Examples, Part A, incorporated herein by reference herein for the powder x-ray diffraction (PXRD) pattern for cebranopadol crystal form A.
  • the cebranopadol crystal form A is characterized by one or more of the following: the PXRD pattern of the Table in Part A (see, Examples).
  • the crystalline form comprises a characteristic peak at 11.7 ⁇ 0.2 degrees 2 ⁇ . In certain embodiments, the crystalline form comprises characteristic peak at 18.3 ⁇ 0.2 degrees 2 ⁇ .
  • the crystalline form comprises characteristic peaks at 8.8 ⁇ 0.2 degrees 2 ⁇ and/or at 15.8 ⁇ 0.2 degrees 2 ⁇ . In certain embodiments, the crystalline form comprises characteristic peaks at about 20.4+0.2 degrees 2 ⁇ and/or at 23.3 ⁇ 0.2 degrees 2 ⁇ . In certain embodiments, the crystalline form comprises characteristic peaks at 11.7 ⁇ 0.2 degrees 2 ⁇ , at one or both of 8.8 ⁇ 0.2 degrees 2 ⁇ and/or 15.8 ⁇ 0.2 degrees 2 ⁇ , and at one or both of 20.4 ⁇ 0.2 degrees 2 ⁇ and/or 23.3 ⁇ 0.2 degrees 2 ⁇ . In certain embodiments, the crystalline form has an endothermal event with a peak temperature at about 298-308° C., as determined by DSC.
  • the crystalline form A has a Raman peak at about 1569 +2 cm -1 and/or at about 1002 +2 cm -1 .
  • the active ingredient comprises a (lr,4r)-6'-fluoro-N,N-dim- ethyl-4-phenyl-4',9,- dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diasteromeric excess of at least about 95%de.
  • the active ingredient comprises a (lr,4r)-6'-fluoro- N,N-dimethyl-4-phenyl-4',9,-dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diasteromeric excess of at least about 97%de.
  • the active ingredient comprises a (lr,4r)-6'-fluoro-N,N-dim- ethyl-4-phenyl-4',9,-dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diasteromeric excess of at least about 99%de.
  • crystalline form A is present in the active ingredient in an amount of at least about 60 wt.
  • crystalline form A is present in the active ingredient in an amount of at least about 80 wt.
  • crystalline form A is present in the active ingredient in an amount of at least about 90 wt.
  • crystalline form A is present in the active ingredient in an amount of at least about 95 wt.
  • the pharmaceutical composition contains at most about 1.0 wt.-% 4- dimethylamino-4-phenylcyclohexanone, relative to the total content of 6'-fluoro-N,N-dimethyl-4- phenyl-4',9'- dihydro-3'H-spiro[cyclohexane-l,T-pyran [3,4b]indol]-4- amine.
  • the composition contains at most about 1.0 wt.-% 4-dimethylamino-4- phenylcyclohexanone, relative to the total content of 6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- dihydro-3'H-spiro[cyclohexane-l,T-pyran [3,4b]indol]-4- amine.
  • Methods of making the compound are described, e.g., US 8,779,160; US8,658,827; US10,323,040, all of which are incorporated by reference herein.
  • cebranopadol may include salts of inorganic acids, such as hydrochloric acid (cebranopadol HCl), hydrobromic acid and sulfuric acid, and salts of organic acids, such as methane sulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, lactic acid, citric acid, glutamic acid, acetylsalicylic acid, nicotinic acid, aminobenzoic acid, ⁇ -liponic acid, hippuric acid and asparaginic acid.
  • inorganic acids such as hydrochloric acid (cebranopadol HCl), hydrobromic acid and sulfuric acid
  • organic acids such as methane sulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, lactic acid, cit
  • cebranopadol is present in the non-salt form (free base). In other embodiments, the cebranopadol is present as cebranopadol hemicitrate (CAS number CAS No.863513-92-2).
  • a cebranopadol compound useful in certain embodiments of the invention has the structure of: thereof. e.g., up to 7 hours after intravenous dosing (e.g., 5 to 7 hours), or greater than 9 hours after oral dosing (e.g, 8 to 16 hours, 9 to 18 hours, or longer, e.g., 8 to 24 hours.
  • doses of cebranopadol relate to the free base.
  • micronized cebranopadol refers to the size of the drug particle, in which the average size of the drug particles are less than 10 microns.
  • a pharmaceutically acceptable salt when used instead, its dose has to be adapted to the equivalent dose of the free base.
  • a dose of “200 ⁇ g” means an amount of 200 ⁇ g of the free base or any equivalent amount of a pharmaceutically acceptable salt, solvate, hydrate, or salt hydrate, corresponding to 200 ⁇ g of the free base.
  • unit dosage forms e.g., coated tablets, comprising 100 ⁇ g cebranopadol, 200 ⁇ g cebranopadol, 300 ⁇ g cebranopadol, or 400 ⁇ g cebranopadol, wherein the dose is determined based on equivalence to the free base.
  • these unit dosage forms comprise micronized cebranopadol free base as the sole active ingredient.
  • other forms of cebranopadol are present in the unit dosage form.
  • Cebranopadol or the physiologically acceptable salt thereof may be administered systemically or orally. In certain embodiments, Cebranopadol or the physiologically acceptable salt thereof is administered once daily.
  • a patient may receive a daily dose in the range of about 10 ⁇ g to about 2000 ⁇ g of cebranopadol free base or equivalent (e.g., a pharmaceutically salt, hydrate, solvate, salt hydrate, or combination thereof).
  • the patient may be an adult human, e.g., age 18 or older.
  • the patient may be younger, e.g., in the age range of 12 – 17 years old, 12 to 17 years old, 6 to 17 years old, or younger.
  • a dose generally involves delivery of a dose in excess of 400 ⁇ g to 2000 ⁇ g, e.g., at least 450 ⁇ g, at least 500 ⁇ g, at least 550 ⁇ g, at least 600 ⁇ g, at least 650 ⁇ g, at least 700 ⁇ g, at least 750 ⁇ g, at least 800 ⁇ g, at least 850 ⁇ g, at least 900 ⁇ g, at least 950 ⁇ g, at least 1000 ⁇ g, at least 1100 ⁇ g, at least 1200 ⁇ g, at least 1300 ⁇ g, at least 1400 ⁇ g, at least 1500 ⁇ g, at least 1600 ⁇ g, at least 1700 ⁇ g, at least 1800 ⁇ g, at least 1900 ⁇ g, or at least 2000 ⁇ g, as
  • the supratherapeutic dose is at least 600 ⁇ g, at least 450 ⁇ g, at least 500 ⁇ g, at least 550 ⁇ g, at least 600 ⁇ g, at least 650 ⁇ g, at least 700 ⁇ g, at least 750 ⁇ g, at least 800 ⁇ g, at least 850 ⁇ g, at least 900 ⁇ g, at least 950 ⁇ g, at least 1000 ⁇ g, at least 1100 ⁇ g, at least 1200 ⁇ g, at least 1300 ⁇ g, at least 1400 ⁇ g, at least 1500 ⁇ g, at least 1600 ⁇ g, at least 1700 ⁇ g, at least 1800 ⁇ g, at least 1900 ⁇ g, or at least 2000 ⁇ g, as equivalent dose relative to cebranopadol free base.
  • the doses provided herein are for use in human adults, e.g., age 18 and above. Doses may be titrated, e.g., as described in US Patent 10,022,353 which is incorporated herein by reference, using a subtherapeutic analgesic dose(s) as the starting dose.
  • the cebranopadol subtherapeutic analgesic doses are combined into a therapeutic regimen comprising a dosing regimen which comprises starting at a subtherapeutic dose or a therapeutic dose of cebranopadol, and incorporating a therapeutic dose or doses of another drug into the otherwise titrated regimen over 1-3 weeks, or as needed.
  • a patient may receive a subtherapeutic dose for 1, 3 or 3 days, followed by therapeutic or subtherapeutic doses on subsequent days.
  • cebranopadol may be delivered in a regimen comprising a single daily dosage delivered over a period of days to weeks without a change in daily dosage.
  • cebranopadol may be delivered in a first dose, followed by an increase in daily dose on day 2 and subsequent days.
  • dosage is adjusted as needed.
  • the duration of treatment is not particularly limited and may last for several weeks, months, or years, especially when the pain to be treated or prevented is chronic. In certain embodiments, when the pain is chronic, the pain is treated for at least one week or at least two weeks. Pain and/or opioid drug dependence are treated or prevented.
  • the pain When pain is to be treated or prevented, the pain may be moderate, moderate to severe, or severe.
  • the pain may be chronic or acute; and/or central and/or peripheral; and/or neuropathic and/or nociceptive.
  • central/peripheral pain and with nociceptive/neuropathic pain “and/or” reflects the possibility that the overall pain may have different components, e.g., a nociceptive component as well as a neuropathic component.
  • the pain is chronic neuropathic pain, which may be peripheral or central; acute neuropathic pain, which may be peripheral or central; chronic nociceptive pain, which may be peripheral or central; or acute nociceptive pain, which may be peripheral or central.
  • the pain is chronic, acute, subacute, central, peripheral, neuropathic, and/or nociceptive pain.
  • pain is visceral pain, skeletal pain, and/or nervous pain.
  • pain is a deep somatic pain.
  • pain is a superficial somatic pain.
  • pain is head-and-face pain.
  • pain is associated with tissue damage following surgery.
  • pain is associated with undergoing surgical procedures (e.g., peri-operative, post-operative pain).
  • pain is trauma pain.
  • pain is associated with hyperalgesia (i.e., increased sensation of pain on a noxious stimulus, typically associated with inflamed tissue).
  • pain is associated with opioid-induced hyperalgesia.
  • Nociceptive pain refers to the discomfort that results when a stimulus causes tissue damage to the muscles, bones, skin or internal organs.
  • nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being “thermal” (heat or cold), “mechanical” (crushing, tearing, etc.) and “chemical” (iodine in a cut, chili powder in the eyes).
  • Nociceptive pain may also be divided into “visceral,” “deep somatic” and “superficial somatic” pain.
  • Visceral pain describes a type of nociceptive pain originating in the body's internal organs or their surrounding tissues. This form of pain usually results from the infiltration of harmful cells, as well as the compression or extension of healthy cells. Subjects suffering from visceral pain tend to feel generally achy, as this pain tends to not be localized to a specific area. Cancer is a common source of visceral pain. Somatic pain is nociceptive pain that results from some injury to the body. It's generally localized to the affected area and abates when the body repairs the damage to that area. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly localized pain.
  • Examples include sprains and broken bones.
  • Superficial pain is initiated by activation of nociceptors in the skin or superficial tissues, and is sharp, well-defined and clearly located. Pain may be classified as chronic if it has occurred for at least 3 months or extends beyond the time of healing.
  • the chronic nociceptive pain is selected from chronic visceral pain, chronic deep somatic pain and chronic superficial somatic pain.
  • causes of nociceptive pain include broken or fractured bones, bruises, burns, cuts, inflammation (from infection or arthritis), and sprains.
  • nociceptive pain includes post- operative pain, cancer pain, low back pain, pain due to radiculopathy, and inflammatory pain.
  • Neuropathic pain is pain that originates from nerve damage or nerve malfunction.
  • the neuropathic pain is selected from acute neuropathic pain and chronic neuropathic pain.
  • Neuropathic pain may be caused by damage or disease affecting the central or peripheral portions of the nervous system involved in bodily feelings (the somatosensory system).
  • the composition is for use in the treatment of chronic neuropathic pain or acute neuropathic pain, peripheral neuropathic pain or central neuropathic pain, mononeuropathic pain or polyneuropathic pain.
  • the neuropathic pain is chronic, it may be chronic peripheral neuropathic pain or chronic central neuropathic pain, in certain embodiments, chronic peripheral mononeuropathic pain or chronic central mononeuropathic pain, in certain embodiments, chronic peripheral polyneuropathic pain or chronic central polyneuropathic pain.
  • neuropathic pain When the neuropathic pain is acute, it may be acute peripheral neuropathic pain or acute central neuropathic pain, in certain embodiments, acute peripheral mononeuropathic pain or acute central mononeuropathic pain, in certain embodiments, acute peripheral polyneuropathic pain or acute central polyneuropathic pain.
  • Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Fibromyalgia is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain.
  • peripheral neuropathies Aside from diabetic neuropathy and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic, and immune mediated disorders or physical trauma to a nerve trunk (e.g., due to disorders from the spinal disc, joint degeneration, or compression fracture). Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery.
  • the pain is selected from postoperative pain, pain due to bunionectomy, visceral pain, cancer pain, pain due to diabetic polyneuropathy, pain due to osteoarthritis, fibromyalgia, low back pain, pain radiating down the lower limbs, pain due to (cervical or lumbar) radiculopathy, and inflammatory pain.
  • the pain is selected from the group consisting of pain being or being associated with panic disorder [episodic paroxysmal anxiety]; dissociative [conversion] disorders; persistent somatoform pain disorder; pain disorders exclusively related to psychological factors; nonorganic dyspareunia; other enduring personality changes; sadomasochism; elaboration of physical symptoms for psychological reasons; migraine; other headache syndromes; trigeminal neuralgia [G50.0]; atypical facial pain [G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndrome without pain [G54.7]; acute and chronic pain, not elsewhere classified [G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris, unspecified [120.9]; other specified disorders of nose and nasal sinuses [J34.8]; other diseases of pharynx [J39.2]; temporomandibular joint disorders [K07.6]; other specified disorders
  • cebranopadol or of the physiologically acceptable salt thereof that is administered to the subject is not particularly limited, as it has been unexpectedly found that cebranopadol is so well tolerated that it may even be administered to subjects with impaired hepatic function and/or impaired renal function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime.
  • cebranopadol or the physiologically acceptable salt thereof is administered at a dose that would also be administered to a subject in the same condition but without impaired hepatic and/or without impaired renal function.
  • composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered to a subject with impaired lung function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime.
  • impaired lung function is associated with a decreased lung capacity.
  • decreased lung function is associated with an existing lung disease in individuals, including, but not limited to, lung cancer, chronic obstructive pulmonary disease (COPD), pneumonia, septic embolization, noncardiogenic pulmonary edema, foreign body granulomatosis, bullous lung disease, emphysema, interstitial lung disease, pulmonary vascular disease, pneumothorax, pneumomediastinum, pulmonary hypertension, asthma, amyloidosis, chronic pulmonary complications associated with injection cocaine use which lung scarring due to repeated pulmonary infections and pulmonary infarction, and pulmonary arterial hypertension.
  • COPD chronic obstructive pulmonary disease
  • pneumonia septic embolization
  • noncardiogenic pulmonary edema foreign body granulomatosis
  • bullous lung disease emphysema
  • interstitial lung disease pulmonary vascular disease
  • pneumothorax pneumomediastinum
  • pulmonary hypertension asthma
  • amyloidosis chronic pulmonary complications associated with injection cocaine use
  • the composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered at least one of immediately prior to a surgical procedure, intraoperatively, and/or immediately following a surgical procedure or trauma.
  • Cebranopadol or the physiologically acceptable salt thereof is administered at a dose that in the subject's perception results in an amelioration of pain at acceptable side effects.
  • the dose is within the range of from 20 ⁇ g to 2000 ⁇ g, as equivalent dose relative to Cebranopadol free base.
  • the dosage form is adapted for administration once daily and contains the pharmacologically active agent in a dose of from 150 ⁇ g to 800 ⁇ g, more than 190 ⁇ g to 800 ⁇ g, i.e., the dosage form contains the pharmacologically active agent (e.g, cebranopadol or salt thereof) in a daily dose of from 150 ⁇ g to 800 ⁇ g.
  • the dose is from 200 ⁇ g to 800 ⁇ g, from 210 ⁇ g to 750 ⁇ g, from 220 ⁇ g to 700 ⁇ g, from 230 ⁇ g to 650 ⁇ g, from 240 ⁇ g to 600 ⁇ g, from 250 ⁇ g to 550 ⁇ g.
  • this dose corresponds to the daily dose.
  • “administration once daily” in certain embodiments means that the pharmaceutical composition is adapted for being administered according to a regimen comprising the administration of a first pharmaceutical composition and the subsequent administration of a second pharmaceutical composition according to the invention, wherein both, the first and the second pharmaceutical composition are administered during a time interval of about 48 hours, but wherein the second pharmaceutical composition is administered not earlier than 18 hours, not earlier than 20 hours, not earlier than 22 hours and in particular, about 24 hours after the first pharmaceutical composition has been administered.
  • Administration regimens “once daily” may be realized by administering a single pharmaceutical composition containing the full amount of the cebranopadol or pharmaceutically acceptable salt thereof to be administered at a particular point in time or, alternatively, administering a multitude of dose units, i.e. two, three or more dose units, the sum of which multitude of dose units containing the full amount of the cebranopadol or a pharmaceutically acceptable salt thereof to be dosed at said particular point in time, where the individual dose units are adapted for simultaneous administration or administration within a short period of time, e.g. within 5, 10 or 15 minutes.
  • a pharmaceutical composition (e.g., pharmaceutical dosage form) comprises at least one form of cebranopadol and/or a pharmaceutically acceptable salt thereof, or a hydrate of the cebranopadol or salt thereof, or a solvate of a cebranopadol or a salt or hydrate thereof.
  • the pharmaceutical composition provides immediate release of the cebranopadol or pharmaceutically acceptable salt thereof (or other active ingredient).
  • Such a pharmaceutical composition may be specifically designed to provide immediate release of the cebranopadol in accordance with Ph. Eur or the equivalent.
  • the release kinetic may be monitored after such coating has been dissolved.
  • the term “immediate release” refers to any release profile that fulfills at least one, preferably both, of the following requirements.
  • the pharmaceutical composition disintegrates in 10 minutes or less following exposure to a disintegrating medium. Methods to determine the disintegration time are known to a person skilled in the art. For instance, they can be determined according to the USP XXIV disintegration test procedure, using, for example, an Erweka ZT-71 disintegration tester.
  • the pharmaceutical composition releases at least 70 wt% of the drug within 15 minutes following exposure to a dissolution medium.
  • the in vitro release properties of the pharmaceutical composition are determined according to the paddle method with sinker at 50, 75 or 100 rpm, under in vitro conditions at 37 ⁇ 0.5° C. in 900 mL artificial gastric juice at pH 1.2, or under the same conditions in non-artificial gastric juice.
  • the pharmaceutical composition releases under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 and 37 ⁇ 0.5° C.
  • the pharmaceutical composition is a tablet, chewable tablet, chewing gum, coated tablet or powder, optionally filled into a capsule.
  • the pharmaceutical composition in multi-particulate form in form of a micro-tablet, micro capsule, granulate, pellet or active-substance crystal, optionally filled into a capsule or compressed to form a tablet.
  • a solid pharmaceutical composition may contain pharmaceutical excipients including one or more lubricants, binders, disintegrants, fillers, diluents, glidants, surfactants, and preservatives.
  • One suitable lubricant that may be contained in the pharmaceutical composition is magnesium stearate.
  • the content of the lubricant is within the range of from 0.001 to 5.0 wt%, for example 0.01 to 5 wt.-%, 0.1 to 5 wt.-%, 0.1 to 3 wt.-%, 0.1 to 2 wt.-%, or even 0.5 to 1.5 wt.-% , based on the total weight of the composition (e.g., tablet).
  • the pharmaceutical composition further contains a binder.
  • Suitable binders include but are not limited to gelatin, cellulose, modified cellulose such as microcrystalline cellulose, methyl cellulose, polyvinyl pyrrolidone (povidone), starch, sucrose and polyethylene glycol; especially preferred are polyvinyl pyrrolidone and/or microcrystalline cellulose.
  • the content of lubricant is within the range of from 0.001 to 30 wt.-%, or 0.1 to 25 wt.-%, based on the total weight of the composition (e.g., tablet).
  • the composition comprises 1 to 20 wt.-%, 5 to 20 wt.-%, or 10 to 20 wt.-% of binder(s), based on the total weight of the composition (e.g., tablet).
  • the pharmaceutical composition further contains a filler and/or diluent, e.g., selected from the group consisting of but are not limited to cellulose (e.g., microcrystalline cellulose), calcium diphosphate, lactose (e.g., lactose monohydrate), sucrose, glucose, mannitol, sorbitol, and calcium carbonate.
  • the content of filler and/or diluent is within the range of from 0.001 to 95 wt.-%, 30 wt% to about 90 wt%, 0.01 to 85 wt.-%, 0.1 to 80 wt.-%, or 10 to 75 wt.-% , based on the total weight of the composition (e.g., tablet).
  • the pharmaceutical composition further contains a lubricant such as magnesium stearate, stearic acid and stearin.
  • the content of the lubricant is within the range of from 0.001 to 5 wt %, e.g., from 0.1 to 3 wt%, or about 0.5 wt% to 1.5% wt%, based on the total weight of the composition (e.g., tablet).
  • the pharmaceutical composition further contains a disintegrant such as cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), cross-linked polyvinyl pyrrolidone and sodium starch glycolate.
  • the content of the disintegrant is within the range of from 0.001 to 5 wt. %, e.g., from 0.1 to 3 wt.
  • the pharmaceutical composition may further contain at least one preservative. Suitable preservatives include but are not limited to antioxidants, such as vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium; cysteine, methionine, citric acid, sodium citrate, methyl paraben and propyl paraben.
  • a solid pharmaceutical composition further contains a coating, in particular a polymer-based coating, more in particular a polyvinyl alcohol-based coating such as the ones commercially available under the trade name “Opadry”.
  • the pharmaceutical composition is a tablet which comprises the cebranopadol or pharmaceutically acceptable salt thereof (e.g., in an amount from 0.6 ⁇ 0.4 wt %, 0.6 ⁇ 0.3 wt -%, 0.6 ⁇ 0.2 wt%, 0.6 ⁇ 0.1 wt %, 0.04 ⁇ 0.03 wt %, 0.04 ⁇ 0.02 wt. %, or 0.04 ⁇ 0.01 wt %), one or more lubricants (e.g., magnesium stearate) in an amount from 0.001 to 5.0 wt.
  • binders e.g., polyvinyl pyrrolidone and/or microcrystalline cellulose
  • fillers or diluents e.g., microcrystalline cellulose and/or lactose
  • the tablet also comprises one or more lubricants (e.g., magnesium stearate, stearic acid and/or stearin) in an amount from 0.001 to 5 wt % (e.g., from 0.1 to 3 wt %) and/or one or more disintegrants (e.g., croscarmellose sodium, cross-linked polyvinyl pyrrolidone and/or sodium starch glycolate) in an amount from 0.001 to 5 wt % (e.g., from 0.1 to 3 wt %), based on the total weight of the composition (e.g., tablet).
  • the coating protects the pharmaceutical composition from moisture, but dissolves rapidly in gastric juice.
  • the coated composition has a disintegration time of less than 5 minutes in gastric juice, of at most 4.5 minutes, at most 4 minutes, at most 3.5 minutes, at most 3 minutes, at most 2.5 minutes and/or at most 2 minutes.
  • the various solid auxiliary substances and the pharmacologically active agent may be homogenized, processed by means of wet, dry or fusion granulation to form granulates, and compressed to form tablets. Alternatively, they are manufactured by direct tableting of the auxiliary substances and the pharmacologically active agent.
  • the pharmaceutical composition is prepared by means of wet granulation from a granulating fluid containing the pharmacologically active agent in particular from an aqueous granulating fluid containing said pharmacologically active agent and the surfactant.
  • the resulting granulating fluid is then top-sprayed or bottom-sprayed onto a solid formulation containing at least one auxiliary substance to yield compressible granules, which may optionally be mixed with further auxiliary substances before being compressed to tablets.
  • Further provided herein are methods and regimens using the pharmaceutical compositions comprising at least cebranopadol or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the composition comprises cebranopadol free base.
  • the composition is an immediate release composition.
  • a method for treatment and/or prevention of opioid use disorder (OUD) in a patient in need therefor comprising dosing a patient with a pharmaceutical composition comprising a cebranopadol and/or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof.
  • cebranopadol is selected as a first line analgesic in the absence of any opioid or opioid-like analgesic in a subject having one or more risk factors for developing OUD.
  • cebranopadol may be selected as a secondary analgesic providing opioid-like analgesic effect by discontinuing opioid treatment within 1 to two hours after administering a cebranopadol composition.
  • the patient may have received opioid treatment for less than 24 hours, less than 18 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours.
  • opioid treatment is discontinued after a single dose, followed by cebranopadol.
  • the first dose of cebranopadol may be delivered concomitantly, or shortly after, the first opioid dose.
  • cebranopadol treatment is initiated in a patient having or previously diagnosed with opioid use disorder, but in need of analgesic treatment.
  • the cebranopadol is used for treatment of pain associated with opioid-induced hyperalgesia.
  • the cebranopadol is used for treatment of acute pain.
  • the pain is associated with tissue damage following surgery. In certain embodiments, the pain is associated with hyperalgesia. In certain embodiments, methods, compositions and uses are provided for reducing the risk of apnea and/or preventing oxygen desaturation in a patient receiving pain treatment by administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol. In certain embodiments, the composition comprising an immediate release cebranopadol composition and the active pain ingredient is at least one form of cebranopadol. In certain embodiments, the patient receiving cebranopadol treatment has impaired lung function.
  • the patient has asthma, chronic obstructive pulmonary disease (COPD), pneumonia, chronic or acute bronchitis, emphysema, cystic fibrosis, interstitial lung disease (ILD), pulmonary embolism, pleural effusion, mesothelioma, tuberculosis, acute respiratory distress syndrome (ARDS), neuromuscular disorders, obesity hypoventilation syndrome, or lung cancer.
  • COPD chronic obstructive pulmonary disease
  • ILD interstitial lung disease
  • pulmonary embolism pleural effusion
  • mesothelioma tuberculosis
  • ARDS acute respiratory distress syndrome
  • neuromuscular disorders obesity hypoventilation syndrome
  • lung cancer chronic obstructive pulmonary disease
  • the cebranopadol prevents apnea and/or oxygen desaturation in a patient receiving pain treatment in the first hour and/or the first two hours post-dosing of an immediate release cebranopadol composition independent of dose
  • the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate.
  • a daily dose in an amount of about 10 ⁇ g to about 2000 ⁇ g cebranopadol, optionally in more than one form (e.g., free base, salt, hydrate, etc).
  • the composition comprises cebranopadol free base.
  • the composition comprises at least 80% of the cebranopadol in crystal form A.
  • a method is provided for treating pain while reducing the abuse potential and/or side effects of Class II, III and Class IV- opioids over a period of about 8 to 24 hours in a patient.
  • the method comprises dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof which has a mechanism of action comprising dual agonism of the nociceptin/orphanin FQ peptide (NOP) and ⁇ -opioid peptide (MOP) receptors.
  • NOP nociceptin/orphanin FQ peptide
  • MOP ⁇ -opioid peptide
  • the abuse potential is assessed using a visual analog scale (VAS) rating.
  • VAS visual analog scale
  • the abuse potential is further assessed using a Multi-Task Test.
  • the method further comprises dosing the patient with cebranopadol at a dose of about 50 ⁇ g to 800 ⁇ g or more than 190 ⁇ g to 800 ⁇ g, i.e., the dosage form a contains the pharmacologically active agent in a daily dose of from 150 ⁇ g to 800 ⁇ g.
  • the dose of the pharmacologically active agent is in the range of from 200 ⁇ g to 800 ⁇ g, from 210 ⁇ g to 750 ⁇ g, from 220 ⁇ g to 700 ug, from 230 ⁇ g to 650 ⁇ g, from 240 ⁇ g to 600 ⁇ g, from 250 ⁇ g to 550 ⁇ g.
  • a supratherapeutic dose may be selected.
  • a supratherapeutic dose may comprise greater than 450 ⁇ g to about 1000 ⁇ g cebranopadol, as calculated based on equivalence to free base cebranopadol.
  • the supratherapeutic dose is about 600 ⁇ g to about 1000 ⁇ g cebranopadol, as calculated based on equivalence to free base cebranopadol.
  • the composition comprises the cebranopadol is a tablet, optionally a film coated tablet.
  • a regimen is provided for reducing the abuse potential and sides effects of Class II and Class IV- opioids in a patient susceptible thereto.
  • the method comprises: (a) discontinuing treatment of a patient with an opioid or opioid agonist; and (b) dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof which comprises a dual receptor for nociceptin/orphanin FQ peptide (NOP) and ⁇ -opioid peptide (MOP) receptor.
  • (a) comprises titrating down the dosage of a Class II or Class IV opioid or opioid agonist by decreasing the dose of the opioid or opioid agonist in (a) over the period of 1 to 3 days. Steps (a) and (b) may be performed during the same or overlapping time periods.
  • the opioid or opioid agonist of (a) is selected from tramadol, oxycodone, morphine, hydrocodone, fentanyl, oxymorphone, hydromorphone, buprenorphine, codeine, tapentadol, methadone, meperidine, or levorphanol.
  • one or more of the side effects selected from nausea, vomiting, dizziness, pruritis, and/or hot flush sensation are reduced or eliminated.
  • the patient is renally or hepatically impaired.
  • a method is provided for treating pain in a patient having nociceptive pain with reduced risk of abuse.
  • a regimen comprises dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof.
  • the composition used is cebranopadol free base.
  • the composition is a film-coated tablet.
  • a dosage unit comprises 100 mcg ( ⁇ g) cebranopadol (equivalent to free base).
  • a dosage unit comprises 200 mcg cebranopadol (equivalent to free base).
  • a dosage unit is 300 mcg cebranopadol (equivalent to free base).
  • a dosage unit is 400 mcg cebranopadol.
  • a single daily oral dose may comprise 1, 2, 3, 4, 5, 6, 7, or 8 tablets taken essentially at the same time (e.g., 100 mcg tablet taken within five minutes of each other). In certain embodiments, a single daily oral dose may comprise 1, 2, 3 or 4 tablets (e.g., 200 mcg tablet taken within five minutes of each other). In certain embodiments, a single daily oral dose may comprise 1 or 2 tablets (e.g., 100, 200, 300 or 400 mcg tablets, or combinations thereof, taken within five minutes of each other). Other combinations may be selected.
  • a method for treatment of opioid use disorder (OUD) in a patient in need thereof comprises treating the patient with at least one dose of cebranopadol or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition provides an immediate release profile for the cebranopadol or pharmaceutically acceptable salt thereof.
  • composition comprises cebranopadol in its free base form.
  • the composition is delivered once daily for the desired duration of treatment, e.g., 1 day to 14 days, 3 weeks, 4 weeks, or longer, or shorter durations therebetween. In certain embodiments, herein the composition is delivered no more than once a day for three to 14 days.
  • the pharmacokinetic parameters of cebranopadol may be calculated from plasma concentration- time data.
  • AUC0-t refers to “Area under the concentration-time curve” from administration up to the sampling time t. If it is not replaced by a numerical value, then t is the last sampling time with quantifiable concentration and this parameter will not contain an extrapolated portion.
  • AUCinf refers to Area under the concentration-time curve from time 0 to infinite time. Areas under the curves in the study examples below may be calculated using the log- linear trapezoidal rule, i.e., linear up to the maximum concentration and log thereafter. However, others may readily select another method.
  • C max refers to the maximum observed plasma concentration level.
  • Tmax refers to the time post-dosing to attain maximum plasma concentration.
  • the PK values may be determined using geometric mean and/or the arithmetic mean. In certain embodiments, mean, individual, and overlay concentration-time profiles are plotted on both linear and semi-logarithmic scales on the same, portrait-oriented page.
  • Pharmacodynamics may be assessed using a Visual Analog Scale (VAS), Pupillometry, and/or the Multi-Tasking Test (MTT), such as described in the examples herein. Additional or alternative tests may be selected.
  • VAS Visual Analog Scale
  • MTT Multi-Tasking Test
  • the VAS assessment is one of the most sensitive indices of abuse liability. See, Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse liability and reinforcing efficacy of oral tramadol in humans.
  • the VAS for Drug Liking assesses the subject’s liking of the drug at this moment the question is asked.
  • the VAS is a bipolar scale.
  • the scale is not administered pre-dose as it refers specifically to the drug.
  • Pupillometry may be used as an objective physiological PD measure as it is one of the most sensitive measures of central opioid action and appears to be resistant to tolerance development with repeated opioid administration.
  • NeurOptics Pupillometer (Irvine, CA, USA) or similar equipment will be used to measure pupil diameter.
  • MTT Multi-Tasking Test
  • AST Attention Switching Task
  • Some trials display congruent stimuli (e.g., arrow on the right side of the screen pointing to the right) whereas other trials display incongruent stimuli which require a higher cognitive demand (e.g., arrow on the right side of the screen pointing to the left).
  • both rules are used, presented in a randomized order, requiring the participant to adjust their response depending on whether the rule is repeated or switched (multitasking).
  • Outcome measures for the Multitasking Test include response latencies and error scores that reflect the participant’s ability to manage multitasking and the interference of incongruent task- irrelevant information on task performance.
  • the administration time for the test is about 8 minutes.
  • a cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate which when administered to a subject provides the subject with a therapeutic effect of a pharmaceutically acceptable full mu agonist and a lower potential for abuse than a pharmaceutically acceptable partial mu agonist.
  • the subject is being treated for pain.
  • the pain is chronic acute; central; peripheral; neuropathic and/or nociceptive pain, or another of the types of pain provided in this specification or known in the art.
  • the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol.
  • the cebranopadol is a free base.
  • cebranopadol is in crystal form A.
  • the partial mu agonist is tramadol.
  • use of cebranopadol in treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu agonist therapeutic effect and a lower abuse potential than a partial mu agonist.
  • cebranopadol in preparing a medicament for treating a subject
  • the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu agonist therapeutic effect and a lower abuse potential than a partial mu agonist.
  • a method, use or composition is provided for treatment of opioid use disorder.
  • a method, use or composition is provided for opioid use disorder in subjects having impaired lung function.
  • a method, use or composition for treating pain while reducing the abuse potential and/or sides effects of Class II, III and Class IV- opioids and opioid- like analgesics over a period of about 8 to 24 hours in a patient in need of analgesic treatment, said method comprising dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt or hydrate thereof.
  • the mu-agonist effect is assessed using a visual analog scale (VAS) rating and/or a Multi-Task Test.
  • VAS visual analog scale
  • the patient is dosed with 100 ⁇ g to 400 ug cebranopadol, as calculated based on equivalence to free base cebranopadol.
  • the cebranopadol is at dose which comprises greater than 450 ⁇ g to about 1000 ⁇ g cebranopadol, or about 600 ⁇ g to about 1000 ⁇ g, as calculated based on equivalence to free base cebranopadol.
  • the cebranopadol is a tablet unit dosage form.
  • the tablet is a film coated tablet.
  • the cebranopadol is in free base form.
  • a regimen for providing analgesic treatment while e reducing the abuse potential and/or sides effects of Class II and Class IV- opioids in a patient susceptible thereto, said method comprising: (a) discontinuing treatment of a patient with an opioid or opioid agonist ; and (b) dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof .
  • the regimen (a) comprises titrating down the dosage of a Class II, Class III or Class IV opioid or opioid agonist by decreasing the dose of the opioid or opioid agonist in (a) over the period of 1 to 3 days.
  • steps (a) and (b) are performed during the same or overlapping time periods.
  • opioid or mu opioid agonist is selected from tramadol, oxycodone, morphine, hydrocodone, fentanyl, oxymorphone, hydromorphone, buprenorphine, codeine, tapentadol, methadone, meperidine, or levorphanol.
  • the mu agonist activity (or abuse potential) is assessed using a visual analog scale (VAS) rating and/or a Multi-Task Test.
  • composition comprising the cebranopadol is a tablet. In certain embodiments, the tablet is film coated tablet.
  • the side effects comprise nausea, vomiting, dizziness, pruritis, hyperhidrosis and/or hot flush sensation.
  • the patient is renally or hepatically impaired.
  • the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol is crystal form A.
  • a method, use or composition is provided for treating pain. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is chronic, acute, subacute, central, peripheral, neuropathic, and/or nociceptive pain.
  • a method, use or composition for treating pain, wherein pain is visceral pain, skeletal pain, and/or nervous pain. Patients more reliably discontinue the use of Cebranopadol at the end of prescribed treatment periods as compared to known Schedule II, Class III, and class IV opioids and opioid- like analgesics.
  • a composition comprising cebranopadol treats a subject by delivering full mu ( ⁇ ) agonist activity (e.g., analgesic or other therapeutic effect), while avoiding addictive properties of full mu agonists (e.g., fentanyl, oxycodone, morphine, heroin, codeine, meperidine, or other Class I, Class II or Class III analgesics) and providing less addictive properties and/or less abuse potential than a partial mu agonist (e.g., tramadol or another Class IV opioid-like analgesic).
  • full mu ( ⁇ ) agonist activity e.g., analgesic or other therapeutic effect
  • addictive properties of full mu agonists e.g., fentanyl, oxycodone, morphine, heroin, codeine, meperidine, or other Class I, Class II or Class III analgesics
  • a partial mu agonist e.g., tramadol or another Class IV opioid-like analgesic
  • cebranopadol unlike after treatment with oxycodone and tramadol, administration of cebranopadol does not produce pruritus, hyperhidrosis, feeling hot and/or hot flushing, that have been associated with the use of opioid analgesics.
  • methods for providing a patient with opioid-level analgesic effect while preventing pruritus by administering cebranopadol comprising administering an effective amount of cebranopadol.
  • methods for providing a patient with opioid-level analgesic effect while preventing hyperhidrosis by administering an effective amount of cebranopadol are provided herein.
  • methods for preventing hyperhidrosis in a patient receiving an opioid-level analgesic effect, comprising administering an effective amount of cebranopadol comprising administering an effective amount of cebranopadol.
  • methods for preventing hot flushing in a patient receiving an opioid-level analgesic effect comprising administering an effective amount of cebranopadol.
  • a cebranopadol composition useful for reducing pruritus, hyperhidrosis, feeling hot and/or hot in a subject receiving analgesic treatment for pain is provided, which provides the analgesic therapeutic effect of an opioid.
  • the cebranopadol is in free base form.
  • at least 80% of the cebranopadol in the composition is in crystal form A.
  • a method for reducing pruritus, hyperhidrosis, feeling hot and/or hot in a subject receiving analgesic treatment for pain is provided, which provides the therapeutic effect of an opioid, comprising administering a composition comprising cebranopadol.
  • a composition which is useful in treating a subject, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a therapeutic effect of a pharmaceutically acceptable full mu-agonist and a lower potential for abuse than a pharmaceutically acceptable partial mu-agonist.
  • the subject is being treated for pain.
  • the pain is chronic; acute; central; peripheral; neuropathic and/or nociceptive pain.
  • the pain is visceral pain, skeletal pain, and/or nervous pain.
  • the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol.
  • cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the partial mu-agonist is tramadol. In certain embodiments, use of cebranopadol in treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu-agonist.
  • cebranopadol in preparing a medicament for treating a subject
  • the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu agonist.
  • a composition, use or method is provided for treating a subject, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu-agonist.
  • the subject is being treated for pain.
  • the pain is chronic; acute; central; peripheral; neuropathic and/or nociceptive pain.
  • the pain is visceral pain, skeletal pain, and/or nervous pain.
  • the mu-agonist activity is assessed using a visual analog scale (VAS rating) and/or a Multi-Task Test.
  • the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol.
  • the cebranopadol is a free base.
  • at least 80% of the cebranopadol is in crystal form A.
  • the partial mu- agonist is tramadol.
  • a composition, use or method treating pain in a patient having nociceptive pain with reduced risk of abuse comprising dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof.
  • the composition is a film- coated tablet.
  • the cebranopadol is in free base form.
  • at least 80% of the cebranopadol in the composition is in crystal form A.
  • a composition, use or method which is useful for reducing pruritus, hyperhidrosis, feeling hot and/or hot in a subject receiving analgesic treatment for pain, while providing the analgesic therapeutic effect of an opioid, wherein the composition comprises cebranopadol.
  • the cebranopadol is in free base form.
  • at least 80% of the cebranopadol in the composition is in crystal form A.
  • a composition or regimen provided herein comprises cebranopadol as the sole active pharmaceutical ingredient or the sole analgesic in the composition.
  • a composition, use or method for treatment of pain in humans which provides reduced the abuse potential and reduced sides effects as compared to Class II, III and Class IV- opioids and opioid-like analgesics.
  • the method involves dosing a human patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt or hydrate thereof.
  • the composition is an immediate release composition administered once daily and provides an analgesic effect over a period of at least about 8 to 24 hour hours post-administration.
  • the pain is visceral pain, skeletal pain, and/or nervous pain.
  • the mu-agonist activity is assessed using a visual analog scale (VAS rating) and/or a Multi-Task Test.
  • VAS rating visual analog scale
  • patient is dosed with 100 ⁇ g to 400 ug cebranopadol, as calculated based on equivalence to free base cebranopadol.
  • the patient is dosed with greater than 450 ⁇ g to about 1000 ⁇ g cebranopadol, as calculated based on equivalence to free base cebranopadol.
  • the dose is about 600 ⁇ g to about 1000 ⁇ g cebranopadol, as calculated based on equivalence to free base cebranopadol.
  • the composition comprising the cebranopadol is a tablet unit dosage form.
  • the tablet is a film coated tablet.
  • the cebranopadol is in free base form.
  • at least 80% of the cebranopadol is crystal form A.
  • a method for treating and/or preventing opioid use disorder (OUD) in human patients receiving analgesic treatment comprises treating a patient with cebranopadol, optionally a film coated tablet.
  • a regimen is provided for reducing the abuse potential and side effects of Class II and Class IV- opioids in a patient susceptible thereto.
  • the method comprises: (a) discontinuing treatment of a patient with an opioid or opioid agonist; and (b) dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof.
  • (a) comprises titrating down the dosage of a Class II or Class IV opioid or opioid agonist by decreasing the dose of the opioid or opioid agonist in (a) over the period of 1 to 3 days. Steps (a) and (b) may be performed during the same or overlapping time periods.
  • the opioid or opioid agonist of (a) is selected from tramadol, oxycodone, morphine, hydrocodone, fentanyl, oxymorphone, hydromorphone, buprenorphine, codeine, tapentadol, methadone, meperidine, or levorphanol.
  • one or more of the side effects selected from nausea, vomiting, dizziness, pruritis, and/or hot flush sensation are reduced or eliminated.
  • the patient is renally or hepatically impaired.
  • a method is provided for treating pain in a patient having nociceptive pain with reduced risk of abuse.
  • the regimen comprises dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof.
  • the composition used is cebranopadol free base.
  • the composition is a film-coated tablet.
  • cebranopadol may be the sole active pharmaceutical ingredient in the composition and/or regimen. It will be understood from the specification that the following examples are not limitations on the various embodiments of the invention.
  • cebranopadol oral human abuse potential study in the following example was a phase I single-dose, randomized, double-blind, five-way crossover study of 47 participants to evaluate the abuse potential of two supratherapeutic doses of cebranopadol in adult nondependent recreational opioid users versus placebo and commonly used opioids, oxycodone, a schedule II narcotic, and tramadol, a schedule IV narcotic.
  • Eligible participants randomly received a single dose of placebo, cebranopadol 600 ⁇ g, cebranopadol 1000 ⁇ g, tramadol IR 600mg, or oxycodone IR 40mg.
  • hygroscopicity was measured in a slightly different manner, it was classified according to the European Pharmacopoeia as follows: very hygroscopic (vh): increase of the mass ⁇ 15%; hygroscopic (h): increase of the mass is less than 15% and equal or greater than 2%; slightly hygroscopic (sh): increase of the mass is less than 2% and equal or greater than 0.2%; not hygroscopic (nh): increase of the mass is less than 0.2%; deliquescent (d): sufficient water is absorbed to form a liquid. DVS with two cycles was performed on a sample of crystalline form A. The first cycle was not symmetric, the sample contained still water when the DVS cycle returned to 50% r.h.
  • Example 1 A single-dose, randomized, double-blind, placebo- and active- controlled crossover trial to evaluate the abuse potential of two doses of cebranopadol in adult nondependent recreational opioid users.
  • each subject will be randomly allocated to receive a single oral dose of the IMP in each of the 5 periods.
  • subjects will receive an oral single dose of 6 identically appearing capsules that will contain one of the following treatments: • Cebranopadol film coated tablets, 200 ⁇ g: single oral dose of 600 ⁇ g • Cebranopadol film coated tablets, 200 ⁇ g: single oral dose of 1000 ⁇ g.
  • Oxycodone HCl tablets 20 mg: single oral dose of 40 mg (Positive control; Schedule II opioid). The 40 mg dose is expected to show significant abuse-related subjective effects without interfering with completion of PD measures or producing aversive effects, and although higher doses have been shown to produce higher positive effects without significant adverse effects, 40 mg is expected to be sufficient to demonstrate a difference in all endpoints between oxycodone IR and placebo.
  • Tramadol HCl tablets 100 mg: single oral dose 600 mg (Positive control; Schedule IV opioid).
  • tramadol IR appears to have a lower abuse potential compared with other opioids (most commonly Schedule II; see Dunn et al., 2019, for systematic review7); however, the effects of tramadol IR in a human abuse potential study can vary based on route of administration and if the subject sample is physically dependent on opioids. Oral tramadol IR doses ranging between 25 mg to 700 mg have been evaluated in non- physically dependent individuals. The dose of tramadol IR in the present study (600 mg) has been selected based on variable findings of liking at doses ⁇ 400 mg and because the 700 mg dose was shown to be safe and reasonably well tolerated in a similar subject population.
  • Study Population The study will enroll healthy men and women, 18 to 55 years old, with a history of recreational opioid use defined as nontherapeutic use of opioids at least 10 times in the subject’s lifetime and at least once in the 12 weeks prior to the Enrollment Visit.
  • Inclusion Criteria for Enrollment 1. Willing and able to provide written informed consent 2.
  • Adult men or women aged 18 to 55 years, inclusive 3.
  • Body mass index between 19 kg/m 2 and 32 kg/m 2 inclusive, with a body weight of not less than 50 kg at Enrollment 5.
  • Subjects must be in good health as determined by medical history, physical examination, 12-lead electrocardiogram (ECG), and vital signs (pulse rate, systolic blood pressure and diastolic blood pressure, respiratory rate, and oxygen saturation using pulse oximetry) at Enrollment 6.
  • ECG electrocardiogram
  • vital signs pulse rate, systolic blood pressure and diastolic blood pressure, respiratory rate, and oxygen saturation using pulse oximetry
  • Prolongation of QTcF (after repeated assessment) at Enrollment, i.e., >450 ms for men or >470 ms for women, or presence of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia), or use of concomitant medications that prolong the QT interval 10.
  • History of orthostatic hypotension or other cardiovascular diseases 11. Any clinically significant disease that in the investigator’s opinion may affect efficacy or safety assessments or may compromise the subject’s safety during trial participation, e.g., significant pulmonary, gastrointestinal, cardiac, endocrine, metabolic, neurological, or psychiatric disorders 12. Definite or suspected history of drug allergy or hypersensitivity to opioids or opioid antagonists 13.
  • Positive or missing pregnancy test 4. Positive or missing alcohol breath test; alcohol breath test may be repeated or rescheduled at the discretion of the investigator or designee 5.
  • Positive or missing urine drug of abuse screen result, except for cannabinoids (tetrahydrocannabinol [THC]) 6.
  • Positive or missing viral serology i.e., human immunodeficiency virus Type 1 and Type 2 antibodies and antigen, hepatitis B surface antigens, anti-HBc and IgM anti-HBc, and hepatitis C virus antibodies, based on sample taken at the Enrollment Visit 7.
  • Any abnormal laboratory values or any clinically relevant out-of-range values for safety laboratory parameters (clinical chemistry, coagulation, hematology, and urinalysis) based on sample taken at the Enrollment Visit, as judged by the investigator 8. Blood donation or acute loss of blood (more than 100 mL) since the Enrollment excluding blood samples required by the protocol 9. Any relevant deterioration in the health of the subject that could alter the benefit/risk assessment for the subject, including adverse events (AEs), laboratory parameters, vital signs, or other safety parameters (e.g., ECGs) 10. Failure to comply with trial requirements, e.g., intake of forbidden medications, consumption of alcohol, considered by the investigator to affect subject safety or interfere with the integrity of the trial 11.
  • AEs adverse events
  • ECGs ECGs
  • the study comprises the Enrollment Visit, a Qualification Phase, a Treatment Phase consisting of 5 treatment periods, and an End of Study Visit. See Section 1.2 for a tabular schedule of events for the Qualification Phase and Section 1.3 for the Treatment Phase (which lists all assessments planned). • Enrollment Visit Enrollment will begin no more than 28 days prior to the first dose of study medication.
  • naloxone challenge test Subjects who remain in the clinic on Day ⁇ 1 will undergo a naloxone challenge test to exclude the possibility of physical dependence on opioids.
  • the Objective Opioid Withdrawal Scale (OOWS) will be used to record any signs or symptoms of withdrawal observed during the naloxone challenge test.
  • OOWS Objective Opioid Withdrawal Scale
  • Each subject will attend a double-blind Qualification Phase consisting of a 4-night confinement period during which they will receive, after an overnight fast, a single oral dose of 6 identically appearing capsules that will contain one of the following: oxycodone IR 40 mg, tramadol IR 600 mg, or placebo in a randomized crossover manner separated by ⁇ 24 hours.
  • Pharmacodynamic and safety assessments will be performed from pre-dose through 8 hours after each IMP administration.
  • the purpose of the Qualification Phase is to ensure that the subjects can discriminate between active drug and placebo, can tolerate oxycodone IR 40 mg and tramadol IR 600 mg, can feel comfortable with the pharmacodynamic measures, can follow directions, and are cooperative. Subjects will be confined to the trial site from Day ⁇ 1 until 72 hours after the first IMP administration in the Qualification Phase. • Treatment Phase There will be a washout period of at least 72 hours between the end of the Qualification Phase and the beginning of the first treatment period. Based on the assigned treatment sequence, each subject will be randomly allocated to receive a single oral dose of 6 identically appearing capsules in each of the 5 periods. Each IMP administration will be given under fasted conditions and will be separated by a washout period of at least 14 days between treatments.
  • PK blood sampling
  • assessments will be performed from pre-dose through 48 hours post-dose in each treatment period.
  • An End of Study Visit will be conducted at 5-10 days after discharge from the last treatment period or upon early discontinuation from the trial.
  • Concomitant medications No concomitant medication (including prescription drugs, over-the-counter drugs, and herbal remedies like St. John’s wort) will be allowed during the trial, with the exception of acetaminophen (e.g., for headache), and the continuous use of hormonal contraceptives.
  • Demographics and other subject characteristics Demographic data will comprise sex, age, height, weight, race/ethnicity, and the use of nicotine products. Body mass index will be calculated. Other subject characteristics will comprise medical history (medical history and surgical interventions), recreational drug and alcohol use history, prior and concomitant medications.
  • Pharmacodynamics Primary Measure: • Visual analog scale (VAS) rating for Drug Liking “at this moment” Key Secondary Measures: • VAS rating for Overall Drug Liking • VAS rating for Take Drug Again Other Secondary measures: • VAS rating for Any Drug Effects, High, Good Drug Effects, Bad Drug Effects, Feeling Sick, Alertness/Drowsiness, Floating, and Detached.
  • VAS Visual analog scale
  • the first quantifiable concentration will be excluded from the PK analysis and descriptive statistics will only be determined if at least 75% of the observations at each sampling point have quantifiable results. If a pre-dose concentration is above the assay quantification limit and lower than 5% of C max , it will be set to zero in the PK analysis. Subjects with higher pre-dose values will be excluded from the PK analysis. Areas under the curves will be calculated using the log-linear trapezoidal rule, i.e., linear up to the maximum concentration and log thereafter. The individual concentrations will be listed for each measurement time point and for each period and analyzed descriptively. Tabulated values will be rounded to 3 significant figures. Statistical calculations will be performed with values that have not been rounded.
  • Safety Safety data will comprise physical examinations, oral body temperature, vital signs (pulse rate, systolic blood pressure, diastolic blood pressure, respiratory rate, and oxygen saturation using pulse oximetry), 12-lead ECG, adverse events (AEs), telemetric safety monitoring (5-lead ECG, oxygen saturation, and pulse rate), C-SSRS, safety laboratory parameters (clinical chemistry, coagulation, hematology, and urinalysis), and pregnancy test (females of childbearing potential only).
  • vital signs pulse rate, systolic blood pressure, diastolic blood pressure, respiratory rate, and oxygen saturation using pulse oximetry
  • 12-lead ECG adverse events
  • telemetric safety monitoring (5-lead ECG, oxygen saturation, and pulse rate)
  • C-SSRS safety laboratory parameters (clinical chemistry, coagulation, hematology, and urinalysis), and pregnancy test (females of childbearing potential only).
  • Randomized Population All subjects who are assigned a randomization number in the Treatment Phase.
  • Safety Population All subjects who receive at least one dose of study drug in the Treatment Phase. All safety evaluations in the Treatment Phase will be performed using this Safety Population.
  • Completer Population All randomized subjects who complete all treatment periods of the Treatment Phase and have at least one response on the VAS for Drug Liking within 2 hours of T max for each treatment or, in the case of placebo, at least one response on the VAS for Drug Liking. If Tmax is missing or inestimable for a given subject/treatment (other than placebo), the median Tmax for that treatment for subjects in the Completer Population with non-missing Tmax will be used for this determination.
  • Modified Completer Population All subjects in the Completer Population, excluding subjects with similar E max scores (within 5 points difference) across all study treatments (including placebo) or subjects with an Emax for placebo >60 AND the difference between Emax for placebo and oxycodone IR is ⁇ 5. This population will serve as the primary population for the PD analyses.
  • Pharmacokinetic Population All subjects who receive at least one dose of IMP and have at least one measurable PK sample after dosing. All PK evaluations in the Treatment Phase will be performed using the PK Population. Pharmacodynamic analyses All analyses will be performed using the Modified Completer Population. If the Modified Completer Population and Completer Population differ by more than 10%, Drug Liking Visual Analog Scale (VAS) is analyzed and reported for the Completer Population.
  • VAS Drug Liking Visual Analog Scale
  • a supportive analysis of the primary endpoint may be performed using the Completer Population if this population differs from that of the Completer Population by more than 10%. This supportive analysis will utilize the same hypotheses as that of the primary analysis.
  • the first order carryover effect will be the previous treatment received in the Treatment Phase. If the carryover effect is found to be non-significant at the 25% level, then the term will be dropped from the model. If the carryover effect is significant at the 25% level, but not at the 5% level, then the carryover effect term will be retained in the model; if the carryover effect is significant at the 5% level, a first period analysis will be conducted.
  • CIs least squares means, and confidence intervals
  • difference in least squares mean CIs of the difference
  • p-values will be provided for each treatment comparison.
  • CIs will be 2-sided at the 90% level
  • p-values will be 1-sided
  • significance testing will be performed at 1-sided significance level 0.05.
  • Levene’s test will be used to evaluate potential heterogeneity of variance in the model with a one-way analysis of variance (ANOVA), including residuals as the response and treatment as a fixed effect. If the p-value is not significant at the 0.05 level, the mixed model with equal variances will be performed.
  • the model will be corrected by estimating the variances for treatment separately (unequal variance model using the Satterthwaite method and repeated statement).
  • the residuals from the mixed-effects model will be investigated for normality using the Shapiro-Wilk W test. Parameters will be analyzed under the assumption of a normal distribution of errors if the p-value of the test is ⁇ 0.01, and the mixed effects model will be used for reporting for the final analysis. If the p-value is ⁇ 0.01 for the Shapiro Wilk W test on the residuals from the mixed model, a test of skewness will be conducted on each paired difference.
  • Drug Liking Emax will be analyzed using paired t-tests for each treatment comparison. If the distribution of the paired differences is skewed (skewness value ⁇ -0.5 or skewness value >0.5), then Drug Liking E max will be analyzed non-parametrically.
  • the Sign Test will be used to evaluate treatment differences. If a paired t-test is chosen for Drug Liking Emax, means, mean differences and corresponding one- sided 95% CIs, as well as p-values for the appropriate hypothesis will be presented.
  • oxycodone IR Cebranopadol vs. tramadol
  • Oxycodone IR vs. placebo (study validity) • Tramadol IR vs. placebo
  • Ho ⁇ C1 - ⁇ P ⁇ 15 vs. Ha: ⁇ C1 - ⁇ P > 15 (1) where ⁇ C1 is the mean for oxycodone IR and ⁇ P is mean for placebo.
  • the margin of 15 was selected based on previous studies of this type. Pathak S, Vince B, Kelsh D, et al.
  • tramadol IR fails the validation test, results of all pairwise comparisons with tramadol IR from the model will be considered descriptive. Failure of tramadol IR to separate from placebo will not impact subsequent tests between oxycodone IR, cebranopadol and placebo.
  • cebranopadol The primary treatment comparison for relative abuse potential of cebranopadol will be the comparison of Drug Liking E max between cebranopadol at each dose level and oxycodone IR.
  • cebranopadol and oxycodone IR • Cebranopadol 600 ⁇ g vs. oxycodone IR 40 mg • Cebranopadol 1000 ⁇ g vs. oxycodone IR 40 mg Ho : ⁇ C1 - ⁇ T ⁇ 0 vs. Ha : ⁇ C1 - ⁇ T > 0 (3) where ⁇ C1 is the mean for oxycodone IR and ⁇ T is mean for cebranopadol.
  • the secondary treatment comparisons for relative abuse potential of cebranopadol will be the comparison of cebranopadol at each dose level versus tramadol IR.
  • cebranopadol The evaluation of absolute abuse potential of cebranopadol will be the comparison of cebranopadol versus placebo.
  • the following hypothesis will be tested: • Cebranopadol 600 ⁇ g vs. placebo • Cebranopadol 1000 ⁇ g vs. placebo Ho : ⁇ T - ⁇ P ⁇ 11 vs. Ha : ⁇ T - ⁇ P ⁇ 11 (5) where ⁇ T is the mean for cebranopadol and ⁇ P is mean for placebo. A significance level of 0.05 will be used for all 1-sided tests. As the hypotheses will be tested sequentially and must be met at all dose levels, no adjustments in p-values will be made to account for multiple comparisons.
  • the direction of the hypotheses may be reversed for some endpoints (e.g., Emin for Alertness/Drowsiness).
  • Each dose of cebranopadol (T) vs. placebo (P): H0: ⁇ T – ⁇ P 0 vs.
  • This study used a randomized, double-blind, five-way crossover design to evaluate the abuse potential of cebranopadol in adult nondependent recreational opioid users versus placebo, oxycodone, and tramadol.
  • Eligible subjects underwent a naloxone challenge to confirm nondependence to opioids, and a qualification phase to assess that subjects could tolerate oxycodone and tramadol and discriminate their effects from placebo.
  • Qualified subjects underwent a ⁇ 72-hour washout before receiving study drug in the Treatment Phase. Subjects were randomized to receive single doses of cebranopadol 600 ⁇ g or 1000 ⁇ g, oxycodone IR 40mg, tramadol IR 600mg, or placebo in a crossover manner.
  • ⁇ C1 is the mean for oxycodone
  • ⁇ C2 is the mean for tramadol
  • ⁇ P is the mean for placebo
  • ⁇ T is the mean for cebranopadol.
  • Bolded p-values are statistically significant.
  • the overall goal of the current phase of this study is to establish the safety and abuse potential profile of cebranopadol, and to demonstrate the therapeutic efficacy of cebranopadol in decreasing opioid use with low risk of withdrawal signs and symptoms when transitioning.
  • Dosage Form, Route of Administration and Dosing Regimen The test products are film coated tablets and the dosage strengths are 100 ⁇ g, 200 ⁇ g, and 400 ⁇ g.
  • the dosage regimen is determined by conducting the studies discussed in the clinical development plan, as described herein.
  • the preliminary data, preclinical and clinical summary as described below, have provided strong proof of concept for the development of cebranopadol as a novel and safe agent to treat OUD.
  • Cebranopadol is highly effective in animal models of acute pain (approximately equi- potent to the strong opioid fentanyl), visceral, inflammatory, chronic mono- and poly-neuropathic and bone cancer pain.
  • the analgesic potency of cebranopadol is ⁇ 10 to 100 times higher in neuropathic pain than in acute pain, whereas the classical opioids generally have the same analgesic potency in both pain states.
  • Activation of both NOP and classical opioid receptors contributed to antihypersensitive efficacy of cebranopadol in rodent models of chronic neuropathic and chronic inflammatory pain.
  • cebranopadol induced only moderate opioid- typical central nervous system (CNS) effects at doses within and exceeding the antinociceptive dose range and did not exhibit pro-convulsant activity. Cebranopadol induced moderate bradycardia in conscious rabbits and dogs and had a hypertensive effect at high doses in conscious dogs.
  • CNS central nervous system
  • cebranopadol induced electrocardiogram (ECG) changes could be fully antagonized by naloxone or naltrexone and are, thus, attributable to a MOP receptor mediated mechanism.
  • cebranopadol In human plasma, ⁇ 26% of cebranopadol is bound to 1-acid glycoprotein and ⁇ 70% to serum albumin. No evidence of transporter interaction was found for cebranopadol. Cebranopadol has a rather complex metabolism, leading to a broad spectrum of phase 1 and phase 2 metabolites. Different cytochrome P450 (CYP) enzymes (2C9, 2C19, 2D6, and 3A4) are involved and at least 5 different primary metabolic pathways of cebranopadol were identified (mainly hydroxylation and demethylation), followed by a wide variety of conjugation reactions (sulfate-, glucuronide-, glutathione- and cysteine-conjugates).
  • CYP cytochrome P450
  • mice In repeat-dose toxicity studies in mice (up to 13 weeks PO), rats (4 weeks IV and up to 26 weeks PO), dogs (4 weeks IV and up to 39 weeks PO), and minipigs (2 weeks IV), behavioral disorders (e.g., reduced locomotor activity, aggressive behavior [rats], sedation, and stiffness), and vomiting (dogs) were observed that are attributed to exaggerated pharmacodynamic (opioid agonistic) effects of cebranopadol.
  • a 13-week oral repeat-dose toxicity study in the Wistar rat revealed a dose-dependent reduction in organ weight in the seminal vesicles, prostate and ovary. Histopathological changes were seen in the testis, epididymis, seminal vesicle, prostate and ovary.
  • Cebranopadol does not pose a genotoxic or phototoxic risk to humans. No effects on mating or fertility in rats and no teratogenic potential in rats and rabbits were detected after PO administration of cebranopadol. In pregnant rats, dose-dependent maternal toxicity was observed without embryotoxic effects. In rabbits, marked maternal toxicity was associated with embryo-fetal toxicity. Cebranopadol did not induce developmental toxicities at doses free of maternal toxicity.
  • Cebranopadol was locally well tolerated and showed no skin sensitizing potential. Cebranopadol induced only minor and NOP receptor-independent opioid-like withdrawal symptoms in mice compared with equi-antinociceptive doses of morphine. In rats, spontaneous or naloxone-precipitated withdrawal from cebranopadol did not result in typical opioid-like withdrawal symptoms. Development of physical dependence was detected in Rhesus monkeys at a dose producing clearly supra-maximal antinociception. In rats, cebranopadol produced a conditioned place preference and a morphine-like discriminative stimulus effect with a full generalization to the morphine cue.
  • cebranopadol The morphine-like cue of cebranopadol was antagonized by naloxone and enhanced by the NOP receptor antagonist J-113397. Further evidence for a contribution of MOP and NOP receptor activity, but not DOP and KOP receptor activity, to the discriminative stimulus effect of cebranopadol was obtained in mechanistic studies using selective agonists and antagonists in generalization tests in animals trained on a cebranopadol cue. Tolerance development to the analgesic effect after repeated administrations was remarkably slower for cebranopadol compared with morphine in neuropathic pain.
  • cebranopadol The effect of cebranopadol on ventilation was assessed in a single (cebranopadol 600 ⁇ g) and a multiple dose trial (up to daily doses of cebranopadol 1600 ⁇ g). Both trials showed a trend for a decrease in minute ventilation in the cebranopadol groups caused by a reduction in tidal volume, but not by reduction in respiratory rate as could be expected for classical opioids. This effect appeared to level off with increasing doses and time.
  • the abuse potential of cebranopadol was assessed in a single dose trial comparing cebranopadol 200 ⁇ g, 400 ⁇ g, and 800 ⁇ g with placebo and with hydromorphone 8 mg and 16 mg.
  • Cebranopadol showed statistically significant differences from placebo only at the high dose level (800 ⁇ g). No significant subjective effects were observed with cebranopadol 200 ⁇ g, whereas only few effects were seen with the cebranopadol 400 ⁇ g dose. These results suggest that cebranopadol may have some abuse potential at higher doses, but the abuse potential is limited at the lower doses. All cebranopadol doses had significantly lower effects than hydromorphone immediate release (IR) 16 mg on the Drug Liking visual analog scale (VAS) (at this moment) and these effects occurred later. The abuse potential of hydromorphone and cebranopadol therefore appears to be different.
  • IR hydromorphone immediate release
  • VAS Drug Liking visual analog scale
  • the mean terminal phase half-life (t1/2,z) ranged from 61.7 hours to 95.8 hours (this half-life is considered to be relevant for the calculation of washout periods after cessation of dosing).
  • the intrinsic pharmacokinetic properties of cebranopadol (the combination of late time to maximum concentration [tmax], broad concentration plateau around maximum concentration [Cmax] and long half-life) allow a once daily administration.
  • the data currently available do not indicate any clinically relevant gender or food effect on systemic exposure to cebranopadol. After a single oral administration of radiolabeled cebranopadol, cumulative excretion was ⁇ 71% after 31 days.
  • Cebranopadol only accounted for ⁇ 6% and the 3 metabolites M2, M3, and M6, each for ⁇ 3% exposure of the total radioactivity in plasma, which means that ⁇ 15% of the total plasma radioactivity has been identified.
  • contribution of metabolites to pharmacological activity cannot be excluded following multiple dose administration of cebranopadol.
  • no metabolite observed in human plasma was identified as being unique to humans. Adequate exposure to all currently identified metabolites was observed in at least 1 of the species used for nonclinical safety studies.
  • Morphine sulfate CR 60 mg was as effective as cebranopadol 400 ⁇ g and 600 ⁇ g for other SPI time windows (e.g., SPI2-12 and SPI2-14).
  • subjects with moderate to severe cLBP received cebranopadol in 3 fixed maintenance doses (200 ⁇ g, 400 ⁇ g, and 600 ⁇ g once daily), tapentadol prolonged release (PR) 200 mg twice a day (BID), or placebo.
  • the primary endpoint was the change from baseline in the weekly average 24 hour pain intensity during the entire 12 weeks of the maintenance phase (European Union [EU] and rest of the world region) and during Week 12 of the maintenance phase (United States [US] region).
  • a statistically significant difference between cebranopadol and placebo (p ⁇ 0.05) was apparent for all cebranopadol treatment groups for the primary endpoint.
  • the result on the primary endpoint for the tapentadol PR 200 mg BID treatment group was comprised within that of the 2 higher doses of cebranopadol.
  • cebranopadol 80 ⁇ g to 200 ⁇ g once daily for 5 days showed clinically meaningful differences to placebo in pain reduction in subjects with moderate to severe painful DPN, reaching statistical significance for the cebranopadol 80 ⁇ g and cebranopadol 200 ⁇ g group when comparing to overall baseline, and for the cebranopadol 100 ⁇ g group when comparing to period baseline.
  • Cebranopadol 100 ⁇ g demonstrated analgesic effects similar to morphine CR 60 mg for the primary endpoint. Secondary endpoint parameters supported the conclusions drawn from the primary endpoint.
  • the 3 active dose groups (75 ⁇ g, 200 ⁇ g, or 400 ⁇ g of cebranopadol once daily for 4 weeks) showed a dose response trend, with 75 ⁇ g performing numerically worse than placebo, 200 ⁇ g performing numerically better than placebo, and 400 ⁇ g performing significantly better than placebo (p ⁇ 0.05).
  • cebranopadol 200 ⁇ g once daily for 4 weeks gave a numerically (but not statistically significantly) better pain relief than placebo in subjects with moderate to severe painful DPN whereas the pain reduction in subjects on 25 ⁇ g or 75 ⁇ g per day did not substantially differentiate from placebo.
  • subjects suffering from chronic persistent cancer pain received cebranopadol film-coated tablets at a dose range of 200 ⁇ g to 1000 ⁇ g once daily or morphine sulfate PR 30 mg to 150 mg (divided into 2 doses).
  • the primary goal of the trial was to demonstrate non inferiority between the 2 treatment groups with respect to the use of rescue medication. All subjects had a 2-week (16 days) dose titration phase during which their optimum dose within the allowed dose range was achieved and stayed on their individually chosen dose for the entire 4 week maintenance phase. Subjects recorded the amount of used rescue medication on a daily basis in a diary. The primary efficacy endpoint was the average daily use of rescue medication (i.e., morphine sulfate IR) over the last 2 weeks of treatment in the maintenance phase. The primary efficacy analysis for comparing cebranopadol with morphine sulfate PR was performed in Full Analysis Set (FAS) and Per Protocol Set (PPS) populations.
  • FAS Full Analysis Set
  • PPS Per Protocol Set
  • the non-inferiority margin was 8 mg.
  • Another trial was a Phase 2 trial investigating the efficacy of cebranopadol in subjects with painful DPN. Following a forced 2 week titration phase, subjects received target doses of cebranopadol 100 ⁇ g, 300 ⁇ g, or 600 ⁇ g once daily, pregabalin 300 mg BID, or matching placebo for a 6-week maintenance phase.
  • the primary efficacy endpoint was the change from baseline pain to the average 24-hour pain during Week 6 of the maintenance phase of the double-blind treatment period.
  • a significant dose-response relationship could be established using a multiple comparison procedure combined with a modeling approach (MCP-Mod); an increasing dose of cebranopadol led to an increasing difference to placebo.
  • the estimated mean change from baseline of the primary endpoint analysis for pregabalin 300 mg BID was similar to cebranopadol 600 ⁇ g, and confirmed in comparison to placebo assay sensitivity of the trial and the clinical relevance of the results.
  • subjects with moderate to severe chronic pain due to OA of the knee received cebranopadol in 2 flexible dose ranges (200 ⁇ g to 400 ⁇ g or 400 ⁇ g to 800 ⁇ g once daily), oxycodone CR 10 mg to 50 mg BID, or matching placebo in the maintenance phase. All subjects had an up to 3-week dose optimization to their optimum dose within the assigned dose range and stayed on their individually chosen dose for the entire 12 weeks of the maintenance phase.
  • cebranopadol was safe independent of the galenic formulation (oral and IV solution, liquid- filled capsule, film-coated tablet).
  • the limit of good tolerability was 800 ⁇ g.
  • the limit of good tolerability was cebranopadol 1600 ⁇ g. Higher doses were less well tolerated than lower doses of cebranopadol.
  • cebranopadol No clinical experience with lactating women treated with cebranopadol is available to date.
  • Clinical Development Existing data for cebranopadol have several limitations. Cebranopadol has never been tested in opioid-dependent patients. Hence, to conclusively determine the therapeutic potential of cebranopadol in OUD patients, critical data are still lacking. These include (1) Identification of therapeutic doses for treating OUD in patients. (2) Evaluation of the safety profile of cebranopadol when it is used in combination with other opioids. (3) Assessment of how to transition opioid-dependent individuals onto cebranopadol. (4) Determination of the efficacy and safety of chronic treatment with cebranopadol in individuals with OUD.
  • Study 1 Assess Cebranopadol’s ability to Suppress OUD Withdrawal Signs and Symptoms
  • a randomized, double-blind, multiple ascending dose study determines the ability of cebranopadol to suppress opioid withdrawal signs and symptoms in persons with moderate to severe OUD when transitioned to cebranopadol and identify a dose range for further evaluation.
  • the primary objective of this study is to evaluate the ability of multiple doses of cebranopadol to suppress withdrawal signs and symptoms in adults with moderate to severe OUD.
  • Secondary objectives of this study are: (1) to examine the safety and tolerability of multiple doses of cebranopadol and (2) to assess the pharmacokinetics of multiple doses of cebranopadol.
  • CRU clinical research unit
  • subjects are admitted to the clinical research unit (CRU).
  • CRU clinical research unit
  • subjects are transitioned to an oral immediate-release (IR) opioid, morphine, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to initiating cebranopadol.
  • IR immediate-release
  • QID times daily
  • the last active dose of morphine-IR is administered a minimum of 12 hours before administering the first cebranopadol dose.
  • the Clinical Opiate Withdrawal Scale (COWS) is administered prior to cebranopadol dosing on Day 1 (i.e., a minimum of 12 hr since their last dose of morphine-IR).
  • COWS Clinical Opiate Withdrawal Scale
  • Up to a maximum of 40 subjects are enrolled and randomized into a maximum of 4 cohorts in the Treatment Phase.
  • Ascending doses of cebranopadol are evaluated in separate cohorts of 10 subjects each; within each cohort, 7 subjects receive multiple doses of cebranopadol and 3 subjects receive multiple doses of matching placebo.
  • the first cohort receives cebranopadol 600 ⁇ g or matching placebo; thereafter, dose levels are not fixed and are determined by the Drug Safety Review Committee upon completion of each dosing level.
  • Proposed dose levels include 600, 800, 1200 and 1600 ⁇ g. A dose lower than the planned doses may be tested, a dose level may be repeated, or smaller dosing increments may be applied, depending on emerging safety, tolerability, and/or other relevant data, such as available pharmacodynamic data.
  • Subjects receive cebranopadol or placebo once daily for 5 days and remain inpatient in the CRU. Subjects are discharged on Day 5 and a follow-up interview will be conducted on Day 10. Subjects are offered counseling services and referral to treatment while they are in this study. Subjects are required to meet with an addiction counsellor at least once during their stay in clinic.
  • Pharmacodynamic assessments include COWS, Subjective Opiate Withdrawal Scale (SOWS), visual analog scale (VAS) for craving, and rescue medication use.
  • Safety monitoring include assessments of adverse events (AEs), vital signs, electrocardiograms (ECGs), clinical laboratory tests, physical exams, concomitant medications, and Columbia-Suicide Severity Rating Scale (C-SSRS) results. Blood samples for pharmacokinetic assessments are collected to confirm exposure.
  • Study Title A Randomized Double-blind Multiple Ascending Dose Study to Assess the Ability of se d Within approximately 28 days of initiating outpatient screening, subjects will be admitted to the clinical research unit (CRU).
  • CRU clinical research unit
  • C--SSRS Columbia- Suicide Severity Rating Scale
  • Safety Endpoints The following safety endpoints will be evaluated: incidence, severity, and relatedness of . Descriptive statistics will be calculated and presented for each time point by treatment for plasma concentrations of cebranopadol.
  • the primary objective of this study is to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by a change in isohypercapnic minute ventilation.
  • doses identified in Study 1 the effect of cebranopadol at steady-state concentrations on fentanyl- induced (0.25, 0.35, 0.50 and 0.70 mg/70 kg IV doses) RD are assessed in opioid-tolerant participants (Moss, L.A.-O., et al. Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients. PloS one 17, e0256752 (2022).
  • Permanently sterile i.e., both ovaries removed, uterus removed, or bilateral tubal ligation for at least 6 weeks or documented successful f Subjects with positive urine drug screens (UDS) for buprenorphine, barbiturates, benzodiazepines, or methadone or positive breath or urine alcohol s - , y ) s).
  • UDS positive urine drug screens
  • Sample size estimation Subjective Opioid Effects of Cebranopadol in Adults with Moderate to Severe Opioid Use Disorder Using doses identified in Study 1, the effect of cebranopadol in blocking liking of intramuscular (IM) hydromorphone is assessed in a randomized, double-blind, repeat-dose study in non-treatment-seeking participants with moderate to severe OUD (Nasser, A.F., et al. Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder. Journal of clinical psychopharmacology 36, 18-26 (2016); Walsh, S.L., et al.
  • IM intramuscular
  • the primary objective of this study is to evaluate the opioid blocking effects of cebranopadol following administration of IM hydromorphone (6 and 18 mg/70 kg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects, as measured by the Drug Liking visual analog scale (VAS).
  • VAS Drug Liking visual analog scale
  • Blockade of hydromorphone liking by cebranopadol is claimed if the upper bound of the 95% confidence interval of the treatment difference between maximum effect (Emax) scores on Drug Liking VAS (primary outcome) of hydromorphone and placebo is ⁇ 11.8
  • the secondary objectives of this study are (1) to evaluate the degree of opioid blocking effects of cebranopadol following administration of IM hydromorphone (6 and 18 mg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects in subjects with opioid use disorder (2) to explore the relationship between plasma cebranopadol concentration and blockade of the subjective opioid effects of hydromorphone; (3) to examine the safety and tolerability of cebranopadol when co-administered with hydromorphone.
  • Study Title A Multiple Dose Opioid Challenge Study to Assess Blockade of Subjective Opioid Effects f n to of testing (Days -3 to -1). Prior to beginning the Qualification/Baseline HMO Challenge Session on Day -3, subjects will not receive their late evening or early morning dose of n e ], se ch Discussion of Study Design (Including Choice of Control Groups) Subjects with o ioid h sical de endence and moderate to severe o ioid use disorder d, at h e e t ol pharmacokinetic profile of cebranopadol, HMO Challenge Sessions will be conducted on Days 2 to 4, Days 8 to 10 and Days 15 to 17 to investigate the onset and magnitude of s ts The study will enroll enough subjects to ensure that at least 48 subjects complete the study (24 subjects per treatment group with at least 16 females in total).
  • Non-childbearing potential i Permanently sterile (ie both ovaries removed uterus removed or ul f Subjects who currently meet the criteria for a diagnosis of moderate or severe substance use disorder according to DSM-V criteria for any other substances - , R y ) Subject has unsuitable or difficult venous access or is unwilling or unable to undergo an IV catheter insertion.
  • Tmax is 4-6 hr with Thalf of 62-96 hr (Lambert, D.G., Bird, M.F. & Rowbotham, D.J. Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. British journal of anaesthesia 114, 364-366 (2015)). Plasma concentrations are closely correlated with pharmacodynamic effect (Göhler, K., et al. Assessment of the Abuse Potential of Cebranopadol in Nondependent RV Opioid Users: A Phase 1 Randomized Controlled Study. J Clin Psychopharmacol 39, 46-56 (2019)), and the slow onset and decline in the drug’s effects may contribute to its lower abuse potential.
  • HAP Phase 1 oral human abuse potential
  • cebranopadol did not result in clinically relevant drug liking using the visual analog scale (VAS) of drug liking
  • VAS visual analog scale
  • the first study compared 3 doses (200, 400 and 800 ⁇ g) of cebranopadol to 2 doses (8 and 16 mg) of hydromorphone and placebo.
  • Cebranopadol administration did not increase subjective drug liking greater than placebo, whereas an equi-analgesic dose of hydromorphone (8 mg; positive control) produced significantly more drug liking than 800 ⁇ g of cebranopadol (Göhler, K., et al. Assessment of the Abuse Potential of Cebranopadol in Nondependent Regulational Opioid Users: A Phase 1 Randomized Controlled Study. J Clin Psychopharmacol 39, 46-56 (2019)).
  • At twice the maximum planned therapeutic dose for analgesia some liking was seen at 5 hr post-dose, but at levels significantly below the roughly equianalgesic dose of 16 mg hydromorphone and comparable to 8 mg hydromorphone.
  • cebranopadol For some secondary endpoints, 800 ⁇ g of cebranopadol was similar to 8 mg hydromorphone. Results of secondary endpoints, including desire to take the drug again, revealed hydromorphone 8 mg was significantly preferred. Hydromorphone 16 mg was significantly preferred to all doses of cebranopadol across all measures (Göhler, K., et al. Assessment of the Abuse Potential of Cebranopadol in Nondependent RV Opioid Users: A Phase 1 Randomized Controlled Study. J Clin Psychopharmacol 39, 46-56 (2019)).
  • cebranopadol 600 ⁇ g oral was compared to fentanyl IV. cebranopadol lowered the mean respiratory rate from ⁇ 17 breaths per minute to ⁇ 13 bpm over a period of 6 hours which was dramatically different than the change ( ⁇ 17 bpm to ⁇ 10 bmp) produced by fentanyl over the course of ⁇ 0.5 hours.
  • PK/PD modeling predicted that cebranopadol would not produce apnea at any dose in contrast to fentanyl.
  • This respiratory depression ceiling is determined in an ongoing trial (NCT05491785) as part of pain development program.
  • cebranopadol was titrated to much higher doses (up to 1600 ⁇ g daily) in a one-month inpatient study. Doses above 600 ⁇ g did not produce significantly more respiratory depression than seen with 600 ⁇ g, seeming to support the finding of the single dose study.
  • a study is ongoing to evaluate the respiratory drive by measuring ventilatory response to hypercapnia (maximum decrease in minute ventilation).
  • cebranopadol Compared to healthy subjects, this patient population, due to chronic exposure to opioids, may experience opioid receptor reorganization leading to tolerance development. Hence, the therapeutic dose of cebranopadol may be different (possibly higher) than those proven efficacious in patients with pain.
  • Assessment of how to transition opioid-dependent individuals onto cebranopadol (5) Determination of the efficacy and safety of chronic treatment with cebranopadol in individuals with OUD. (6) Non-oral abuse potential and safety in combination with other opioids.
  • cebranopadol exhibits low abuse potential, does not produce respiratory depression (RD), and following acute administration reduces opioid conditioned place preference (CPP) and short access (2-hrs) self-administration (SA).
  • CPP opioid conditioned place preference
  • SA short access
  • Rats surgically implanted with a permanent catheter into the jugular vein are be trained to operant fentanyl SA as described previously (de Guglielmo, G., et al. Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat. Addict Biol 18, 644-653 (2013)).
  • the effect of cebranopadol on fentanyl SA is analyzed by a one-way within-subject analysis of variance (ANOVA). ANOVA is followed by the Newman– Keuls test, when appropriate. Statistical significance is set at p ⁇ .05. All data are expressed as the mean ⁇ standard deviation (SD).
  • Cebranopadol a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349, 535-548 (2014); de Guglielmo, G., et al. Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats. J Pharmacol Exp Ther 362, 378-384 (2017); Shen, Q., Deng, Y., Ciccocioppo, R. & Cannella, N.
  • Cebranopadol a Mixed Opioid Agonist, Reduces Cocaine Self- administration through Nociceptin Opioid and Mu Opioid Receptors. Front Psychiatry 8, 234 (2017); Kleideiter, E., Piana, C., Wang, S., Nemeth, R. & Gautrois, M. Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic. Clin Pharmacokinet 57, 31-50 (2018)).
  • rats are re- trained to fentanyl SA for 3 days, but on day 4 they receive cebranopadol (no fentanyl SA) and tail vein plasma samples are taken at 1.5, 5, and 12 hr after cebranopadol administration for PK analysis.
  • cebranopadol no fentanyl SA
  • tail vein plasma samples are taken at 1.5, 5, and 12 hr after cebranopadol administration for PK analysis.
  • a na ⁇ ve control group are included to compare cebranopadol PK in fentanyl-exposed vs non-exposed rats.
  • Fentanyl-Maintained PR Performance are included to compare cebranopadol PK in fentanyl-exposed vs non-exposed rats.
  • Drug doses are selected based on results of Exp.1.1, using the most efficacious dose not leading to non-specific effects (i.e., inactive lever responses) (Shen, Q., Deng, Y., Ciccocioppo, R. & Cannella, N. Cebranopadol, a Mixed Opioid Agonist, Reduces Cocaine Self- administration through Nociceptin Opioid and Mu Opioid Receptors. Front Psychiatry 8, 234 (2017); Kallupi, M., et al. Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption.
  • non-specific effects i.e., inactive lever responses
  • Rats implanted with a permanent IV catheter are trained to LgA fentanyl SA as described in Exp.1.1, Twenty-four hours after the last fentanyl SA session, rats are placed in a whole-body plethysmography (DSI, St Paul, MN, USA) for 60 min to acclimatize to the chambers and to allow true resting ventilatory parameters to be established. At this point animals are treated with cebranopadol (0, 12.5, 25, 50 ⁇ g/kg, o.s), and 90 min later they receive an IV bolus injection of fentanyl (75 ⁇ g/kg, IV) or vehicle.
  • DSI St Paul, MN, USA
  • ventilatory parameters are recorded: breathing frequency (fr), tidal volume (Vt), minute ventilation (Ve), inspiratory time (Ti), expiratory time (Te), peak inspiratory (PIF) and peak expiratory (PIF) flows using classical protocols described in the literature (Baby, S.M., et al. Bilateral carotid sinus nerve transection exacerbates morphine- induced respiratory depression. Eur J Pharmacol 834, 17-29 (2018); Henderson, F., et al. Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats.
  • the design is a single-dose, randomized, double-blind, placebo- and active-controlled crossover study to evaluate the abuse potential of cebranopadol compared to oxycodone and placebo when administered intravenously in healthy non-dependent recreational opioid users.
  • the study consists of two parts: Dose Escalation Phase (Part A) and Main Study (Part B).
  • the Dose Escalation Phase utilizes a randomized, double-blind, placebo-controlled, dose escalation design in up to 4 separate cohorts of subjects.
  • the Dose Escalation Phase evaluates the safety and tolerability of potential cebranopadol doses to be used in the subsequent Main Study using this infusion rate.
  • the Dose Escalation Phase consists of 3 phases: Screening, Treatment and Follow-up. Subjects participate in an outpatient medical Screening visit (Visit 1), a 3-day Treatment visit (Visit 2), and an outpatient safety Follow-Up visit (Visit 3). Within 28 days of the Screening visit, eligible subjects are admitted to the clinical research unit (CRU) on Day-1 of the Treatment visit.
  • CRU clinical research unit
  • a Naloxone Challenge Test are performed to confirm that subjects are not opioid dependent.
  • Escalating cebranopadol doses are evaluated in separate cohorts of 8 subjects each, randomized in a 3:1 fashion, such that 6 subjects receive a single dose of IV cebranopadol and 2 subjects receive a single dose of IV placebo within each cohort.
  • safety and pharmacodynamic data is collected up to 12 hr post-dose.
  • Safety monitoring includes assessments of adverse events (AEs), vital signs, 12-lead electrocardiogram (ECG), clinical laboratory results, physical exams, concomitant medications and continuous pulse oximetry/ telemetry monitoring for at least 4 hr after study drug administration.
  • Pharmacodynamic assessments includes subjective effects visual analog scales (VAS) (for example, Alertness/Drowsiness VAS, Any Effects VAS, Drug Liking VAS, etc.) and pupillometry.
  • VAS visual analog scales
  • the sponsor and investigator reviews unblinded safety and pharmacodynamic data prior to initiating the next cohort. If the sponsor and investigator interpret that the data from a cohort are insufficient to make a determination to escalate the dose, an additional cohort of 8 new subjects may be added to repeat a dose level or evaluate an alternative dose. Once a maximum tolerated dose (MTD) is identified, the Dose Escalation Phase is concluded. If the MTD is not identified as part of the Dose Escalation process, the highest evaluated dose is considered as the maximum feasible dose for evaluation in the Main Study.
  • MTD maximum tolerated dose
  • Subjects are discharged after completing assessments on Day 2 or, if medically necessary, subjects may remain in the CRU at the discretion of the investigator or designee. All subjects who participate in the Treatment visit return within 3 to 7 days of discharge for a Follow-Up visit. To ensure that all subjects in the Main Study have not had previous exposure to cebranopadol, subjects who participate in the Dose Escalation Phase are not be eligible to participate in the Main Study.
  • Experiment 2.2 Main Study (Part B) The Main Study consists of 4 phases: Screening, Qualification, Treatment and follow- Up.
  • Subjects participate in an outpatient medical Screening visit (Visit 1), an inpatient visit (Visit 2) that comprises a 3-day Qualification Phase, a Treatment Phase that comprises four 2-day treatment periods (Visits 3 through 6), and an outpatient safety Follow Up visit (Visit 7).
  • the Qualification Phase comprise a Naloxone Challenge Test and a Drug Discrimination Test. At least 12 hr prior to first study drug administration in the Drug Discrimination Test, a Naloxone Challenge Test are performed to confirm that subjects are not opioid dependent.
  • subjects receive IV oxycodone (0.07 mg/kg) or matching placebo administered over 1 minute in a randomized, double blind, crossover manner, with each study drug administration separated by approximately 24 hours, to ensure that they can discriminate and show positive subjective effects of oxycodone.
  • Subjects who do not meet Drug Discrimination Test Criteria are discharged from the CRU at approximately 24 hours after the second period.
  • Subjects who do meet the Drug Discrimination Test criteria may remain in the CRU for the first treatment period of the Treatment Phase.
  • a washout interval of approximately 24 hours is required between last study drug administration in the Qualification Phase and first study drug administration in the Treatment Phase.
  • subjects are randomized to 1 of 6 treatment sequences according to a 4 ⁇ 4 Williams square in the Treatment Phase.
  • Subjects receive each of the following 3 treatments, administered IV over 1 min, in a randomized, double-blind, crossover manner following an overnight fast: cebranopadol low dose (as determined by Part A); cebranopadol high dose (as determined by Part A); Oxycodone 0.07 mg/kg; Placebo (saline infusion).
  • cebranopadol low dose as determined by Part A
  • cebranopadol high dose as determined by Part A
  • Oxycodone 0.07 mg/kg Placebo (saline infusion).
  • Placebo saline infusion
  • Safety monitoring includes assessments of AEs, vital signs, clinical laboratory results, 12-lead ECG, physical exams, concomitant medications and continuous pulse oximetry/telemetry monitoring for at least 4 hr after study drug administration.
  • Pharmacodynamic assessments includes subjective effects VAS (including the primary measure of Drug Liking) and pupillometry as an objective measure. Subjects are discharged at approximately 24 hr after each study drug administration. Subjects return within 3 to 7 days following the last study drug administration for a Follow-Up visit. For the Dose Escalation Phase, approximately 8 subjects per cohort are enrolled and randomized in a 3:1 fashion (cebranopadol: placebo), for a total of up to approximately 32 randomized subjects (4 cohorts).
  • VAS visual analog scale
  • a randomized, double-blind, multiple ascending dose study determines the ability of cebranopadol to suppress opioid withdrawal signs/symptoms in persons with moderate to severe OUD when transitioned to cebranopadol and identify a dose range for further evaluation.
  • the primary objective of this study is to evaluate, in adults with moderate to severe OUD, the ability of multiple doses of cebranopadol to suppress withdrawal signs and symptoms; secondary objectives of this study are: (1) to examine the safety and tolerability of multiple doses of cebranopadol and (2) to assess the pharmacokinetics of multiple doses of cebranopadol.
  • Experiment 3.1 Escalating dose study.
  • CRU clinical research unit
  • subjects are admitted to the clinical research unit (CRU).
  • CRU clinical research unit
  • subjects are transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to initiating cebranopadol.
  • IR immediate-release
  • QID times daily
  • the last active dose of morphine-IR is administered a minimum of 12 hr before administering the first cebranopadol dose.
  • the Clinical Opiate Withdrawal Scale (COWS) is administered prior to cebranopadol dosing on Day 1 (i.e., a minimum of 12 hr since their last dose of morphine-IR).
  • COWS Clinical Opiate Withdrawal Scale
  • Up to a maximum of 40 subjects are enrolled and randomized into a maximum of 4 cohorts in the Treatment Phase.
  • Ascending doses of cebranopadol are evaluated in separate cohorts of 10 subjects each; within each cohort, 7 subjects receive multiple doses of cebranopadol and 3 subjects each receive multiple doses of matching placebo.
  • the first cohort receives cebranopadol 600 ⁇ g or matching placebo; thereafter, dose levels are not fixed and are determined by the Drug Safety Review Committee (DSRC) upon completion of each dosing level.
  • DSRC Drug Safety Review Committee
  • Proposed dose levels include 800, 1000 and 1200 ⁇ g. A dose lower than the planned doses may be tested, a dose level may be repeated, or smaller dosing increments may be applied, depending on emerging safety, tolerability, and/or other relevant data, such as available pharmacodynamic data. Subjects receive cebranopadol or placebo once daily for 5 days and remain inpatient in the CRU. Pharmacodynamic assessments include COWS, Subjective Opiate Withdrawal Scale (SOWS), visual analog scale (VAS) for craving, and rescue medication use. Safety monitoring includes assessments of AEs, vital signs, ECGs, clinical laboratory tests, physical exams, concomitant medications, and Columbia- Suicide Severity Rating Scale (C SSRS) results.
  • C SSRS Columbia- Suicide Severity Rating Scale
  • D.2 Transition The next phase of this proposal is considered successful when the following milestones have been met: (1) In rats, demonstration that cebranopadol significantly reduces IV fentanyl SA and does not worsen fentanyl-induced RD (Aim 1); (2) In humans, determination of a range of doses for safe use in OUD demonstrated by: a) lower Emax drug liking compared with oxycodone (positive control) when administered IV in recreational opioid users (Aim 2); b) Attenuation of withdrawal signs/symptoms upon discontinuation of the participants’ opioid (Aim 3).
  • D.3 Phase Overview The next phase of this proposal demonstrates the therapeutic efficacy of cebranopadol in decreasing opioid use with low risk of withdrawal or abuse in a Phase 2 placebo-controlled inpatient trial.
  • cebranopadol determines whether cebranopadol can meaningfully reduce illicit opioid use under real world conditions. 4: Determine the effects of cebranopadol on fentanyl-induced respiratory depression (RD) in opioid-tolerant participants. The effect of cebranopadol on fentanyl-induced RD is critical to understand considering the mortality rate due to fentanyl (U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 – But Are Still Up 15%. National Center for Health Statistics (2022)).
  • the primary objective of this study is to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by change in isohypercapnic minute ventilation.
  • the secondary objectives of this study are: (1) to evaluate the effect of cebranopadol on fentanyl- induced RD in opioid-tolerant adults, as determined by the secondary outcome measures; (2) to evaluate steady-state plasma cebranopadol concentrations in opioid-tolerant adults; and (3) to examine the safety and tolerability of cebranopadol when co-administered with fentanyl.
  • Experiment 4.1 This is a randomized, open-label, fixed-sequence crossover study to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults. The study involves 4 phases: Screening, Morphine Stabilization, Treatment, and Follow-up. Within approximately 28 days of initiating outpatient Screening, subjects are admitted to the clinical research unit (CRU). Following check-in to the CRU, subjects are transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to the first treatment period.
  • CRU clinical research unit
  • IR immediate-release
  • QID 4 times daily
  • subjects Prior to the first treatment period, subjects do not receive their late evening or early morning doses of morphine-IR; therefore, the last active dose of morphine- IR is administered a minimum of 12 hr before first administration of study drug (placebo).
  • Subjects receive placebo and cebranopadol, administered IV, in an open-label, fixed-sequence following an overnight fast.
  • Subjects receive placebo in Period 1 and cebranopadol in Period 2.
  • a washout period of 48 hr separates each treatment period. Subjects receive maintenance morphine- IR during the washout period, with the last morphine-IR dose administered a minimum of 12 hr before administration of cebranopadol.
  • cebranopadol is administered IV to achieve steady-state plasma concentrations based on doses identified in the MAD study (Study 3)); the placebo infusion rate and duration are matched.
  • Escalating IV fentanyl doses of 0.25, 0.35, 0.50, and 0.70 mg/70 kg are administered over 90 sec at 120, 180, 240, and 300 min after the start of the cebranopadol /placebo infusion.
  • Isohypercapnic ventilation is measured during cebranopadol /placebo infusion for approximately 360 min using the dynamic end-tidal forcing technique.
  • Minute ventilation (L/min), respiratory rate (breaths/min), oxygen saturation (SpO2), tidal volume (L), end-tidal PCO2 (kPa; PEiCO2) and end tidal PO2 (kPa; PEiO2) are collected at baseline and during study drug administration.
  • Pulse oximetry continuously monitors oxygen saturation (SpO2) up to 8 hr postdose.
  • Safety monitoring include assessments of AEs, vital signs, clinical laboratory results, 12-lead ECG, physical exams, concomitant medications.
  • Pharmacokinetic samples are collected up to 8 hr postdose in Period 2. Subjects are discharged on Day 3 and a follow-up visit is conducted on Day 7.
  • cebranopadol Given the long half-life of cebranopadol, it might be operationally more feasible to administer it after placebo so that the treatment period can be shortened and there is only 1 morphine stabilization period. If a subject does not tolerate a lower fentanyl dose, higher doses are be administered. Only fentanyl doses the subject tolerated under the placebo condition is evaluated under the cebranopadol condition. 5: Evaluate the ability of cebranopadol to block the subjective effects of hydromorphone.
  • the primary objective of this study is to evaluate the opioid blocking effects of cebranopadol following administration of IV hydromorphone (6 and 18 mg/70 kg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects in subjects with moderate or severe OUD, as measured by the Drug Liking visual analog scale (VAS).
  • the secondary objectives of this study are (1) to evaluate the degree of opioid blocking effects of cebranopadol following administration of IV hydromorphone (6 and 18 mg/70 kg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects in subjects with opioid use disorder, as determined by the secondary outcome measures; (2) to explore the relationship between plasma cebranopadol concentration and blockade of the subjective opioid effects of hydromorphone; (3) to examine the safety and tolerability of cebranopadol when co-administered with hydromorphone.
  • subjects are transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to the Qualification/Baseline Hydromorphone Challenge Session, which consists of 3 consecutive days of testing (Days -3 to -1).
  • IR immediate-release
  • QID times daily
  • subjects Prior to beginning the Qualification/Baseline Hydromorphone Challenge Session on Day -3, subjects do not receive their late evening or early morning dose of morphine-IR; thus, the last active dose of morphine- IR is administered a minimum of 12 hr before administration of each of the Hydromorphone Challenge doses.
  • eligible subjects are randomized in a 1:1 ratio to 1 of 2 groups to receive cebranopadol low dose or high dose stratified by gender (cebranopadol doses and timing of administration relative to last morphine-IR dose to be determined based on results of a dose escalation study).
  • the COWS is administered prior to cebranopadol dosing on Day 1 (i.e., minimum of 12 hr since their last dose of morphine-IR).
  • subjects In order to be dosed on Day 1, subjects must have a COWS score ⁇ 8.
  • Each Hydromorphone Challenge Session consists of 3 doses of hydromorphone IV (doses of 0 mg [placebo], 6 and 18 mg/70 kg) administered on 3 consecutive days in randomized order, with one dose of hydromorphone administered each day. Eligible subjects are randomized in a 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences according to two 3 ⁇ 3 William squares.
  • this study uses a pharmacologic qualification to ensure that subjects who meet the drug use history criteria can also distinguish and demonstrate “liking” of the subjective euphoric experience of both doses of hydromorphone compared to placebo. Therefore, the pharmacologic qualification procedure provides more objective confirmation of drug use history and ensures that subjects can respond appropriately in a laboratory setting as well as tolerate the doses of fentanyl. Studies with opioid-dependent subjects have used a wide array of opioid maintenance drugs/doses to stabilize subjects.
  • the Morphine-IR stabilization phase ensures sufficient opioid washout of opioids used prior to check in and a similar level of physical dependence among the subjects prior to the Qualification/Baseline Hydromorphone Challenge that ensures that subjects are not uncomfortable as a result of opioid withdrawal and allow for a baseline measurement of the Drug Liking Emax of hydromorphone from which the active cebranopadol can be compared for determination of its efficacy to block this effect of hydromorphone.
  • randomization is used to avoid bias in the assignment of treatment for all the Hydromorphone Challenge Sessions and in the assignment of subjects cebranopadol treatment groups during the Treatment Phase.
  • hydromorphone doses administered in ascending order, but with placebo randomly interspersed.
  • Prior to the Hydromorphone Qualification Phase subjects are randomized to 1 of 6 challenge sequences, according to two 3 x 3 William squares (ABC, ACB, BAC, BCA, CAB, CBA), and receive one dose of fentanyl daily over 3 consecutive days, including 2 doses of hydromorphone and 1 dose of placebo.
  • This approach has previously been shown to be is sensitive to identifying dose-related agonist effects, while ensuring that both subjects and staff remain blinded to the dose of hydromorphone or placebo being administered, thereby reducing the risk of potential expectancy effects.
  • Cebranopadol a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349, 535-548 (2014). 19. Schunk, S., et al. Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol. ACS Med Chem Lett 5, 857-862 (2014). 20. Mogil, J.S., et al. Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75, 333- 337 (1996). 21.
  • Orphanin FQ/nociceptin blocks acquisition of morphine place preference. Brain Res 832, 168-170 (1999). 26. Ciccocioppo, R., Angeletti S Fau - Sanna, P.P., Sanna Pp Fau - Weiss, F., Weiss F Fau - Massi, M. & Massi, M. Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur J pharm 404, 153-159 (2000). 27. Kotli ⁇ ska, J. & Rafalski, P. [Nociceptin/orphanin FQ (N/OFQ)--the opioid, antiopioid or neuromodulator?].
  • Cebranopadol reduces cocaine self- administration in male rats: Dose, treatment and safety consideration. Neuropharmacology 172, 108128 (2020). 33. Lambert, D.G., Bird, M.F. & Rowbotham, D.J. Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. British journal of anaesthesia 114, 364-366 (2015). 34. Sa ⁇ at, K., Furga ⁇ a, A. & Sa ⁇ at, R. Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain.
  • Cebranopadol A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain. Pain Physician 21, E193-E206 (2016). 38. Eerdekens M, K.E., Kok M, Sohns M, Forst T. Cebranopadol, a novel first-in-class analgesic: efficacy, safety, tolerability in patients with pain due to diabetic peripheral neuropathy. Postgraduate medicine 128, 25 (2016). 39. Eerdekens, M.H., et al. Cancer-related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial.

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Abstract

Provided herein are methods, compositions and uses of cebranopadol compositions for treating patients, in need of analgesic treatment. The methods and compositions are useful in treating and/or preventing opioid use disorder in humans in need of analgesic treatment. Also provides are methods and compositions useful in preventing apnea and/or oxygen desaturation in a human receiving pain treatment. The method comprises dosing a patient once a day with an immediate release composition comprising cebranopadol in crystal form A and/or in free base form. Also provided are compositions useful for treating and/or preventing opioid use disorder.

Description

REGIMENS AND COMPOSITIONS USEFUL FOR ALLEVIATING PAIN BACKGROUND OF THE INVENTION Opioid agonists provide analgesic effects by acting on opioid receptors in the central and peripheral nervous systems that block the sensation of pain from signaling to the brain. Opioid agonists are available in different dosage forms. Opioid agonists may be characterized as full agonist opioids or partial agonist opioids. However, undesirable common side effects of opioid administration include euphoria, abuseability, sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Opioid Use Disorder (OUD) is a chronic, relapsing condition associated with overdoses and deaths, as well as legal, interpersonal, and employment problems (Opioids. National Institute of Drug Abuse (2022)). Although opioids are recognized as necessary and legitimate therapeutics to treat pain, the risk of developing OUD is significant (Webster, L.R. Risk Factors for Opioid- Use Disorder and Overdose. Anesth Analg 125, 1741-1748 (2017)). Recent studies estimate that among opioid-treated patients with chronic pain, misuse averaged between 21%-29%, and OUD averaged between 8%-12% (Vowles, K.E., et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. PAIN 156(2015)), with some research estimating OUD to be closer to 35% (Boscarino, J.A., et al. Prevalence of Prescription Opioid- Use Disorder Among Chronic Pain Patients: Comparison of the DSM-5 vs. DSM-4 Diagnostic Criteria. Journal of Addictive Diseases 30, 185-194 (2011)). In the most recent year, the U.S. Center for Disease Control and Prevention reported over 100,000 drug-related overdose deaths, 75% of which involved opioids (U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 – But Are Still Up 15%. National Center for Health Statistics (2022)). There is a broad spectrum of risk factors for developing OUD, including poor social support, personal or family history, psychological stress or trauma, and childhood adversity (Webster, L.R. Risk Factors for Opioid-Use Disorder and Overdose. Anesth. Analg.125, 1741-1748 (2017)). Stress because of pain that is uncontrolled can also lead to opioid misuse in a patient with no other risk factors. In addition, despair within socioeconomically disadvantaged communities, binge use and thrill- seeking behavior, and social environments that encourage illicit substance use potentially contribute to adverse outcomes and therapeutic failure (Szalavitz, M. The feds are about to stick it to pain patients in a big way. Vice (2017)). Current pharmacologic treatments for OUD involve the use of medications that work by targeting mu opioid peptide (MOP) receptors. Currently, three medications are registered in the U.S. for treatment of OUD: methadone, buprenorphine, and naltrexone. Methadone is a full MOP receptor agonist which produces dose-dependent analgesia, sedation, cardiotoxicity, and risk of respiratory depression in overdose (Inturrisi, C.E. Pharmacology of methadone and its isomers. Minerva anestesiologica 71, 435-437 (2005)). Buprenorphine is a partial MOP receptor agonist with a high affinity for MOP; at low doses it produces typical MOP receptor agonist effects that at higher doses tend to decline (i.e., analgesia). Naltrexone, a MOP receptor antagonist, blocks the effects of opioids and can precipitate withdrawal if administered to an opioid-dependent patient (Bell, J. & Strang, J. Medication Treatment of Opioid Use Disorder. Biological psychiatry 87, 82-88 (2020)). Methadone is used orally; buprenorphine is available in transmucosal preparations alone or in combination with naloxone and longer-acting implantable or injectable formulations; and naltrexone is available in both oral and long-acting injectable formulations. All of these products have significant limitations. Methadone has significant abuse potential and risk of overdose and is thus only administered in health-care settings, causing substantial burden on patients as they must travel to a clinic daily to receive their medication which results in poor adherence to treatment. Buprenorphine can trigger withdrawal when initiated with opioid- dependent patients, and naltrexone requires full detoxification before initiation. Given the severity of opioid withdrawal symptoms, many patients have difficulty initiating buprenorphine or naltrexone therapy, especially those who are physically dependent on fentanyl (Bell, J. & Strang, J. Medication Treatment of Opioid Use Disorder. Biological psychiatry 87, 82-88 (2020)). Moreover, methadone and buprenorphine themselves can also cause physical dependence, making tapering off of these medications difficult. Finally, due to the high cost of long-acting non-oral drugs and the difficulty of opioid detoxification, oral methadone and transmucosal buprenorphine/naloxone today comprise the vast majority of prescriptions for OUD. Despite the moderate efficaciousness of these existing medications in treating OUD and policy-related decreases in opioid prescriptions (Webster, L.R. Risk Factors for Opioid-Use Disorder and Overdose. Anesth Analg 125, 1741-1748 (2017); Wakeman, S.E., et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open 3, e1920622 (2020)), OUD rates have not decreased, and overdose-related complications and deaths continue at high levels (Opioid Data Analysis and Resources. (2022)). There is thus a clear, urgent need for an improved therapeutic for treatment of OUD. Cebranopadol (trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane- 1,1′-(3′H)-pyrano[3,4-b]indol]-4-amine) is an analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist (WO 2004/043967, WO 2008/040481, WO 2012/016703, WO 2012/016699, WO 2012/016695, WO 2012/016698, WO 2012/016697, WO 2013/007361). Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain with ED50 values of 0.5-5.6 μg/kg after intravenous and 25.1 μg/kg after oral administration. In comparison with selective mu (µ)-opioid receptor (MOP) agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol displays broad activity in various pain states and is highly potent and efficacious in animal models of acute nociceptive, inflammatory, cancer, and, especially, chronic neuropathic pain. In contrast to opioids such as morphine, cebranopadol displays higher analgesic potency in chronic pain, especially of neuropathic origin, than in acute nociceptive pain. In addition, even after doses higher than those required for inducing analgesia, cebranopadol affects neither motor coordination nor respiratory function and thus displays a better tolerability profile than opioids. As a result, there is a broader therapeutic window for cebranopadol than for morphine (K. Linz et al., J. Pharmacol. Exp. Ther.2014535-548). There remains a need for improved therapies for alleviating pain in patients. Further, there is an urgent need for an improved therapeutic for the treatment and/or prevention of OUD. BRIEF DESCRIPTION OF THE FIGURES FIG.1 shows results of a single-dose, randomized, double-blind, placebo- and active- controlled crossover trial of oral human-abuse potential study, graphed as a difference in maximum Drug Liking (VAS) scores in modified completer population. FIG.2 provides shows results of a single-dose, randomized, double-blind, placebo- and active-controlled crossover trial of oral human-abuse potential study, graphed as a difference in maximum Drug Liking (VAS) scores in completer population. FIG.3 shows 600 mcg cebranopadol-induced respiratory depression in healthy volunteers. FIG.4 shows mean drug liking time course profile. FIG.5A shows cebranopadol effect on rat heroin self-administration. FIG.5B shows cebranopadol effect on rat heroin self-administration. FIG.6A shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase. Modified Completer Population. TEmax and TEmin are reported in hours. FIG.6B shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase. Modified Completer Population. TEmax and TEmin are reported in hours. FIG.7A shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase. Completer Population. TEmax and TEmin are reported in hours. FIG.7B shows drug Liking (at this moment) VAS – Summary Parameters by Treatment During the Treatment Phase. Completer Population. TEmax and TEmin are reported in hours. FIG.8 shows drug Liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.9 shows drug Liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.10 shows drug Liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.11 shows drug liking (at this moment) VAS – analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.12 shows drug liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.13 shows drug liking (at this moment) VAS – Analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.14 shows drug liking (at this moment) VAS – analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.15 shows drug liking (at this moment) VAS – analysis results. Modified Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.16 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.17 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.18 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.19 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo; For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.20 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.21 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.22 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.23 shows drug liking (at this moment) VAS – analysis results. Completers Population. P-values≤0.05 are bolded. For the primary analysis of Drug Liking Emax, the hypothesis tested are as follows: Testing h0: µC1 - µP ≤ 15 vs ha: µC1 - µP > 15, where µC1 is the mean for oxycodone IR and µP is mean for placebo; Testing h0: µC2 - µP ≤ 15 vs ha: µC2 - µP > 15, where µC2 is the mean for tramadol IR and µP is mean for placebo; Testing h0: µC1 - µT ≤ 0 vs ha: µC1 - µT > 0, where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol; Testing h0: µC2 - µT ≤ 0 vs ha: µC2 - µT > 0, where µC2 is the mean for tramadol IR and µT is mean for cebranopadol; Testing h0: µT - µP ≥ 11 vs ha: µT - µP < 11, where µT is the mean for cebranopadol and µP is mean for placebo. For all other analyses, the hypotheses are the same as above, but with margins of 0 and the cebranopadol versus placebo comparison hypothesis is two-sided. Sign tests hypotheses test medians rather than means. FIG.24 shows overall summary of treatment emergent adverse events (TEAEs). Safety Population. Abbreviations: AE = adverse event, TEAE = treatment emergent adverse event, SAE = serious adverse event. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1. Percentages are based on the number of subjects in the Safety Population. For patient counts, if a subject experienced one or more events, the subject is counted only once in the subject count. TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination (See, Example 1). FIG.25 shows summary of treatment emergent adverse events, by system organ class and preferred term. Safety Population. Abbreviations: TEAE = treatment emergent adverse event. A TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination. At each level of summarization (System Organ Class or Preferred Term), subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1. System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population. FIG.26 shows summary of treatment emergent adverse events, by system organ class and preferred term. Safety Population. Abbreviations: TEAE = treatment emergent adverse event. A TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination. At each level of summarization (System Organ Class or Preferred Term), subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1. System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population. FIG.27 shows summary of treatment emergent adverse events, by system organ class and preferred term. Safety Population. Abbreviations: TEAE = treatment emergent adverse event. A TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination. At each level of summarization (System Organ Class or Preferred Term), subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1. System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population. FIG.28 shows summary of treatment emergent adverse events, by system organ class and preferred term. Safety Population. Abbreviations: TEAE = treatment emergent adverse event. A TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination. At each level of summarization (System Organ Class or Preferred Term), subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1. System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population. FIG.29 shows summary of treatment emergent adverse events, by system organ class and preferred term. Safety Population. Abbreviations: TEAE = treatment emergent adverse event. A TEAE is defined as any new AE that occurs after dosing of study medication until End of Study or Early Termination. At each level of summarization (System Organ Class or Preferred Term), subjects who have more than one adverse event were only counted once. All adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1. System Organ Classes and Preferred Terms are sorted in order of frequency. Percentages are based on the number of subjects in the Safety Population. FIG.30 shows that in the two hours patients post-administration of an immediate release cebranopadol composition at 600 microgram (mcg or µg), 800 mcg, or 1000 mcg), cebranopadol patients have less respiratory depression and a slower onset of respiratory depression than patients receiving oxycodone at two hours post-administration (placebo (13% reduction VE55 at 1 hour); cebranopadol 600 mgc (13% VE55 reduction after 1 hour) cebranopadol 800 mcg (15% VE55 reduction after 1 hour), cebranopadol 1000 mcg (16% VE55 reduction after 1 hour). At 30 mg and 60 mg, oxycodone patients showed 49% and 55% reduction in VE55, respectively, at one hour post-administration. This figure shows that Cebranopadol patients have less respiratory depression and a much slower onset. FIG.31 shows results from a generated PK/PD model to quantify respiratory depression following doses of 600 mcg, 800 mcg, 1000 mcg of cebranopadol and . A PK/PD model predicts the amount of respiratory depression for a given level of analgesic effect of Cebranopadol and Oxycodone. This model shows that cebranopadol patients experience meaningfully lower levels of respiratory depression than Oxycodone at all comparable dose levels therapeutic and supratherapeutic (e.g., Cebranopadol equivalent concentrations; 200 microgram (mcg or µg), 400 mcg, 600 mcg, 800 mcg, 1000 mcg). FIG.32 shows respiratory AEs (respiratory depression and oxygen saturation decrease), plotted as %, at supratherapeutic doses of Cebranopadol in comparison to Oxycodone (60 mg). These results show that milder effects plus slower onset of Cebranopadol lead to drastically lower respiratory AEs than an equivalent opioid comparator. FIG.33 shows mean (SD, standard deviation) O2 saturation peripheral pharmacodynamic analysis population, plotted as percent of O2 saturation peripheral. FIG.34 shows mean (SD, standard deviation) O2 saturation peripheral change from baseline (CFB) pharmacodynamic analysis, plotted as percent O2 saturation peripheral CFB. FIG.35A shows the “Take Drug Again” visual analog scale (VAS; 100-point bipolar scale, where 0 = “Definitely not”; 50 = “Do not care”; 100 = “Definitely would”) Emax in the study where subjects rated Cebranopadol, 600 µg and 1000 µg, and Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Cebranopadol has demonstrated significantly lower abuse potential compared to both Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Standard Deviation is represented by error bars. Ceb – Cebranopadol; Oxy – Oxycodone; Tram – Tramadol; PBO – Placebo. FIG.35B shows the “Overall Drug Liking” visual analog scale (VAS; 100-point bipolar scale where 0 = “Definitely not”; 50 = “Do not care”; 100 = “Definitely would”) Emax in the study where subjects rated Cebranopadol, 600 µg and 1000 µg, and Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Cebranopadol has demonstrated significantly lower abuse potential compared to both Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Standard Deviation is represented by error bars. Ceb – Cebranopadol; Oxy – Oxycodone; Tram – Tramadol; PBO – Placebo. SUMMARY OF THE INVENTION In one aspect, a method is provided for preventing and/or treating opioid use disorder (OUD) in a subject, said method comprising treating a dosing a subject being treated for pain with a pharmaceutical composition comprising at least one cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition provides an immediate release profile for the cebranopadol or pharmaceutically acceptable salt thereof, hydrate, or salt hydrate. In certain embodiments, the composition comprises cebranopadol in its free base form. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the composition is delivered once daily. In certain embodiments, the composition is delivered no more than once a day for three to 14 days. In certain embodiments, a composition useful in treating a subject being treated for pain and having or susceptible to opioid use disorder is provided. In certain embodiments, the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, administrable to the subject. In certain embodiments, the composition is administered daily at a dose in an amount of about 10 μg to about 2000 μg cebranopadol. In certain embodiments, the cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, use of cebranopadol in treating a subject having opioid use disorder is provided. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the subject is being treated for pain. In certain embodiments, the pain is chronic, acute, central, peripheral, neuropathic, and/or nociceptive pain. In certain embodiments, the pain is visceral pain, skeletal pain, and/or nervous pain. In certain embodiments, a method for reducing the risk of apnea and/or oxygen desaturation in a patient in need of pain treatment is provided. The method comprises administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol. In certain embodiments, an immediate release cebranopadol composition for use in reducing the risk of apnea and/or oxygen desaturation in a patient in need of pain treatment, said method comprising administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol. In certain embodiments, use of cebranopadol in preparing a medicament for use in reducing the risk of apnea and/or oxygen desaturation in a patient receiving pain treatment is provided. The method comprises administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol. In certain embodiments, in the method, composition, or use, wherein the patient has impaired lung function. In certain embodiments, the patient has asthma, chronic obstructive pulmonary disease (COPD), pneumonia, chronic or acute bronchitis, emphysema, cystic fibrosis, interstitial lung disease (ILD), pulmonary embolism, pleural effusion, mesothelioma, tuberculosis, acute respiratory distress syndrome (ARDS), neuromuscular disorders, obesity hypoventilation syndrome, or lung cancer. In certain embodiments, a method, composition or use is provided, wherein cebranopadol prevents apnea and/or oxygen desaturation in a patient receiving pain treatment in the first two hours post-dosing of an immediate release composition independent of dose. In certain embodiments, the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate. In certain embodiments, the composition is administered daily at a dose in an amount of about 10 μg to about 2000 μg cebranopadol. In certain embodiments, the cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. Still other aspects and advantages of the invention will be apparent from the following detailed description of the invention. DETAILED DESCRIPTION OF THE INVENTION In certain embodiments, methods, compositions, and uses are provided for treating and/or preventing opioid use disorder using cebranopadol. In certain embodiments, methods, compositions and uses are provided for treating post-surgical pain by administering a cebranopadol composition, optionally by starting administration of a cebranopadol by administering prior to or during surgery. In certain embodiments, methods, compositions and uses are provided by for treating and/or preventing apnea in a pain patient having diminished lung capacity. In certain embodiments, composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered to a subject with impaired lung function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime. In certain embodiments, impaired lung function is associated with a decreased lung capacity. In certain embodiments, decreased lung function is associated with an existing lung disease in individuals, including, but not limited to, lung cancer, chronic obstructive pulmonary disease (COPD), pneumonia, septic embolization, noncardiogenic pulmonary edema, foreign body granulomatosis, bullous lung disease, emphysema, interstitial lung disease, pulmonary vascular disease, pneumothorax, pneumomediastinum, pulmonary hypertension, asthma, amyloidosis, chronic pulmonary complications associated with injection cocaine use which lung scarring due to repeated pulmonary infections and pulmonary infarction, and pulmonary arterial hypertension.. In some embodiments, the composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered at least one of immediately prior to a surgical procedure, intraoperatively, and/or immediately following a surgical procedure or trauma. In certain embodiments, cebranopadol is used in a pain therapy following a rapid onset opioid, following by discontinuation of the opioid or opioid like drug. Alternatively, in certain embodiments, cebranopadol may be administered after prior, short-term, treatment with an opioid; treatment with cebranopadol may be continued for a day, days, or weeks following removal of opioid treatment. Cebranopadol provides the activity of a full mu-agonist, while providing less abuse potential than a partial mu-agonist. The terms “µ” or “mu” are used interchangeably in reference to a full agonist or a partial agonist of the µ opioid receptor. Full agonists bind tightly to the opioid receptor and may undergo conformational changes to produce effect. Examples of full agonists may include, e.g., codeine, fentanyl, heroin, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, and oxymorphone. These full agonists are typically classified as opioids as a Class (Schedule II) drug. In certain instances, a full agonist may be on Class (Schedule) III drug (e.g., buprenorphine, codeine when mixed with acetaminophen). Examples of partial mu opioid receptor agonists includes tramadol and other opioid-like compounds, e.g., , butorphanol, typically classified as a Class (Schedule) IV drug. It has surprisingly found that when cebranopadol is administered according to the methods provided herein, particularly crystal form A cebranopadol, subjects are therapeutically treated as effectively as with a full mu agonist, yet the potential for abuse is reduced in relation to partial mu opioids or opioid-like drugs, such as tramadol. This combination of properties is unexpected. In certain embodiments, the mu-agonist activity is assessed using a visual analog scale (VAS rating) and/or a Multi-Task Test. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is associated with tissue damage following surgery. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is associated with undergoing surgical procedures (e.g., peri-operative, post-operative pain). In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is trauma pain. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is associated with hyperalgesia (i.e., increased sensation of pain on a noxious stimulus, typically associated with inflamed tissue. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is associated with opioid-induced hyperalgesia, which may occur in both short and chronic opioid administration. In certain embodiments, a method for treating pain with reduced risk of abuse is provided in a patient having nociceptive or neuropathic pain, said regimen comprising dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition is a film- coated tablet. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol in the composition is in crystal form A. For the purpose of the specification, “treatment of pain” refers to any amelioration of pain, alleviation of pain or pain relief including the prevention thereof. As used herein, “Cebranopadol” is intended to include trans-6′-fluoro-4′,9′-dihydro-N,N- dimethyl-4-phenyl-spiro[cyclohexane-1,1′-(3′H)-pyrano[3,4-b]indol]-4-amine (also referred to as (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4- b]indol]-4-amine; free base: CAS Number 86351391-1), its pharmaceutically acceptable salts and solvates thereof: See, e.g., US 7799931, incorporated by reference herein. See, also, crystal forms described in US 8895604; US8765800, US8618156, and US8614245, which are incorporated herein by reference. In certain embodiments, a free base form of cebranopadol is selected. In certain embodiments, a cebranopadol API composition comprises at least 50% to 100% of crystal form A, or at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or about 100% crystal form A. The crystal form may be present in a pharmaceutically acceptable salt form, e.g., HCl salt, and/or a hemihydrate, hydrate, solute, or anhydrous form. In certain embodiments, the cebranopadol is present in the active pharmaceutical ingredient (API) and/or the pharmaceutical composition as a free base and/or in crystal form A. See, Examples, Part A, incorporated herein by reference herein for the powder x-ray diffraction (PXRD) pattern for cebranopadol crystal form A. In certain embodiments, the cebranopadol crystal form A is characterized by one or more of the following: the PXRD pattern of the Table in Part A (see, Examples). X-ray powder diffraction pattern comprising characteristic peaks at 7.8±0.2 degrees 2Θand at 31.6±0.2 degrees 2Θ, and wherein the active ingredient comprises (lr,4r)-6'-fluoro-N,N- dimethyl-4-phe- nyl-4',9'-dihydro-3,EI-spiro-[cyclohexane-l,l,-pyrano-[3,4, b]indol]-4-amine at a diasteromeric excess of about 90% de. In certain embodiments, the crystalline form comprises a characteristic peak at 11.7±0.2 degrees 2Θ. In certain embodiments, the crystalline form comprises characteristic peak at 18.3±0.2 degrees 2Θ. In certain embodiments, the crystalline form comprises characteristic peaks at 8.8±0.2 degrees 2Θ and/or at 15.8±0.2 degrees 2Θ. In certain embodiments, the crystalline form comprises characteristic peaks at about 20.4+0.2 degrees 2Θ and/or at 23.3±0.2 degrees 2Θ. In certain embodiments, the crystalline form comprises characteristic peaks at 11.7±0.2 degrees 2Θ, at one or both of 8.8±0.2 degrees 2Θ and/or 15.8±0.2 degrees 2Θ, and at one or both of 20.4±0.2 degrees 2Θ and/or 23.3±0.2 degrees 2Θ. In certain embodiments, the crystalline form has an endothermal event with a peak temperature at about 298-308° C., as determined by DSC. In certain embodiments, the crystalline form A has a Raman peak at about 1569+2 cm-1 and/or at about 1002+2 cm-1. In certain embodiments, the active ingredient comprises a (lr,4r)-6'-fluoro-N,N-dim- ethyl-4-phenyl-4',9,- dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diasteromeric excess of at least about 95%de. In certain embodiments, the active ingredient comprises a (lr,4r)-6'-fluoro- N,N-dimethyl-4-phenyl-4',9,-dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diasteromeric excess of at least about 97%de. In certain embodiments, the active ingredient comprises a (lr,4r)-6'-fluoro-N,N-dim- ethyl-4-phenyl-4',9,-dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diasteromeric excess of at least about 99%de. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 60 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r-6'-fluoro- N,N-dimethyl-4-phenyl-4',9'-dihydro-3,H-spiro-[cyclohex- ane-1, T-pyrano-[3,4,b]indol] -4- amine. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 80 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r-6'-fluoro- N,N-dimethyl-4-phenyl-4',9'-dihydro-3,H-spiro-[cyclohex- ane-1, T- pyrano-[3,4,b]indol] -4-amine. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 90 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r-6'-fluoro- N,N-dimethyl-4-phenyl-4',9'-dihydro-3,H-spiro- [cyclohex- ane-1, T-pyrano-[3,4,b]indol] -4-amine. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 95 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r)-6'- fluoro-N,N-dimethyl-4-phenyl-4',9'- dihydro-3,H-spiro-[cy- clohexane-1,1' -pyrano - [3,4 ,b] indol] -4 -amine. In certain embodiments, the pharmaceutical composition contains at most about 1.0 wt.-% 4- dimethylamino-4-phenylcyclohexanone, relative to the total content of 6'-fluoro-N,N-dimethyl-4- phenyl-4',9'- dihydro-3'H-spiro[cyclohexane-l,T-pyran [3,4b]indol]-4- amine. In certain embodiments, the composition contains at most about 1.0 wt.-% 4-dimethylamino-4- phenylcyclohexanone, relative to the total content of 6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- dihydro-3'H-spiro[cyclohexane-l,T-pyran [3,4b]indol]-4- amine. Methods of making the compound are described, e.g., US 8,779,160; US8,658,827; US10,323,040, all of which are incorporated by reference herein. Although the free base of cebranopadol is preferred, one may select a pharmaceutically acceptable salts of cebranopadol, which may include salts of inorganic acids, such as hydrochloric acid (cebranopadol HCl), hydrobromic acid and sulfuric acid, and salts of organic acids, such as methane sulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, lactic acid, citric acid, glutamic acid, acetylsalicylic acid, nicotinic acid, aminobenzoic acid, α-liponic acid, hippuric acid and asparaginic acid. In certain embodiments, cebranopadol is present in the non-salt form (free base). In other embodiments, the cebranopadol is present as cebranopadol hemicitrate (CAS number CAS No.863513-92-2). In certain embodiments, a cebranopadol compound useful in certain embodiments of the invention has the structure of: thereof.
Figure imgf000019_0001
e.g., up to 7 hours after intravenous dosing (e.g., 5 to 7 hours), or greater than 9 hours after oral dosing (e.g, 8 to 16 hours, 9 to 18 hours, or longer, e.g., 8 to 24 hours. For the purpose of the specification, doses of cebranopadol relate to the free base. As used herein, “micronized” cebranopadol refers to the size of the drug particle, in which the average size of the drug particles are less than 10 microns. Thus, when a pharmaceutically acceptable salt is used instead, its dose has to be adapted to the equivalent dose of the free base. For example, a dose of “200 μg” means an amount of 200 μg of the free base or any equivalent amount of a pharmaceutically acceptable salt, solvate, hydrate, or salt hydrate, corresponding to 200 μg of the free base. Provided herein are unit dosage forms, e.g., coated tablets, comprising 100 µg cebranopadol, 200 µg cebranopadol, 300 µg cebranopadol, or 400 µg cebranopadol, wherein the dose is determined based on equivalence to the free base. In certain embodiments, these unit dosage forms comprise micronized cebranopadol free base as the sole active ingredient. In other embodiments, other forms of cebranopadol are present in the unit dosage form. Cebranopadol or the physiologically acceptable salt thereof may be administered systemically or orally. In certain embodiments, Cebranopadol or the physiologically acceptable salt thereof is administered once daily. While the examples provided herein were generated with one illustrative composition comprising the cebranopadol, other compositions may be used in the methods provided herein. See, e.g., US 9289416, which is incorporated by reference herein. As used herein, the term micrograms is abbreviated “µg” or “mcg”, which may be used interchangeably. In certain embodiments, a patient may receive a daily dose in the range of about 10 μg to about 2000 μg of cebranopadol free base or equivalent (e.g., a pharmaceutically salt, hydrate, solvate, salt hydrate, or combination thereof). In certain embodiments, the patient may be an adult human, e.g., age 18 or older. In certain embodiments, the patient may be younger, e.g., in the age range of 12 – 17 years old, 12 to 17 years old, 6 to 17 years old, or younger. As used herein, for a human patient experiencing acute pain, a dose generally involves delivery of a dose in excess of 400 μg to 2000 µg, e.g., at least 450 μg, at least 500 μg, at least 550 μg, at least 600 μg, at least 650 μg, at least 700 μg, at least 750 μg, at least 800 μg, at least 850 μg, at least 900 μg, at least 950 μg, at least 1000 μg, at least 1100 μg, at least 1200 μg, at least 1300 μg, at least 1400 μg, at least 1500 μg, at least 1600 μg, at least 1700 μg, at least 1800 μg, at least 1900 μg, or at least 2000 μg, as equivalent dose relative to Cebranopadol free base. In certain embodiments, the supratherapeutic dose is at least 600 µg, at least 450 μg, at least 500 μg, at least 550 μg, at least 600 μg, at least 650 μg, at least 700 μg, at least 750 μg, at least 800 μg, at least 850 μg, at least 900 μg, at least 950 μg, at least 1000 μg, at least 1100 μg, at least 1200 μg, at least 1300 μg, at least 1400 μg, at least 1500 μg, at least 1600 μg, at least 1700 μg, at least 1800 μg, at least 1900 μg, or at least 2000 μg, as equivalent dose relative to cebranopadol free base. In most instances, the doses provided herein are for use in human adults, e.g., age 18 and above. Doses may be titrated, e.g., as described in US Patent 10,022,353 which is incorporated herein by reference, using a subtherapeutic analgesic dose(s) as the starting dose. In certain embodiment, the cebranopadol subtherapeutic analgesic doses are combined into a therapeutic regimen comprising a dosing regimen which comprises starting at a subtherapeutic dose or a therapeutic dose of cebranopadol, and incorporating a therapeutic dose or doses of another drug into the otherwise titrated regimen over 1-3 weeks, or as needed. In certain embodiments, a patient may receive a subtherapeutic dose for 1, 3 or 3 days, followed by therapeutic or subtherapeutic doses on subsequent days. In certain embodiments, cebranopadol may be delivered in a regimen comprising a single daily dosage delivered over a period of days to weeks without a change in daily dosage. Alternatively, cebranopadol may be delivered in a first dose, followed by an increase in daily dose on day 2 and subsequent days. Alternatively, dosage is adjusted as needed. The duration of treatment is not particularly limited and may last for several weeks, months, or years, especially when the pain to be treated or prevented is chronic. In certain embodiments, when the pain is chronic, the pain is treated for at least one week or at least two weeks. Pain and/or opioid drug dependence are treated or prevented. When pain is to be treated or prevented, the pain may be moderate, moderate to severe, or severe. The pain may be chronic or acute; and/or central and/or peripheral; and/or neuropathic and/or nociceptive. In connection with central/peripheral pain and with nociceptive/neuropathic pain “and/or” reflects the possibility that the overall pain may have different components, e.g., a nociceptive component as well as a neuropathic component. In certain embodiments, the pain is chronic neuropathic pain, which may be peripheral or central; acute neuropathic pain, which may be peripheral or central; chronic nociceptive pain, which may be peripheral or central; or acute nociceptive pain, which may be peripheral or central. In certain embodiments, the pain is chronic, acute, subacute, central, peripheral, neuropathic, and/or nociceptive pain. In certain embodiments pain is visceral pain, skeletal pain, and/or nervous pain. In certain embodiments pain is a deep somatic pain. In certain embodiments pain is a superficial somatic pain. In certain embodiments, pain is head-and-face pain. In certain embodiments, pain is associated with tissue damage following surgery. In certain embodiments, pain is associated with undergoing surgical procedures (e.g., peri-operative, post-operative pain). In certain embodiments pain is trauma pain. In certain embodiments, pain is associated with hyperalgesia (i.e., increased sensation of pain on a noxious stimulus, typically associated with inflamed tissue). In certain embodiments, pain is associated with opioid-induced hyperalgesia. Nociceptive pain refers to the discomfort that results when a stimulus causes tissue damage to the muscles, bones, skin or internal organs. For the purpose of the specification, nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being “thermal” (heat or cold), “mechanical” (crushing, tearing, etc.) and “chemical” (iodine in a cut, chili powder in the eyes). Nociceptive pain may also be divided into “visceral,” “deep somatic” and “superficial somatic” pain. Visceral pain describes a type of nociceptive pain originating in the body's internal organs or their surrounding tissues. This form of pain usually results from the infiltration of harmful cells, as well as the compression or extension of healthy cells. Subjects suffering from visceral pain tend to feel generally achy, as this pain tends to not be localized to a specific area. Cancer is a common source of visceral pain. Somatic pain is nociceptive pain that results from some injury to the body. It's generally localized to the affected area and abates when the body repairs the damage to that area. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or superficial tissues, and is sharp, well-defined and clearly located. Pain may be classified as chronic if it has occurred for at least 3 months or extends beyond the time of healing. In certain embodiments, the chronic nociceptive pain is selected from chronic visceral pain, chronic deep somatic pain and chronic superficial somatic pain. Causes of nociceptive pain include broken or fractured bones, bruises, burns, cuts, inflammation (from infection or arthritis), and sprains. Thus, nociceptive pain includes post- operative pain, cancer pain, low back pain, pain due to radiculopathy, and inflammatory pain. Neuropathic pain is pain that originates from nerve damage or nerve malfunction. In certain embodiments, the neuropathic pain is selected from acute neuropathic pain and chronic neuropathic pain. Neuropathic pain may be caused by damage or disease affecting the central or peripheral portions of the nervous system involved in bodily feelings (the somatosensory system). In certain embodiments, the composition is for use in the treatment of chronic neuropathic pain or acute neuropathic pain, peripheral neuropathic pain or central neuropathic pain, mononeuropathic pain or polyneuropathic pain. When the neuropathic pain is chronic, it may be chronic peripheral neuropathic pain or chronic central neuropathic pain, in certain embodiments, chronic peripheral mononeuropathic pain or chronic central mononeuropathic pain, in certain embodiments, chronic peripheral polyneuropathic pain or chronic central polyneuropathic pain. When the neuropathic pain is acute, it may be acute peripheral neuropathic pain or acute central neuropathic pain, in certain embodiments, acute peripheral mononeuropathic pain or acute central mononeuropathic pain, in certain embodiments, acute peripheral polyneuropathic pain or acute central polyneuropathic pain. Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Fibromyalgia is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain. Aside from diabetic neuropathy and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic, and immune mediated disorders or physical trauma to a nerve trunk (e.g., due to disorders from the spinal disc, joint degeneration, or compression fracture). Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery. In certain embodiments, the pain is selected from postoperative pain, pain due to bunionectomy, visceral pain, cancer pain, pain due to diabetic polyneuropathy, pain due to osteoarthritis, fibromyalgia, low back pain, pain radiating down the lower limbs, pain due to (cervical or lumbar) radiculopathy, and inflammatory pain. In certain embodiments, the pain is selected from the group consisting of pain being or being associated with panic disorder [episodic paroxysmal anxiety]; dissociative [conversion] disorders; persistent somatoform pain disorder; pain disorders exclusively related to psychological factors; nonorganic dyspareunia; other enduring personality changes; sadomasochism; elaboration of physical symptoms for psychological reasons; migraine; other headache syndromes; trigeminal neuralgia [G50.0]; atypical facial pain [G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndrome without pain [G54.7]; acute and chronic pain, not elsewhere classified [G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris, unspecified [120.9]; other specified disorders of nose and nasal sinuses [J34.8]; other diseases of pharynx [J39.2]; temporomandibular joint disorders [K07.6]; other specified disorders of teeth and supporting structures [K08.8]; other specified diseases of jaws [K10.8]; other and unspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; other specified diseases of anus and rectum [K62.8]; pain in joint [M25.5]; shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhere classified [M53.3]; spine pain [M54.]; radiculopathy [M54.1]; cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain in thoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified [M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders, not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis, unspecified [M79.2]; pain in limb [M79.6]; other specified disorders of bone [M89.8]; unspecified renal colic [N23]; other specified disorders of penis [N48.8]; other specified disorders of male genital organs [N50.8]; mastodynia [N64.4]; pain and other conditions associated with female genital organs and menstrual cycle [N94]; mittelschmerz [N94.0]; other specified conditions associated with female genital organs and menstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat [R07.0]; chest pain on breathing [R07.1]; precordial pain [R07.2]; other chest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal and pelvic pain [R10]; acute abdomen pain [R10.0]; pain localized to upper abdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized to other parts of lower abdomen [R10.3]; other and unspecified abdominal pain [R10.4]; flatulence and related conditions [R14]; abdominal rigidity [R19.3]; other and unspecified disturbances of skin sensation [R20.8]; pain associated with micturition [R30]; other and unspecified symptoms and signs involving the urinary system [R39.8]; headache [R51]; pain, not elsewhere classified [R52]; acute pain [R52.0]; chronic intractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified [R52.9]; other complications of cardiac and vascular prosthetic devices, implants and grafts [T82.8]; other complications of genitourinary prosthetic devices, implants and grafts [T83.8]; other complications of internal orthopedic prosthetic devices, implants and grafts [T84.8]; other complications of internal prosthetic devices, implants and grafts, not elsewhere classified [T85.8]; wherein the information in brackets refers to the classification according to ICD-10. The dose of cebranopadol or of the physiologically acceptable salt thereof that is administered to the subject is not particularly limited, as it has been unexpectedly found that cebranopadol is so well tolerated that it may even be administered to subjects with impaired hepatic function and/or impaired renal function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime. Thus, in certain embodiments, cebranopadol or the physiologically acceptable salt thereof is administered at a dose that would also be administered to a subject in the same condition but without impaired hepatic and/or without impaired renal function. In certain embodiments, composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered to a subject with impaired lung function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime. In certain embodiments, impaired lung function is associated with a decreased lung capacity. In certain embodiments, decreased lung function is associated with an existing lung disease in individuals, including, but not limited to, lung cancer, chronic obstructive pulmonary disease (COPD), pneumonia, septic embolization, noncardiogenic pulmonary edema, foreign body granulomatosis, bullous lung disease, emphysema, interstitial lung disease, pulmonary vascular disease, pneumothorax, pneumomediastinum, pulmonary hypertension, asthma, amyloidosis, chronic pulmonary complications associated with injection cocaine use which lung scarring due to repeated pulmonary infections and pulmonary infarction, and pulmonary arterial hypertension.. In some embodiments, the composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered at least one of immediately prior to a surgical procedure, intraoperatively, and/or immediately following a surgical procedure or trauma. Depending upon the type and degree of pain to be treated or prevented, Cebranopadol or the physiologically acceptable salt thereof is administered at a dose that in the subject's perception results in an amelioration of pain at acceptable side effects. Typically, the dose is within the range of from 20 μg to 2000 μg, as equivalent dose relative to Cebranopadol free base. In certain embodiments, the dosage form is adapted for administration once daily and contains the pharmacologically active agent in a dose of from 150 µg to 800 µg, more than 190 µg to 800 µg, i.e., the dosage form contains the pharmacologically active agent (e.g, cebranopadol or salt thereof) in a daily dose of from 150 µg to 800 µg. In a certain embodiment, the dose is from 200 µg to 800 µg, from 210 µg to 750 µg, from 220 µg to 700 µg, from 230 µg to 650 µg, from 240 µg to 600 µg, from 250 µg to 550 µg. In certain embodiments, as Cebranopadol or the physiologically acceptable salt thereof is administered once daily, this dose corresponds to the daily dose. For the purpose of the specification, “administration once daily” (sid, OD) in certain embodiments means that the pharmaceutical composition is adapted for being administered according to a regimen comprising the administration of a first pharmaceutical composition and the subsequent administration of a second pharmaceutical composition according to the invention, wherein both, the first and the second pharmaceutical composition are administered during a time interval of about 48 hours, but wherein the second pharmaceutical composition is administered not earlier than 18 hours, not earlier than 20 hours, not earlier than 22 hours and in particular, about 24 hours after the first pharmaceutical composition has been administered. Administration regimens “once daily” may be realized by administering a single pharmaceutical composition containing the full amount of the cebranopadol or pharmaceutically acceptable salt thereof to be administered at a particular point in time or, alternatively, administering a multitude of dose units, i.e. two, three or more dose units, the sum of which multitude of dose units containing the full amount of the cebranopadol or a pharmaceutically acceptable salt thereof to be dosed at said particular point in time, where the individual dose units are adapted for simultaneous administration or administration within a short period of time, e.g. within 5, 10 or 15 minutes. In certain embodiments, a pharmaceutical composition (e.g., pharmaceutical dosage form) comprises at least one form of cebranopadol and/or a pharmaceutically acceptable salt thereof, or a hydrate of the cebranopadol or salt thereof, or a solvate of a cebranopadol or a salt or hydrate thereof. In certain embodiments, the pharmaceutical composition provides immediate release of the cebranopadol or pharmaceutically acceptable salt thereof (or other active ingredient). Such a pharmaceutical composition may be specifically designed to provide immediate release of the cebranopadol in accordance with Ph. Eur or the equivalent. When the pharmaceutical composition is coated, e.g., with a coating that is soluble in gastric juice, the release kinetic may be monitored after such coating has been dissolved. For the purpose of specification, the term “immediate release” refers to any release profile that fulfills at least one, preferably both, of the following requirements. First, the pharmaceutical composition disintegrates in 10 minutes or less following exposure to a disintegrating medium. Methods to determine the disintegration time are known to a person skilled in the art. For instance, they can be determined according to the USP XXIV disintegration test procedure, using, for example, an Erweka ZT-71 disintegration tester. Second, the pharmaceutical composition releases at least 70 wt% of the drug within 15 minutes following exposure to a dissolution medium. In certain embodiments, the in vitro release properties of the pharmaceutical composition (dosage form) are determined according to the paddle method with sinker at 50, 75 or 100 rpm, under in vitro conditions at 37±0.5° C. in 900 mL artificial gastric juice at pH 1.2, or under the same conditions in non-artificial gastric juice. In certain embodiments, the pharmaceutical composition releases under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 and 37±0.5° C. after 30 minutes according to the paddle method with sinker at 100 rpm at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, or at least 95 wt% of the cebranopadol or salt thereof, based on the total amount of the cebranopadol or salt thereof originally contained in the pharmaceutical composition. Various components for pharmaceutical compositions may be selected. See, e.g., US 9289416 and US 10,912,763, which are incorporated by reference herein. In certain embodiments, the pharmaceutical composition is a tablet, chewable tablet, chewing gum, coated tablet or powder, optionally filled into a capsule. In certain embodiments, the pharmaceutical composition in multi-particulate form, in form of a micro-tablet, micro capsule, granulate, pellet or active-substance crystal, optionally filled into a capsule or compressed to form a tablet. A solid pharmaceutical composition may contain pharmaceutical excipients including one or more lubricants, binders, disintegrants, fillers, diluents, glidants, surfactants, and preservatives. One suitable lubricant that may be contained in the pharmaceutical composition is magnesium stearate. the content of the lubricant is within the range of from 0.001 to 5.0 wt%, for example 0.01 to 5 wt.-%, 0.1 to 5 wt.-%, 0.1 to 3 wt.-%, 0.1 to 2 wt.-%, or even 0.5 to 1.5 wt.-% , based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a binder. Suitable binders include but are not limited to gelatin, cellulose, modified cellulose such as microcrystalline cellulose, methyl cellulose, polyvinyl pyrrolidone (povidone), starch, sucrose and polyethylene glycol; especially preferred are polyvinyl pyrrolidone and/or microcrystalline cellulose. In certain embodiments, the content of lubricant is within the range of from 0.001 to 30 wt.-%, or 0.1 to 25 wt.-%, based on the total weight of the composition (e.g., tablet). In some embodiments, the composition comprises 1 to 20 wt.-%, 5 to 20 wt.-%, or 10 to 20 wt.-% of binder(s), based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a filler and/or diluent, e.g., selected from the group consisting of but are not limited to cellulose (e.g., microcrystalline cellulose), calcium diphosphate, lactose (e.g., lactose monohydrate), sucrose, glucose, mannitol, sorbitol, and calcium carbonate. In certain embodiments, the content of filler and/or diluent is within the range of from 0.001 to 95 wt.-%, 30 wt% to about 90 wt%, 0.01 to 85 wt.-%, 0.1 to 80 wt.-%, or 10 to 75 wt.-% , based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a lubricant such as magnesium stearate, stearic acid and stearin. In certain embodiments, the content of the lubricant is within the range of from 0.001 to 5 wt %, e.g., from 0.1 to 3 wt%, or about 0.5 wt% to 1.5% wt%, based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a disintegrant such as cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), cross-linked polyvinyl pyrrolidone and sodium starch glycolate. In certain embodiments, the content of the disintegrant is within the range of from 0.001 to 5 wt. %, e.g., from 0.1 to 3 wt. %, based on the total weight of the composition (e.g., tablet). The pharmaceutical composition may further contain at least one preservative. Suitable preservatives include but are not limited to antioxidants, such as vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium; cysteine, methionine, citric acid, sodium citrate, methyl paraben and propyl paraben. In certain embodiments, a solid pharmaceutical composition further contains a coating, in particular a polymer-based coating, more in particular a polyvinyl alcohol-based coating such as the ones commercially available under the trade name “Opadry”. In some embodiments, the pharmaceutical composition is a tablet which comprises the cebranopadol or pharmaceutically acceptable salt thereof (e.g., in an amount from 0.6±0.4 wt %, 0.6±0.3 wt -%, 0.6±0.2 wt%, 0.6±0.1 wt %, 0.04±0.03 wt %, 0.04±0.02 wt. %, or 0.04±0.01 wt %), one or more lubricants (e.g., magnesium stearate) in an amount from 0.001 to 5.0 wt. % (e.g., 0.01 to 5 wt %, 0.1 to 5 wt %, 0.1 to 3 wt %, 0.1 to 2 wt %, or even 0.5 to 1.5 wt %), one a more binders (e.g., polyvinyl pyrrolidone and/or microcrystalline cellulose) in an amount from 0.001 to 30 wt % (e.g., from 0.1 to 25 wt %, 1 to 20 wt %, 5 to 20 wt %, or 10 to 20 wt %), and one or more fillers or diluents (e.g., microcrystalline cellulose and/or lactose) in an amount from 0.001 to 90 wt % (e.g., 0.01 to 85 wt %, 0.1 to 80 wt %, or 10 to 75 wt %), based on the total weight of the composition (e.g., tablet). In some embodiments, the tablet also comprises one or more lubricants (e.g., magnesium stearate, stearic acid and/or stearin) in an amount from 0.001 to 5 wt % (e.g., from 0.1 to 3 wt %) and/or one or more disintegrants (e.g., croscarmellose sodium, cross-linked polyvinyl pyrrolidone and/or sodium starch glycolate) in an amount from 0.001 to 5 wt % (e.g., from 0.1 to 3 wt %), based on the total weight of the composition (e.g., tablet). In certain embodiments, the coating protects the pharmaceutical composition from moisture, but dissolves rapidly in gastric juice. In certain embodiments, the coated composition has a disintegration time of less than 5 minutes in gastric juice, of at most 4.5 minutes, at most 4 minutes, at most 3.5 minutes, at most 3 minutes, at most 2.5 minutes and/or at most 2 minutes. For the manufacture of the pharmaceutical compositions, the various solid auxiliary substances and the pharmacologically active agent may be homogenized, processed by means of wet, dry or fusion granulation to form granulates, and compressed to form tablets. Alternatively, they are manufactured by direct tableting of the auxiliary substances and the pharmacologically active agent. In certain embodiments, the pharmaceutical composition is prepared by means of wet granulation from a granulating fluid containing the pharmacologically active agent in particular from an aqueous granulating fluid containing said pharmacologically active agent and the surfactant. In certain embodiments, the resulting granulating fluid is then top-sprayed or bottom-sprayed onto a solid formulation containing at least one auxiliary substance to yield compressible granules, which may optionally be mixed with further auxiliary substances before being compressed to tablets. Further provided herein are methods and regimens using the pharmaceutical compositions comprising at least cebranopadol or a pharmaceutically acceptable salt, hydrate or solvate thereof. In certain embodiments, the composition comprises cebranopadol free base. In certain embodiments, the composition is an immediate release composition. In certain embodiments, provided herein is a method for treatment and/or prevention of opioid use disorder (OUD) in a patient in need therefor, said method comprising dosing a patient with a pharmaceutical composition comprising a cebranopadol and/or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof. In certain embodiments, cebranopadol is selected as a first line analgesic in the absence of any opioid or opioid-like analgesic in a subject having one or more risk factors for developing OUD. There is a broad spectrum of risk factors for developing OUD, including poor social support, personal or family history, psychological stress or trauma, and childhood adversity.12 Stress because of pain that is uncontrolled can also lead to opioid misuse in a patient with no other risk factors. In addition, despair within socioeconomically disadvantaged communities, binge-use and thrill-seeking behavior, and social environments that encourage illicit substance use potentially contribute to adverse outcomes and therapeutic failure. Opioid use disorder is a chronic, relapsing condition. In certain embodiments, cebranopadol may be selected as a secondary analgesic providing opioid-like analgesic effect by discontinuing opioid treatment within 1 to two hours after administering a cebranopadol composition. In certain embodiments, the patient may have received opioid treatment for less than 24 hours, less than 18 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours. In certain embodiments, opioid treatment is discontinued after a single dose, followed by cebranopadol. In other embodiments, the first dose of cebranopadol may be delivered concomitantly, or shortly after, the first opioid dose. In other embodiments, cebranopadol treatment is initiated in a patient having or previously diagnosed with opioid use disorder, but in need of analgesic treatment. In certain embodiments, the cebranopadol is used for treatment of pain associated with opioid-induced hyperalgesia. In certain embodiments, the cebranopadol is used for treatment of acute pain. In certain embodiments, the pain is associated with tissue damage following surgery. In certain embodiments, the pain is associated with hyperalgesia. In certain embodiments, methods, compositions and uses are provided for reducing the risk of apnea and/or preventing oxygen desaturation in a patient receiving pain treatment by administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol. In certain embodiments, the composition comprising an immediate release cebranopadol composition and the active pain ingredient is at least one form of cebranopadol. In certain embodiments, the patient receiving cebranopadol treatment has impaired lung function. In certain embodiments, the patient has asthma, chronic obstructive pulmonary disease (COPD), pneumonia, chronic or acute bronchitis, emphysema, cystic fibrosis, interstitial lung disease (ILD), pulmonary embolism, pleural effusion, mesothelioma, tuberculosis, acute respiratory distress syndrome (ARDS), neuromuscular disorders, obesity hypoventilation syndrome, or lung cancer. In certain embodiments, the cebranopadol prevents apnea and/or oxygen desaturation in a patient receiving pain treatment in the first hour and/or the first two hours post-dosing of an immediate release cebranopadol composition independent of dose. In certain embodiments, the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate. In certain embodiments, a daily dose in an amount of about 10 μg to about 2000 μg cebranopadol, optionally in more than one form (e.g., free base, salt, hydrate, etc). In certain embodiments, the composition comprises cebranopadol free base. In certain embodiments, the composition comprises at least 80% of the cebranopadol in crystal form A. In certain embodiments, a method is provided for treating pain while reducing the abuse potential and/or side effects of Class II, III and Class IV- opioids over a period of about 8 to 24 hours in a patient. The method comprises dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof which has a mechanism of action comprising dual agonism of the nociceptin/orphanin FQ peptide (NOP) and µ-opioid peptide (MOP) receptors. In certain embodiments, the abuse potential is assessed using a visual analog scale (VAS) rating. Optionally, the abuse potential is further assessed using a Multi-Task Test. In certain embodiments, the method further comprises dosing the patient with cebranopadol at a dose of about 50 µg to 800 µg or more than 190 µg to 800 µg, i.e., the dosage form a contains the pharmacologically active agent in a daily dose of from 150 µg to 800 µg. In certain embodiments, the dose of the pharmacologically active agent is in the range of from 200 µg to 800 µg, from 210 µg to 750 µg, from 220 µg to 700 ug, from 230 µg to 650 µg, from 240 µg to 600 µg, from 250 µg to 550 µg. In certain embodiments, a supratherapeutic dose may be selected. A supratherapeutic dose may comprise greater than 450 µg to about 1000 µg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the supratherapeutic dose is about 600 µg to about 1000 µg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the composition comprises the cebranopadol is a tablet, optionally a film coated tablet. In certain embodiments, a regimen is provided for reducing the abuse potential and sides effects of Class II and Class IV- opioids in a patient susceptible thereto. The method comprises: (a) discontinuing treatment of a patient with an opioid or opioid agonist; and (b) dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof which comprises a dual receptor for nociceptin/orphanin FQ peptide (NOP) and µ-opioid peptide (MOP) receptor. In certain embodiments, (a) comprises titrating down the dosage of a Class II or Class IV opioid or opioid agonist by decreasing the dose of the opioid or opioid agonist in (a) over the period of 1 to 3 days. Steps (a) and (b) may be performed during the same or overlapping time periods. In certain embodiments, the opioid or opioid agonist of (a) is selected from tramadol, oxycodone, morphine, hydrocodone, fentanyl, oxymorphone, hydromorphone, buprenorphine, codeine, tapentadol, methadone, meperidine, or levorphanol. In certain embodiments, one or more of the side effects selected from nausea, vomiting, dizziness, pruritis, and/or hot flush sensation, are reduced or eliminated. In certain embodiments, the patient is renally or hepatically impaired. In certain embodiments, a method is provided for treating pain in a patient having nociceptive pain with reduced risk of abuse. In certain embodiments, a regimen comprises dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition used is cebranopadol free base. In certain embodiments, the composition is a film-coated tablet. In certain embodiments, a dosage unit comprises 100 mcg (µg) cebranopadol (equivalent to free base). In certain embodiments, a dosage unit comprises 200 mcg cebranopadol (equivalent to free base). In certain embodiments, a dosage unit is 300 mcg cebranopadol (equivalent to free base). In certain embodiments, a dosage unit is 400 mcg cebranopadol. In certain embodiments, a single daily oral dose may comprise 1, 2, 3, 4, 5, 6, 7, or 8 tablets taken essentially at the same time (e.g., 100 mcg tablet taken within five minutes of each other). In certain embodiments, a single daily oral dose may comprise 1, 2, 3 or 4 tablets (e.g., 200 mcg tablet taken within five minutes of each other). In certain embodiments, a single daily oral dose may comprise 1 or 2 tablets (e.g., 100, 200, 300 or 400 mcg tablets, or combinations thereof, taken within five minutes of each other). Other combinations may be selected. In certain embodiments, a method for treatment of opioid use disorder (OUD) in a patient in need thereof is provided, which comprises treating the patient with at least one dose of cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, a pharmaceutical composition provides an immediate release profile for the cebranopadol or pharmaceutically acceptable salt thereof. In certain embodiments, composition comprises cebranopadol in its free base form. In certain embodiments, the composition is delivered once daily for the desired duration of treatment, e.g., 1 day to 14 days, 3 weeks, 4 weeks, or longer, or shorter durations therebetween. In certain embodiments, herein the composition is delivered no more than once a day for three to 14 days. The pharmacokinetic parameters of cebranopadol may be calculated from plasma concentration- time data. AUC0-t refers to “Area under the concentration-time curve” from administration up to the sampling time t. If it is not replaced by a numerical value, then t is the last sampling time with quantifiable concentration and this parameter will not contain an extrapolated portion. AUCinf refers to Area under the concentration-time curve from time 0 to infinite time. Areas under the curves in the study examples below may be calculated using the log- linear trapezoidal rule, i.e., linear up to the maximum concentration and log thereafter. However, others may readily select another method. Cmax refers to the maximum observed plasma concentration level. Tmax refers to the time post-dosing to attain maximum plasma concentration. The PK values may be determined using geometric mean and/or the arithmetic mean. In certain embodiments, mean, individual, and overlay concentration-time profiles are plotted on both linear and semi-logarithmic scales on the same, portrait-oriented page. Pharmacodynamics (PD) may be assessed using a Visual Analog Scale (VAS), Pupillometry, and/or the Multi-Tasking Test (MTT), such as described in the examples herein. Additional or alternative tests may be selected. The VAS assessment is one of the most sensitive indices of abuse liability. See, Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend.2013 Apr 1;129(1-2):116-24l; Food and Drug Administration Guidance for Industry. Assessment of Abuse Potential of Drugs. January 2017.] The VAS for Drug Liking assesses the subject’s liking of the drug at this moment the question is asked. The VAS is a bipolar scale. The scale is not administered pre-dose as it refers specifically to the drug. Pupillometry may be used as an objective physiological PD measure as it is one of the most sensitive measures of central opioid action and appears to be resistant to tolerance development with repeated opioid administration. NeurOptics Pupillometer (Irvine, CA, USA) or similar equipment will be used to measure pupil diameter. Data from a series of frames will be used in the calculation, and the final display will show the weighted average and standard deviation of the pupil size. Measurements may be collected under mesopic lighting conditions. The Multi-Tasking Test (MTT) (formerly known as the Attention Switching Task, AST) is a test of executive function which provides a measure of the ability to use multiple sources of potentially conflicting information to guide behavior. In this task the participant is presented with a series of arrows on-screen, pointing in either direction (to the right or to the left). Each trial displays a cue at the top of the screen that indicates to the participant whether they have to press the right or left button according to the “side on which the arrow appeared” or the “direction in which the arrow was pointing”. Some trials display congruent stimuli (e.g., arrow on the right side of the screen pointing to the right) whereas other trials display incongruent stimuli which require a higher cognitive demand (e.g., arrow on the right side of the screen pointing to the left). In the final section, both rules are used, presented in a randomized order, requiring the participant to adjust their response depending on whether the rule is repeated or switched (multitasking). Outcome measures for the Multitasking Test include response latencies and error scores that reflect the participant’s ability to manage multitasking and the interference of incongruent task- irrelevant information on task performance. In certain embodiments, the administration time for the test is about 8 minutes. In certain embodiments, a cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, is provided which when administered to a subject provides the subject with a therapeutic effect of a pharmaceutically acceptable full mu agonist and a lower potential for abuse than a pharmaceutically acceptable partial mu agonist. In certain embodiments, the subject is being treated for pain. In certain embodiments, the pain is chronic acute; central; peripheral; neuropathic and/or nociceptive pain, or another of the types of pain provided in this specification or known in the art. In certain embodiments, the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol. In certain embodiments, the cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the partial mu agonist is tramadol. In certain embodiments, use of cebranopadol in treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu agonist therapeutic effect and a lower abuse potential than a partial mu agonist. In certain embodiments, use of cebranopadol in preparing a medicament for treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu agonist therapeutic effect and a lower abuse potential than a partial mu agonist. In certain embodiments, a method, use or composition is provided for treatment of opioid use disorder. In certain embodiments, a method, use or composition is provided for opioid use disorder in subjects having impaired lung function. In certain embodiments, a method, use or composition is provided for treating pain while reducing the abuse potential and/or sides effects of Class II, III and Class IV- opioids and opioid- like analgesics over a period of about 8 to 24 hours in a patient in need of analgesic treatment, said method comprising dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt or hydrate thereof. In certain embodiments, the mu-agonist effect is assessed using a visual analog scale (VAS) rating and/or a Multi-Task Test. In certain embodiments, the patient is dosed with 100 µg to 400 ug cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the cebranopadol is at dose which comprises greater than 450 µg to about 1000 µg cebranopadol, or about 600 µg to about 1000 µg, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the cebranopadol is a tablet unit dosage form. In certain embodiments, the tablet is a film coated tablet. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol is crystal form A. In certain embodiments, a regimen is provided for providing analgesic treatment while e reducing the abuse potential and/or sides effects of Class II and Class IV- opioids in a patient susceptible thereto, said method comprising: (a) discontinuing treatment of a patient with an opioid or opioid agonist ; and (b) dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof . In certain embodiments, the regimen (a) comprises titrating down the dosage of a Class II, Class III or Class IV opioid or opioid agonist by decreasing the dose of the opioid or opioid agonist in (a) over the period of 1 to 3 days. In certain embodiments, steps (a) and (b) are performed during the same or overlapping time periods. In certain embodiments, opioid or mu opioid agonist is selected from tramadol, oxycodone, morphine, hydrocodone, fentanyl, oxymorphone, hydromorphone, buprenorphine, codeine, tapentadol, methadone, meperidine, or levorphanol. In certain embodiments, the mu agonist activity (or abuse potential) is assessed using a visual analog scale (VAS) rating and/or a Multi-Task Test. In certain embodiments, composition comprising the cebranopadol is a tablet. In certain embodiments, the tablet is film coated tablet. In certain embodiments, the side effects comprise nausea, vomiting, dizziness, pruritis, hyperhidrosis and/or hot flush sensation. In certain embodiments, the patient is renally or hepatically impaired. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol is crystal form A. In certain embodiments, a method, use or composition is provided for treating pain. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is chronic, acute, subacute, central, peripheral, neuropathic, and/or nociceptive pain. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is visceral pain, skeletal pain, and/or nervous pain. Patients more reliably discontinue the use of Cebranopadol at the end of prescribed treatment periods as compared to known Schedule II, Class III, and class IV opioids and opioid- like analgesics. In certain embodiments, a composition comprising cebranopadol treats a subject by delivering full mu (µ) agonist activity (e.g., analgesic or other therapeutic effect), while avoiding addictive properties of full mu agonists (e.g., fentanyl, oxycodone, morphine, heroin, codeine, meperidine, or other Class I, Class II or Class III analgesics) and providing less addictive properties and/or less abuse potential than a partial mu agonist (e.g., tramadol or another Class IV opioid-like analgesic). In further embodiments, unlike after treatment with oxycodone and tramadol, administration of cebranopadol does not produce pruritus, hyperhidrosis, feeling hot and/or hot flushing, that have been associated with the use of opioid analgesics. Provided herein are methods for providing a patient with opioid-level analgesic effect while preventing pruritus by administering cebranopadol. In certain embodiments, methods are provided for preventing pruritus in a patient receiving an opioid-level analgesic effect, comprising administering an effective amount of cebranopadol. Provided herein are methods for providing a patient with opioid-level analgesic effect while preventing hyperhidrosis by administering an effective amount of cebranopadol. In certain embodiments, methods are provided for preventing hyperhidrosis in a patient receiving an opioid-level analgesic effect, comprising administering an effective amount of cebranopadol. Provided herein are methods for providing a patient with opioid-level analgesic effect while preventing feeling hot and/or hot flushing by administering an effective amount of cebranopadol. In certain embodiments, methods are provided for preventing hot flushing in a patient receiving an opioid-level analgesic effect, comprising administering an effective amount of cebranopadol. In certain embodiments, a cebranopadol composition useful for reducing pruritus, hyperhidrosis, feeling hot and/or hot in a subject receiving analgesic treatment for pain is provided, which provides the analgesic therapeutic effect of an opioid. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol in the composition is in crystal form A. In certain embodiments, a method for reducing pruritus, hyperhidrosis, feeling hot and/or hot in a subject receiving analgesic treatment for pain is provided, which provides the therapeutic effect of an opioid, comprising administering a composition comprising cebranopadol. In certain embodiments, a composition is provided which is useful in treating a subject, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a therapeutic effect of a pharmaceutically acceptable full mu-agonist and a lower potential for abuse than a pharmaceutically acceptable partial mu-agonist. In certain embodiments, the subject is being treated for pain. In certain embodiments, the pain is chronic; acute; central; peripheral; neuropathic and/or nociceptive pain. In certain embodiments, the pain is visceral pain, skeletal pain, and/or nervous pain. In certain embodiments, the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol. In certain embodiments, cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the partial mu-agonist is tramadol. In certain embodiments, use of cebranopadol in treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu-agonist. In certain embodiments, use of cebranopadol in preparing a medicament for treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu agonist. In certain embodiments, a composition, use or method is provided for treating a subject, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu-agonist. In certain embodiments, the subject is being treated for pain. In certain embodiments, the pain is chronic; acute; central; peripheral; neuropathic and/or nociceptive pain. In certain embodiments, the pain is visceral pain, skeletal pain, and/or nervous pain. In certain embodiments, the mu-agonist activity is assessed using a visual analog scale (VAS rating) and/or a Multi-Task Test. In certain embodiments, the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol. In certain embodiments, the cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the partial mu- agonist is tramadol. In certain embodiments, a composition, use or method treating pain in a patient having nociceptive pain with reduced risk of abuse is provided, said regimen comprising dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition is a film- coated tablet. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol in the composition is in crystal form A. In certain embodiments, a composition, use or method is provided which is useful for reducing pruritus, hyperhidrosis, feeling hot and/or hot in a subject receiving analgesic treatment for pain, while providing the analgesic therapeutic effect of an opioid, wherein the composition comprises cebranopadol. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol in the composition is in crystal form A. In certain embodiments, a composition or regimen provided herein comprises cebranopadol as the sole active pharmaceutical ingredient or the sole analgesic in the composition. In certain embodiments, a composition, use or method for treatment of pain in humans is provided which provides reduced the abuse potential and reduced sides effects as compared to Class II, III and Class IV- opioids and opioid-like analgesics. The method involves dosing a human patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt or hydrate thereof. In certain embodiments, the composition is an immediate release composition administered once daily and provides an analgesic effect over a period of at least about 8 to 24 hour hours post-administration. In certain embodiments, the pain is visceral pain, skeletal pain, and/or nervous pain. In certain embodiments, the mu-agonist activity is assessed using a visual analog scale (VAS rating) and/or a Multi-Task Test. In certain embodiments, patient is dosed with 100 µg to 400 ug cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the patient is dosed with greater than 450 µg to about 1000 µg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the dose is about 600 µg to about 1000 µg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the composition comprising the cebranopadol is a tablet unit dosage form. In certain embodiments, the tablet is a film coated tablet. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol is crystal form A. In certain embodiments, a method for treating and/or preventing opioid use disorder (OUD) in human patients receiving analgesic treatment is provided, which comprises treating a patient with cebranopadol, optionally a film coated tablet. In certain embodiments, a regimen is provided for reducing the abuse potential and side effects of Class II and Class IV- opioids in a patient susceptible thereto. The method comprises: (a) discontinuing treatment of a patient with an opioid or opioid agonist; and (b) dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, (a) comprises titrating down the dosage of a Class II or Class IV opioid or opioid agonist by decreasing the dose of the opioid or opioid agonist in (a) over the period of 1 to 3 days. Steps (a) and (b) may be performed during the same or overlapping time periods. In certain embodiments, the opioid or opioid agonist of (a) is selected from tramadol, oxycodone, morphine, hydrocodone, fentanyl, oxymorphone, hydromorphone, buprenorphine, codeine, tapentadol, methadone, meperidine, or levorphanol. In certain embodiments, one or more of the side effects selected from nausea, vomiting, dizziness, pruritis, and/or hot flush sensation, are reduced or eliminated. In certain embodiments, the patient is renally or hepatically impaired. In certain embodiments, a method is provided for treating pain in a patient having nociceptive pain with reduced risk of abuse. The regimen comprises dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition used is cebranopadol free base. In certain embodiments, the composition is a film-coated tablet. In one or more of these embodiments, uses and/or compositions, cebranopadol may be the sole active pharmaceutical ingredient in the composition and/or regimen. It will be understood from the specification that the following examples are not limitations on the various embodiments of the invention. Examples: The cebranopadol oral human abuse potential study in the following example was a phase I single-dose, randomized, double-blind, five-way crossover study of 47 participants to evaluate the abuse potential of two supratherapeutic doses of cebranopadol in adult nondependent recreational opioid users versus placebo and commonly used opioids, oxycodone, a schedule II narcotic, and tramadol, a schedule IV narcotic. Eligible participants randomly received a single dose of placebo, cebranopadol 600µg, cebranopadol 1000µg, tramadol IR 600mg, or oxycodone IR 40mg. Abuse potential was determined based on participant-reported likeability using a Visual Analog Scale (VAS) following administration of study drug or placebo. Topline results show that one 600 µg dose of cebranopadol was similarly liked as placebo. Both 600 µg and 1000 µg doses of cebranopadol were liked significantly less than tramadol 600mg (17.34, p< 0.0001 and 7.77, p=0.0077, respectively) and oxycodone 40mg (24.43, p< 0.0001 and 14.86, p< 0.0001, respectively), suggesting cebranopadol has significantly less potential for abuse compared to both schedule II and schedule IV narcotic. Overall, both supratherapeutic dosages of cebranopadol did not raise any safety concerns. The most common reported adverse event was nausea, which was greatest after the administration of tramadol 600mg (49%) versus either dose of cebranopadol 1000 µg and 600 µg (35% and 15%) or oxycodone (32%). The rate of vomiting after the administration of tramadol 600 mg and 1000 µg of cebranopadol was similar, 31% versus 30%. The fewest reports of vomiting were received when participants received 600 µg of cebranopadol (16%). Adverse events involving the nervous system were observed most often after the administration of tramadol with fewest reported after the administration of cebranopadol or placebo. Reports of pruritis (itchy skin) were greater after administration of oxycodone (30%) and tramadol (18%) when compared to 600 µg and 1000 µg of cebranopadol (4% and 7%). Illustrative Synthesis of Crystalline Form A The following abbreviations are used in the examples: iBuOAc iso-butyl acetate; 1BuOH n-butanol (1-butanol); DMSO dimethyl sulfoxide; EtOAc ethyl acetate; EtOH ethanol; Ex example; FT-Raman Fourier transformation Raman spectroscopy; IPE diisopropyl ether; Δm change in mass; MeCN acetonitrile; MEK 2-butanone; MeOH methanol; min minute; NMP N- methyl-2-pyrrolidone; 1PrOH n-propanol (1-propanol); 2PrOH iso-propanol (2-propanol); PXRD powder x-ray diffraction; r.h. relative humidity; RT room temperature, preferably 20-25° C; SCXRD single crystal X-ray diffraction; sec seconds ; t time (duration) ; TBME tert-butyl methyl ether; TG-FTIR thermogravimetry coupled with Fourier transform infrared spectroscopy; THF tetrahydrofuran; XRPD X-ray powder diffraction. Unless otherwise specified, solvent mixtures are always volume/volume. 100 mg (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane- 1,1′-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by PXRD. The following Table shows the peak list for crystalline form A. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum intensity is 100. 2 θ d value Å Intensity Cps rel. I % 78 113 324 16
Figure imgf000041_0001
2 θ d value Å Intensity Cps rel. I % 25.8 3.5 505 25
Figure imgf000042_0001
Analysis—DVS Crystalline Form A was previously characterized by dynamic vapor sorption (DVS) using a Projekt Messtechnik SPS 11-100n multi sample water vapor sorption analyzer. For the DVS analysis, each sample was allowed to equilibrate at 50% r.h. (relative humidity) before starting a pre-defined humidity program during which the change in weight of the sample is determined. All measurements were performed according to the following program: 2 h at 50% r.h.; 50% r. h.→0% r.h. (10%/h); 5 h at 0% r.h.; 0→95% r.h. (5%/h); 3 h at 95% r.h.; 95→50% (10%/h), and 2 h at 50% r.h. Although hygroscopicity was measured in a slightly different manner, it was classified according to the European Pharmacopoeia as follows: very hygroscopic (vh): increase of the mass≧15%; hygroscopic (h): increase of the mass is less than 15% and equal or greater than 2%; slightly hygroscopic (sh): increase of the mass is less than 2% and equal or greater than 0.2%; not hygroscopic (nh): increase of the mass is less than 0.2%; deliquescent (d): sufficient water is absorbed to form a liquid. DVS with two cycles was performed on a sample of crystalline form A. The first cycle was not symmetric, the sample contained still water when the DVS cycle returned to 50% r.h. (relative humidity in %). The second cycle was reversible. Below 40% r.h. the relative mass returned to ˜100% (water content=0%). The hysteresis between 40% and 70% r.h. indicates a metastable zone. The second cycle indicated the following transformations: hemi- hydrate→ansolvate (<38% r. h.)→hemi-hydrate (>70% r. h.). The sample was classified to be hygroscopic (Δm=3-4% at 85% r. h.; Δm: change in mass) Example 1: A single-dose, randomized, double-blind, placebo- and active- controlled crossover trial to evaluate the abuse potential of two doses of cebranopadol in adult nondependent recreational opioid users. Investigational Medicinal Products (IMPs): Study Design: Randomized, single site, double-blind, placebo- and active-controlled, crossover, single oral dose, Phase 1 trial, in non- dependent recreational opioid users Cebranopadol film coated tablets, Oxycodone HCl tablets, Tramadol HCl tablets, and matching placebos. Objectives: Primary Objective: To evaluate the abuse potential of single doses of cebranopadol relative to oxycodone immediate-release (IR), tramadol IR, and placebo in non-dependent recreational opioid users Secondary Objectives: • To evaluate the abuse potential of oxycodone IR and tramadol IR compared with placebo • To evaluate the safety and tolerability of cebranopadol • To evaluate the pharmacokinetics (PK) of cebranopadol and active metabolites M2, M3, and M6 Study Treatments: Qualification Phase: Based on the assigned treatment sequence, each subject will be randomly allocated to receive a single oral dose of the IMP on each day of the Qualification Phase. On each day, subjects will receive after an overnight fast, a single oral dose of 6 identically appearing capsules that will contain one of the following treatments: • Oxycodone HCl tablets, 20 mg: single oral dose of 40 mg • Tramadol HCl tablets, 100 mg: single oral dose of 600 mg • Matching placebo Treatment Phase: Based on the assigned treatment sequence, each subject will be randomly allocated to receive a single oral dose of the IMP in each of the 5 periods. At each period, subjects will receive an oral single dose of 6 identically appearing capsules that will contain one of the following treatments: • Cebranopadol film coated tablets, 200 µg: single oral dose of 600 µg • Cebranopadol film coated tablets, 200 µg: single oral dose of 1000 µg. Ingredients for 200 µg film-coated Amount per tablet Function
Figure imgf000044_0001
Ingredients for 200 µg film-coated Amount per tablet Function tablet [mg] t
Figure imgf000045_0001
• Oxycodone HCl tablets, 20 mg: single oral dose of 40 mg (Positive control; Schedule II opioid). The 40 mg dose is expected to show significant abuse-related subjective effects without interfering with completion of PD measures or producing aversive effects, and although higher doses have been shown to produce higher positive effects without significant adverse effects, 40 mg is expected to be sufficient to demonstrate a difference in all endpoints between oxycodone IR and placebo. • Tramadol HCl tablets, 100 mg: single oral dose 600 mg (Positive control; Schedule IV opioid). In human laboratory studies, tramadol IR appears to have a lower abuse potential compared with other opioids (most commonly Schedule II; see Dunn et al., 2019, for systematic review7); however, the effects of tramadol IR in a human abuse potential study can vary based on route of administration and if the subject sample is physically dependent on opioids. Oral tramadol IR doses ranging between 25 mg to 700 mg have been evaluated in non- physically dependent individuals. The dose of tramadol IR in the present study (600 mg) has been selected based on variable findings of liking at doses ≤400 mg and because the 700 mg dose was shown to be safe and reasonably well tolerated in a similar subject population. [Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend.2013 Apr 1;129(1-2):116-24; Duke AN, Bigelow GE, Lanier RK, Strain EC. Discriminative stimulus effects of tramadol in humans. J Pharmacol Exp Ther.2011 Jul;338(1):255-62. Doi: 10.1124/jpet.111.181131. Epub 2011 Apr 5. PMID: 21467190; PMCID: PMC3126638; Epstein DH, Preston KL, Jasinski DR. Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol. Biol Psychol.2006 Jul;73(1):90-9. Doi: 10.1016/j.biopsycho.2006.01.010. Epub 2006 Feb 23. PMID: 16497429; PMCID: PMC2943845]. However, in those studies, subjects did not undergo a Qualification Phase to confirm that they could discriminate and like the effects of tramadol IR relative to placebo in contrast to the present trial. • Matching placebo(s) Assigned Treatment # Capsules containing # Placebo Active Treatment l *Naloxon
Figure imgf000046_0001
e w e use or t e na oxone c a enge test on ay - o t e Qua cat on ase to confirm that subjects are not physically dependent on opioids. The subcutaneous dose in the upper arm will be 0.8 mg (2.0 mL) of naloxone. Study Centers: Single center in the US Study Duration: Individual subject participation is expected to be up to ~4 months, including an Enrollment period up to 4 weeks. Sample Size: 50 adult men and women total with the intention of at least 38 completing the study and being included in the primary analysis population (Modified Completer Population). Study Population: The study will enroll healthy men and women, 18 to 55 years old, with a history of recreational opioid use defined as nontherapeutic use of opioids at least 10 times in the subject’s lifetime and at least once in the 12 weeks prior to the Enrollment Visit. Inclusion Criteria for Enrollment: 1. Willing and able to provide written informed consent 2. Adult men or women aged 18 to 55 years, inclusive 3. History of recreational opioid use defined as non-therapeutic use at least 10 times in the subject’s lifetime and at least once in the 12 weeks prior to the Enrollment Visit 4. Body mass index between 19 kg/m2 and 32 kg/m2 inclusive, with a body weight of not less than 50 kg at Enrollment 5. Subjects must be in good health as determined by medical history, physical examination, 12-lead electrocardiogram (ECG), and vital signs (pulse rate, systolic blood pressure and diastolic blood pressure, respiratory rate, and oxygen saturation using pulse oximetry) at Enrollment 6. Females who participate in this study will be of childbearing or non-childbearing potential • Childbearing potential: Physically capable of becoming pregnant • Non-childbearing potential: Permanently sterile (i.e., both ovaries removed, uterus removed, or bilateral tubal ligation for at least 6 weeks or documented successful hysteroscopic sterilization); and/or Post-menopausal (no menstrual period for at least 12 consecutive months without any other medical cause) 7. Females of childbearing potential must be non-lactating and must have a negative serum pregnancy test at Screening 8. Willing to use acceptable, effective methods of contraception 9. Male subjects must agree not to donate sperm for at least 4 weeks after the final visit 10. Be able to attend the clinic regularly and reliably 11. Be able to understand, read, write, and speak English fluently to complete the study related materials 12. Be informed of the nature of the study and give written consent prior to any study procedure Exclusion Criteria for Enrollment: 1. Self-reported history of drug or alcohol dependence (lifetime) other than caffeine or nicotine as defined by DSM-IV-TR criteria 2. Current treatment or treatment within their lifetime for substance disorders, other than treatment for smoking cessation 3. Positive or missing alcohol breath test at Enrollment; the alcohol breath test can be repeated and/or the subject rescheduled at the discretion of the investigator or designee 4. Pregnant or breastfeeding or missing pregnancy test 5. Unwillingness or inability to abstain from recreational drug use for the duration of the trial 6. Current consumption of greater than 20 cigarettes per day or inability to abstain from smoking (or use of any nicotine-containing substance) for at least 8 hours 7. Participation in another clinical trial within 30 days prior to Enrollment that resulted in the administration of at least 1 dose of IMP 8. Diseases or conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs. Subjects with a history of cholecystectomy are not excluded 9. Prolongation of QTcF (after repeated assessment) at Enrollment, i.e., >450 ms for men or >470 ms for women, or presence of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia), or use of concomitant medications that prolong the QT interval 10. History of orthostatic hypotension or other cardiovascular diseases 11. Any clinically significant disease that in the investigator’s opinion may affect efficacy or safety assessments or may compromise the subject’s safety during trial participation, e.g., significant pulmonary, gastrointestinal, cardiac, endocrine, metabolic, neurological, or psychiatric disorders 12. Definite or suspected history of drug allergy or hypersensitivity to opioids or opioid antagonists 13. Use of prescription medications within the longer of 14 days or 5 half-lives or use of over- the-counter medications within the longer of 7 days or 5 half-lives prior to dosing, exceptions may be made on a case-by-case basis (e.g., for medications with a short half-life or for topical medications) if approved by the medical monitor in agreement with the investigator 14. Any contraindication for naloxone, oxycodone IR, or tramadol IR administration 15. Not able to abstain from consumption of: • Beverages or food containing caffeine (tea, coffee, cola, chocolate, etc.) or alcohol from 2 days prior to each Day 1 until discharge from the research unit • Beverages or food containing quinine (e.g., bitter lemon, tonic water) from 1 week before Day 1 of the Qualification Phase until the final examination. • Grapefruit juice (sweet or sour) or Seville oranges from 1 week before Day 1 of the Qualification Phase until the final examination. 16. Blood loss of 500 mL or more within 4 weeks before dosing in the treatment phase in this trial, including blood donation. Planned blood donations during the trial and up to 12 weeks after the Final Examination 17. History of seizure disorder including unprovoked seizure and/or epilepsy or any condition associated with a significant risk for seizure disorder or epilepsy at the Enrollment Visit at the discretion of the investigator 18. Known or suspected of not being able to comply with the trial protocol 19. Not able to communicate meaningfully with the investigator or trial site staff 20. Employee of the investigator or trial site, with direct involvement in the proposed trial or other trials under the direction of that investigator or trial site, as well as family members of the employees or the investigator 21. Considered by the Investigator not to be suitable for the study for any other reason Exclusion Criteria for Day 1 (Qualification Phase): 1. Positive naloxone challenge on Day −1 of the Qualification Phase 2. Use of forbidden medication since the Enrollment Visit (within 7 days for OTC, 14 days for prescription) 3. Positive or missing pregnancy test 4. Positive or missing alcohol breath test; alcohol breath test may be repeated or rescheduled at the discretion of the investigator or designee 5. Positive or missing urine drug of abuse screen result, except for cannabinoids (tetrahydrocannabinol [THC]) 6. Positive or missing viral serology, i.e., human immunodeficiency virus Type 1 and Type 2 antibodies and antigen, hepatitis B surface antigens, anti-HBc and IgM anti-HBc, and hepatitis C virus antibodies, based on sample taken at the Enrollment Visit 7. Any abnormal laboratory values or any clinically relevant out-of-range values for safety laboratory parameters (clinical chemistry, coagulation, hematology, and urinalysis) based on sample taken at the Enrollment Visit, as judged by the investigator 8. Blood donation or acute loss of blood (more than 100 mL) since the Enrollment excluding blood samples required by the protocol 9. Any relevant deterioration in the health of the subject that could alter the benefit/risk assessment for the subject, including adverse events (AEs), laboratory parameters, vital signs, or other safety parameters (e.g., ECGs) 10. Failure to comply with trial requirements, e.g., intake of forbidden medications, consumption of alcohol, considered by the investigator to affect subject safety or interfere with the integrity of the trial 11. Uncooperative subjects or subjects who refused to continue in the trial 12. Withdrawal of informed consent 13. Any contraindication for naloxone, oxycodone IR, or tramadol IR administration. Discontinuation Criteria Following Qualification and Prior to Treatment Phase: 1. Failure to successfully fulfill any of the following criteria based on the qualification phase prior to the first treatment period (Treatment Period 1, Day −1): • Peak score in response to oxycodone IR and tramadol IR is numerically greater than that of placebo on “at the moment” Drug Liking VAS (difference of at least 15 points), with a minimum score of 65 points. • Acceptable placebo response based on Drug Liking VAS, defined as a peak score between 40 and 60 points (a score that is considered neutral on the scale as neither like nor dislike), inclusive • Acceptable overall responses to oxycodone IR 40 mg, tramadol IR 600 mg, and placebo on the subjective measures, as judged by the investigator or designee and sponsor • The ability to tolerate oxycodone IR and tramadol IR, as judged by the investigator based on available safety data (e.g., respiratory rate ≥8 breaths/min and no vomiting within 4 hours after dosing) • General behavior suggestive that they could successfully complete the trial, as judged by the investigator 2. Positive or missing alcohol breath test; alcohol breath test may be repeated or rescheduled at the discretion of the investigator or designee 3. If a subject tests positive for other drugs of abuse, except for cannabinoids (THC), the urine drug screen can be repeated and/or the subject rescheduled at the discretion of the investigator or designee Methodology: The study comprises the Enrollment Visit, a Qualification Phase, a Treatment Phase consisting of 5 treatment periods, and an End of Study Visit. See Section 1.2 for a tabular schedule of events for the Qualification Phase and Section 1.3 for the Treatment Phase (which lists all assessments planned). • Enrollment Visit Enrollment will begin no more than 28 days prior to the first dose of study medication. After completing the informed consent process and signing the informed consent form, subjects will undergo study-specific Enrollment procedures. A physical examination, including measurement of height, weight, and vital signs; blood and urine laboratory testing; review of medical and medication history; a 12-lead ECG will be performed, as well as the Columbia- Suicide Severity Rating Scale (C-SSRS) and an assessment of current substance dependence (DSM-IV-TR). • Naloxone Challenge: Subjects will check-in on Day −1 of the Qualification Phase following the return of a negative urine drug screen test, excluding THC. Subjects with a positive urine drug screen test for opioids will be screen failed and dismissed from the research clinic. Subjects who remain in the clinic on Day −1 will undergo a naloxone challenge test to exclude the possibility of physical dependence on opioids. The Objective Opioid Withdrawal Scale (OOWS) will be used to record any signs or symptoms of withdrawal observed during the naloxone challenge test. • Qualification Phase Each subject will attend a double-blind Qualification Phase consisting of a 4-night confinement period during which they will receive, after an overnight fast, a single oral dose of 6 identically appearing capsules that will contain one of the following: oxycodone IR 40 mg, tramadol IR 600 mg, or placebo in a randomized crossover manner separated by ~24 hours. Pharmacodynamic and safety assessments will be performed from pre-dose through 8 hours after each IMP administration. The purpose of the Qualification Phase is to ensure that the subjects can discriminate between active drug and placebo, can tolerate oxycodone IR 40 mg and tramadol IR 600 mg, can feel comfortable with the pharmacodynamic measures, can follow directions, and are cooperative. Subjects will be confined to the trial site from Day −1 until 72 hours after the first IMP administration in the Qualification Phase. • Treatment Phase There will be a washout period of at least 72 hours between the end of the Qualification Phase and the beginning of the first treatment period. Based on the assigned treatment sequence, each subject will be randomly allocated to receive a single oral dose of 6 identically appearing capsules in each of the 5 periods. Each IMP administration will be given under fasted conditions and will be separated by a washout period of at least 14 days between treatments. Subjects will be confined to the trial site from Day −1 until 48 hours after IMP administration in each of the treatment periods. Pharmacodynamic, safety and pharmacokinetic (PK; blood sampling) assessments will be performed from pre-dose through 48 hours post-dose in each treatment period. An End of Study Visit will be conducted at 5-10 days after discharge from the last treatment period or upon early discontinuation from the trial. • Concomitant medications No concomitant medication (including prescription drugs, over-the-counter drugs, and herbal remedies like St. John’s wort) will be allowed during the trial, with the exception of acetaminophen (e.g., for headache), and the continuous use of hormonal contraceptives. Data Collection and Assessment: Demographics and other subject characteristics: Demographic data will comprise sex, age, height, weight, race/ethnicity, and the use of nicotine products. Body mass index will be calculated. Other subject characteristics will comprise medical history (medical history and surgical interventions), recreational drug and alcohol use history, prior and concomitant medications. Pharmacodynamics: Primary Measure: • Visual analog scale (VAS) rating for Drug Liking “at this moment” Key Secondary Measures: • VAS rating for Overall Drug Liking • VAS rating for Take Drug Again Other Secondary measures: • VAS rating for Any Drug Effects, High, Good Drug Effects, Bad Drug Effects, Feeling Sick, Alertness/Drowsiness, Floating, and Detached. • VAS rating for Drug Similarity • Pupillometry • Multi-Task Test Pharmacokinetics Plasma concentrations of cebranopadol and active metabolites M2, M3, and M6, oxycodone IR and tramadol IR will be assayed. Descriptive PK parameters will be derived from plasma concentration-time data using noncompartmental methods: Cmax , Tmax , AUC0-t, and AUCinf. A separate PK report will be generated. Pharmacokinetic Parameters to be calculated from Plasma Concentration- time Data Parameter Description o m
Figure imgf000053_0001
Cmax Maximum observed concentration. Tmax Time to attain maximum concentration.
Figure imgf000054_0001
the first quantifiable concentration) will be excluded from the PK analysis and descriptive statistics will only be determined if at least 75% of the observations at each sampling point have quantifiable results. If a pre-dose concentration is above the assay quantification limit and lower than 5% of Cmax, it will be set to zero in the PK analysis. Subjects with higher pre-dose values will be excluded from the PK analysis. Areas under the curves will be calculated using the log-linear trapezoidal rule, i.e., linear up to the maximum concentration and log thereafter. The individual concentrations will be listed for each measurement time point and for each period and analyzed descriptively. Tabulated values will be rounded to 3 significant figures. Statistical calculations will be performed with values that have not been rounded. Mean, individual, and overlay concentration-time profiles will be plotted on both linear and semi-logarithmic scales on the same, portrait-oriented page. Safety Safety data will comprise physical examinations, oral body temperature, vital signs (pulse rate, systolic blood pressure, diastolic blood pressure, respiratory rate, and oxygen saturation using pulse oximetry), 12-lead ECG, adverse events (AEs), telemetric safety monitoring (5-lead ECG, oxygen saturation, and pulse rate), C-SSRS, safety laboratory parameters (clinical chemistry, coagulation, hematology, and urinalysis), and pregnancy test (females of childbearing potential only). Statistical Methods: Analysis populations Qualification Safety Population: All subjects who receive at least one dose of study drug in the Qualification Phase. All safety evaluations in the Qualification Phase will be performed using this population. Randomized Population: All subjects who are assigned a randomization number in the Treatment Phase. Safety Population: All subjects who receive at least one dose of study drug in the Treatment Phase. All safety evaluations in the Treatment Phase will be performed using this Safety Population. Completer Population: All randomized subjects who complete all treatment periods of the Treatment Phase and have at least one response on the VAS for Drug Liking within 2 hours of Tmax for each treatment or, in the case of placebo, at least one response on the VAS for Drug Liking. If Tmax is missing or inestimable for a given subject/treatment (other than placebo), the median Tmax for that treatment for subjects in the Completer Population with non-missing Tmax will be used for this determination. Modified Completer Population: All subjects in the Completer Population, excluding subjects with similar Emax scores (within 5 points difference) across all study treatments (including placebo) or subjects with an Emax for placebo >60 AND the difference between Emax for placebo and oxycodone IR is ≤5. This population will serve as the primary population for the PD analyses. Pharmacokinetic Population: All subjects who receive at least one dose of IMP and have at least one measurable PK sample after dosing. All PK evaluations in the Treatment Phase will be performed using the PK Population. Pharmacodynamic analyses All analyses will be performed using the Modified Completer Population. If the Modified Completer Population and Completer Population differ by more than 10%, Drug Liking Visual Analog Scale (VAS) is analyzed and reported for the Completer Population. The following summary parameters will be calculated for all assessments except for pupillometry and Overall Drug Liking, Take Drug Again, and Drug Similarity VAS: • Peak effect (Emax and/or Emin) • Time of peak effect (TEmax and/or TEmin) • Area under the effect curve to 1 hour (AUE0-1h) • Area under the effect curve to 8 hours (AUE0-8h) For Overall Drug Liking and Take Drug Again VAS, Emax and Emin will be calculated. For Drug Similarity VAS, a descriptive analysis will be conducted. For pupillometry, the following summary parameters will be calculated: • Maximum pupil constriction (MPC) • Time of MPC (TMPC) • Pupillometry area over the effect curve to 1 hour (PAOC0-1h) • Pupillometry area over the effect curve to 8 hours (PAOC0-8h) The primary endpoint will be Drug Liking VAS Emax and the key secondary endpoints will be Overall Drug Liking VAS Emax and Take Drug Again VAS Emax. Primary Endpoint Analysis: Drug Liking VAS Emax The primary PD endpoint (Drug Liking VAS Emax) will be evaluated with a linear mixed effects model containing treatment, period, sequence, and first-order carryover as fixed effects and subject nested within sequence as random effect, using the Modified Completer Population. A supportive analysis of the primary endpoint may be performed using the Completer Population if this population differs from that of the Completer Population by more than 10%. This supportive analysis will utilize the same hypotheses as that of the primary analysis. The first order carryover effect will be the previous treatment received in the Treatment Phase. If the carryover effect is found to be non-significant at the 25% level, then the term will be dropped from the model. If the carryover effect is significant at the 25% level, but not at the 5% level, then the carryover effect term will be retained in the model; if the carryover effect is significant at the 5% level, a first period analysis will be conducted. From the model, least squares means, and confidence intervals (CIs) will be provided for each treatment, and difference in least squares mean, CIs of the difference, and p-values will be provided for each treatment comparison. Unless otherwise indicated, CIs will be 2-sided at the 90% level, p-values will be 1-sided, and significance testing will be performed at 1-sided significance level 0.05. Levene’s test will be used to evaluate potential heterogeneity of variance in the model with a one-way analysis of variance (ANOVA), including residuals as the response and treatment as a fixed effect. If the p-value is not significant at the 0.05 level, the mixed model with equal variances will be performed. If the p-value of the Levene’s test is ≤0.05, it will be concluded that there is a difference in variance among treatments, and the model will be corrected by estimating the variances for treatment separately (unequal variance model using the Satterthwaite method and repeated statement). The residuals from the mixed-effects model will be investigated for normality using the Shapiro-Wilk W test. Parameters will be analyzed under the assumption of a normal distribution of errors if the p-value of the test is ≥0.01, and the mixed effects model will be used for reporting for the final analysis. If the p-value is <0.01 for the Shapiro Wilk W test on the residuals from the mixed model, a test of skewness will be conducted on each paired difference. If the distribution of the paired differences is not skewed (-0.5< skewness value <0.5), then Drug Liking Emax will be analyzed using paired t-tests for each treatment comparison. If the distribution of the paired differences is skewed (skewness value < -0.5 or skewness value >0.5), then Drug Liking Emax will be analyzed non-parametrically. The Sign Test will be used to evaluate treatment differences. If a paired t-test is chosen for Drug Liking Emax, means, mean differences and corresponding one- sided 95% CIs, as well as p-values for the appropriate hypothesis will be presented. If a Sign Test is chosen, medians from each treatment as well as medians, and first and third quartiles of the differences between treatments, and corresponding Sign Test p-values will be provided for each treatment comparison. The overall treatment effect will be assessed using Friedman’s test. If a first period analysis is conducted, Drug Liking VAS Emax will be analyzed using an ANOVA model containing treatment group as the fixed effect. Least squares means and 95% CIs will be provided for each treatment, and difference in least squares mean, one-sided 95% CIs of the difference, and p-values will be provided for each treatment comparison subject to a hypothesis test. The comparisons of interest are as follows: • Cebranopadol vs. placebo • Cebranopadol vs. oxycodone IR • Cebranopadol vs. tramadol IR • Oxycodone IR vs. placebo (study validity) • Tramadol IR vs. placebo For study validity, the primary endpoint, Drug Liking Emax, will be compared between oxycodone IR (primary positive control) and placebo, the following hypothesis will be tested: Ho: µC1 - µP ≤ 15 vs. Ha: µC1 - µP > 15 (1) where µC1 is the mean for oxycodone IR and µP is mean for placebo. The margin of 15 was selected based on previous studies of this type. Pathak S, Vince B, Kelsh D, et al. Abuse potential of samidorphan: A Phase I, Oxycodone -, pentazocine-, naltrexone-, and placebo-controlled study. J Clin Pharmacol.2019 Feb;59(2):218-228; Setnik B, Roland CL, Cleveland JM, Webster L. The abuse potential of Remoxy®, an extended-release formulation of Oxycodone, compared with immediate- and extended-release Oxycodone. Pain Med.2011 Apr;12(4):618-31]. If the treatment difference of oxycodone IR compared with placebo is statistically significant at alpha level 0.05, validity is established for the study. The evaluation of abuse potential of tramadol IR (secondary positive control) will be the comparison of tramadol IR versus placebo. Despite an absence of published literature on liking of tramadol IR (using a bipolar VAS among qualified recreational drug users), a margin of 15 has been selected. The following hypothesis will be tested for tramadol IR compared with placebo: Ho: µC2 - µP ≤ 15 vs. Ha: µC2 - µP > 15 (2) where µC2 is the mean for tramadol IR and µP is mean for placebo. If tramadol IR fails the validation test, results of all pairwise comparisons with tramadol IR from the model will be considered descriptive. Failure of tramadol IR to separate from placebo will not impact subsequent tests between oxycodone IR, cebranopadol and placebo. The primary treatment comparison for relative abuse potential of cebranopadol will be the comparison of Drug Liking Emax between cebranopadol at each dose level and oxycodone IR. The following hypothesis will be tested for each comparison of cebranopadol and oxycodone IR: • Cebranopadol 600 µg vs. oxycodone IR 40 mg • Cebranopadol 1000 µg vs. oxycodone IR 40 mg Ho : µC1 - µT ≤ 0 vs. Ha : µC1 - µT > 0 (3) where µC1 is the mean for oxycodone IR and µT is mean for cebranopadol. The secondary treatment comparisons for relative abuse potential of cebranopadol will be the comparison of cebranopadol at each dose level versus tramadol IR. For each comparison, the following hypothesis will be tested: • Cebranopadol 600 µg vs. tramadol IR 600 mg • Cebranopadol 1000 µg vs. tramadol IR 600 mg Ho : µC2 - µT ≤ 0 vs. Ha : µC2 - µT > 0 (4) where µC2 is the mean for tramadol IR and µT is mean for cebranopadol. The evaluation of absolute abuse potential of cebranopadol will be the comparison of cebranopadol versus placebo. The following hypothesis will be tested: • Cebranopadol 600 µg vs. placebo • Cebranopadol 1000 µg vs. placebo Ho : µT - µP ≥ 11 vs. Ha : µT - µP < 11 (5) where µT is the mean for cebranopadol and µP is mean for placebo. A significance level of 0.05 will be used for all 1-sided tests. As the hypotheses will be tested sequentially and must be met at all dose levels, no adjustments in p-values will be made to account for multiple comparisons. See, results in FIGS 35A and 35B Oxycodone 40 mg and tramadol 600 mg had statistically significantly higher Overall Drug Liking VAS and Take Drug Again VAS Emax values compared with placebo (both p<0.0001). Each dose of cebranopadol had statistically significantly lower Overall Drug Liking VAS and Take Drug Again VAS Emax values compared with oxycodone 40 mg (all p<0.01). Each dose of cebranopadol had statistically significantly lower Take Drug Again VAS Emax values compared with tramadol 600 mg (both p<0.05). Similarly, Overall Drug Liking VAS Emax for cebranopadol 600 μg was significantly lower compared with tramadol 600 mg; however, the difference between cebranopadol 1000 μg and tramadol 600 mg was not statistically significant. Overall Drug Liking VAS and Take Drug Again VAS Emax were significantly higher for cebranopadol 1000 μg compared with placebo, whereas cebranopadol 600 μg differed from placebo on Overall Drug Liking VAS, but not Take Drug Again VAS. Key Secondary and Other Secondary Endpoint Analysis: All secondary PD endpoints, including the key secondary endpoints, are analyzed with the same approach as described above for the primary endpoint analysis, using the Modified Completer Population. From the model, least squares means, and CIs are provided for each treatment. Difference in least squares means and 2-sided 90% CIs for the difference is provided for each of the 5 treatment comparisons: oxycodone IR versus placebo, tramadol IR versus placebo, cebranopadol versus oxycodone IR, cebranopadol versus tramadol IR, and cebranopadol versus placebo. Comparisons among treatments for secondary endpoints is evaluated at 1-sided significance level of 0.05 using the hypotheses shown below. No specific margins have been selected for secondary endpoints as there is currently no scientific literature to support selection of such margins. 1. Primary positive control (oxycodone)) (C1) vs. placebo (P): H0: µC1 - µP ≤ 0 vs. Ha: µC1 - µP > 0 2. Secondary positive control (tramadol IR) (C2) vs. placebo (P): H0: µC2 - µP ≤ 0 vs. Ha: µC2- µP > 0 3. Primary positive control (oxycodone) (C1) vs. each dose of cebranopadol (T): H0 : µC1 - µT ≤ 0 vs. Ha : µC1 - µT > 0 4. Secondary positive control (tramadol IR) (C2) vs. each dose of cebranopadol (T): H0 : µC2 - µT ≤ 0 vs. Ha : µC2 - µT > 0 The direction of the hypotheses may be reversed for some endpoints (e.g., Emin for Alertness/Drowsiness). Comparisons for secondary endpoints between cebranopadol and placebo will be evaluated from 2-sided 90% CIs (α=0.10) using the confirmatory type of hypothesis as shown below: 5. Each dose of cebranopadol (T) vs. placebo (P): H0: μT –μP = 0 vs. Ha: μT – μP ≠ 0 No adjustments for p-values will be made to account for multiple comparisons in the analysis of secondary endpoints. Pharmacokinetic/ pharmacodynamic modeling and simulations Methods and results of the pharmacokinetic/pharmacodynamic modeling and simulation analyses will be provided in separate report(s). Safety analyses: All analyses will be performed using the Safety Population. All safety data will be analyzed as described in the section general descriptive and graphical methods. Potentially clinically significant values will be defined for various parameters, and the results will be summarized in tables. Additional details will be provided in the statistical analysis plan. All AEs will be listed together with information on onset, duration, frequency, intensity, seriousness, expectedness, relationship, outcome, and countermeasures taken. This study used a randomized, double-blind, five-way crossover design to evaluate the abuse potential of cebranopadol in adult nondependent recreational opioid users versus placebo, oxycodone, and tramadol. Eligible subjects underwent a naloxone challenge to confirm nondependence to opioids, and a qualification phase to assess that subjects could tolerate oxycodone and tramadol and discriminate their effects from placebo. Qualified subjects underwent a ≥72-hour washout before receiving study drug in the Treatment Phase. Subjects were randomized to receive single doses of cebranopadol 600µg or 1000µg, oxycodone IR 40mg, tramadol IR 600mg, or placebo in a crossover manner. Each treatment period was separated by a ≥14-day washout period to prevent carryover effects. The primary endpoint was maximum drug liking “at this moment” measured using a bipolar 100-point Visual Analog Scale (VAS). Key secondary measures included “overall drug liking” and “take drug again” measured by VAS. Results: Thirty-eight subjects completed the study, and 33 met criteria for inclusion in the Modified Completers population (pharmacodynamic analysis). For the primary endpoint of maximum drug liking “at this moment,” both cebranopadol 600μg and 1000μg were liked significantly less than tramadol 600mg (17.34; 95%CI[10.99,23.70] and 7.77; [1.51,14.03], respectively) and oxycodone 40mg (24.43; [18.34,30.52] and 14.86; [8.80,20.91], respectively). Results of the key secondary endpoints “overall drug liking” and “take drug again” were generally consistent with the primary endpoint. Neither dose of cebranopadol raised safety concerns, but two subjects experienced seizures after receiving tramadol. The most commonly reported adverse event was nausea. Selected Descriptive Statistics of Overall Drug Liking VAS and Take Drug Again VAS Emax (Modified Completer Population) l ) )
Figure imgf000062_0001
”
Figure imgf000062_0003
Inferential Analysis Results for Overall Drug Liking VAS and Take Drug Again VAS Emax M difid C l P l i e 1
Figure imgf000062_0002
Inferential Analysis Results for Overall Drug Liking VAS and Take Drug Again VAS Emax (Modified Completer Population) 1 1 6 7 0 8 1 og
Figure imgf000063_0001
Note: Validation of primary positive control: Ho: µC1 – µP ≤ 0 vs. Ha: µC1 – µP > 0; 1-sided test (α=0.05). Validation of secondary positive control: Ho: µC2 – µP ≤ 0 vs. Ha: µC2 – µP > 0; 1-sided test (α=0.05). Relative abuse potential: Ho: µC1 – µT ≤ 0 vs. Ha: µC1 – µT > 0 and Ho: µC2 – µT ≤ 0 vs. Ha: µC2 – µT > 0; 1-sided tests (α=0.05). Absolute abuse potential: Ho: µT – µP=0 vs. Ha: µT – µP ≠ 0; 2-sided test (α=0.10). Where µC1 is the mean for oxycodone; µC2 is the mean for tramadol; µP is the mean for placebo; and µT is the mean for cebranopadol. Bolded p-values are statistically significant. Conclusions: This study demonstrated that cebranopadol has significantly lower abuse potential compared to both Schedule II (oxycodone) and Schedule IV (tramadol) opioids. This study confirms what has previously been established while furthering the understanding of the abuse potential of cebranopadol. Cebranopadol may serve as a much-needed alternative treatment option for patients with moderate to severe pain. Unlike after treatment with oxycodone and tramadol, administration of cebranopadol did not produce pruritus, hyperhidrosis, feeling hot and/or hot flushing, that have been associated with the use of opioid analgesics. Specifically, when the incidence of subjects experiencing pruritis was analyzed, treatment with cebranopadol 600 µg and 1000 µg resulted in only 6.7% (n=3) and 7% (n=3) verses 29.5% (n=13) after having taken oxycodone 40 mg and 25.6% (n=10) after having taken tramadol 600 mg. A similar trend in frequency was observed for the AE hyperhidrosis; no subjects experienced the AE after taking either dose of cebranopadol verses 11.4% (n=5) after taking oxycodone and 12.8% (n=5) after tramadol. Moreover, a single subject reported feeling hot after receiving oxycodone (2.3%) and tramadol (2.5%). Finally, while none of the subjects experience hot flush after taking 1000 µg of cebranopadol, only a single subject (2.2%) experienced hot flush after cebranopadol 600 µg compared to 11.4% (n=5) after taking oxycodone and 12.8% (n=5) after taking tramadol. System Organ Placebo Cebranopad Cebranopadol Oxycodone Tramadol Total Class (N=45) ol 1000 HCl HCl (N=47) %) %) %) %) )
Figure imgf000064_0001
System Organ Placebo Cebranopad Cebranopadol Oxycodone Tramadol Total Class (N=45) ol 1000 µg HCl HCl (N=47) %) %) ) ) %) %) )
Figure imgf000065_0001
Example 2: Alternative Cebranopadol Compositions Cebranopadol was dissolved in solvent at 80°C. The carrier material was added portion wise (0.05 g) at 80°C until the mixture was a free flowing homogenous powder. The composition was allowed to cool to room temperature (23°C). The employed amounts and the resulting solid state of the formulations are specified in the following Table. Compound Solvent Cebranopadol Solvent Carrier Carrier [mg] ,no. [ml] [mg]
Figure imgf000066_0001
Example 3: Evaluation of Cebranopadol as a method of treatment for Opioid Use Disorder (OUD). Development of nociceptin/orphanin FQ (N/OFQ) (NOP) receptor agonists and dual MOP/NOP receptor agonists has been the focus of many programs but to date, none have succeeded in clinical development and reached regulatory approval. The overall goal of the current phase of this study is to establish the safety and abuse potential profile of cebranopadol, and to demonstrate the therapeutic efficacy of cebranopadol in decreasing opioid use with low risk of withdrawal signs and symptoms when transitioning. Dosage Form, Route of Administration and Dosing Regimen The test products are film coated tablets and the dosage strengths are 100 µg, 200 µg, and 400 µg. The dosage regimen is determined by conducting the studies discussed in the clinical development plan, as described herein. The preliminary data, preclinical and clinical summary as described below, have provided strong proof of concept for the development of cebranopadol as a novel and safe agent to treat OUD. Preclinical Summary Pharmacodynamics Cebranopadol is highly effective in animal models of acute pain (approximately equi- potent to the strong opioid fentanyl), visceral, inflammatory, chronic mono- and poly-neuropathic and bone cancer pain. The analgesic potency of cebranopadol is ~10 to 100 times higher in neuropathic pain than in acute pain, whereas the classical opioids generally have the same analgesic potency in both pain states. Activation of both NOP and classical opioid receptors contributed to antihypersensitive efficacy of cebranopadol in rodent models of chronic neuropathic and chronic inflammatory pain. Isobolographic analysis revealed that NOP and classical opioid receptor agonistic components of cebranopadol interacted synergistically to produce anti-allodynic activity in neuropathic pain. In acute pain in rodents, only MOP receptor activation contributed to the antinociceptive effect of cebranopadol, whereas in acute pain in non- human primates, both NOP and MOP receptors contributed to antinociception. In rats, cebranopadol has a long (oral [PO] >9 hours) duration of action. Safety Pharmacology In safety pharmacology studies in rodents, cebranopadol induced only moderate opioid- typical central nervous system (CNS) effects at doses within and exceeding the antinociceptive dose range and did not exhibit pro-convulsant activity. Cebranopadol induced moderate bradycardia in conscious rabbits and dogs and had a hypertensive effect at high doses in conscious dogs. In vitro studies indicate a very low potential of cebranopadol and its main metabolites 7-hydroxy cebranopadol (7-OH-cebranopadol) (M2), N-desmethyl cebranopadol (NdM-cebranopadol) (M3), and 7-hydroxy-N-desmethyl cebranopadol (7-OH-NdM- cebranopadol) (M6) for delaying cardiac repolarization and conduction up to the limit of solubility. At high in vivo doses, a moderate increase in heart rate corrected QT time (QTc), a prolongation of cardiac depolarization and/or a moderate delay of atrioventricular conduction was observed in dogs and rabbits. In dogs, the increase of QTc was demonstrated to be correlated to a pronounced reduction of body temperature and was absent if QTc was corrected for changes in body temperature. In antagonism studies, cebranopadol induced electrocardiogram (ECG) changes could be fully antagonized by naloxone or naltrexone and are, thus, attributable to a MOP receptor mediated mechanism. Cebranopadol induced MOP receptor-typical respiratory depression in rats only at high antinociceptive doses. Respiratory depressant effects were markedly lower than those of quiantinociceptive doses of oxycodone. Inhibition of gastrointestinal transit in rats in the antinociceptive dose range for acute pain and dose-dependent anti-diarrheal activity in mice were comparable to effects observed with equi-antinociceptive doses of morphine. Cebranopadol induced slight emesis in ferrets. Dose-dependent anti-diuretic and anti-saluretic effects were observed in rats with saline overload. A tendency to urinary retention was observed at doses within and exceeding the antinociceptive dose range. Pharmacokinetics Cebranopadol is completely absorbed and extensively distributed after oral administration. Mean oral bioavailability ranged from <10% (rabbit, Cynomolgus monkey, minipig) to ~13% (rats) and ≥44% (mouse) to >90% (dog). An almost proportional dose dependency of exposure after repeated PO and IV administrations of cebranopadol was demonstrated for mice, rats, and dogs. There was no indication of time-dependent pharmacokinetics. Apparent distribution volumes were high and variable (~3 L/kg to ~18 L/kg) across the investigated species. Cebranopadol crossed the blood-brain barrier and rapidly distributed between plasma and brain. It also crossed the placental barrier and bound to melanin. Protein binding in mouse, rat, dog, and human plasma was high (>99.8%). In human plasma, ~26% of cebranopadol is bound to 1-acid glycoprotein and ~70% to serum albumin. No evidence of transporter interaction was found for cebranopadol. Cebranopadol has a rather complex metabolism, leading to a broad spectrum of phase 1 and phase 2 metabolites. Different cytochrome P450 (CYP) enzymes (2C9, 2C19, 2D6, and 3A4) are involved and at least 5 different primary metabolic pathways of cebranopadol were identified (mainly hydroxylation and demethylation), followed by a wide variety of conjugation reactions (sulfate-, glucuronide-, glutathione- and cysteine-conjugates). No evidence for any disproportional or unique human metabolites was found so far in vitro and in vivo. There was no evidence for relevant inhibition or induction of human CYP enzymes by cebranopadol. Disposition half-lives after IV administration ranged between 2.2 hours and 43 hours across the investigated species. Excretion of radioactivity in mice, rats and dogs occurred predominantly via feces. Toxicology In single-dose toxicity studies in rats and mice (IV and PO), cebranopadol induced clinical opioid-typical signs (e.g., increased activity or hypoactivity, stiffness, straub-tail, and dyspnea) that could be antagonized by naloxone. In repeat-dose toxicity studies in mice (up to 13 weeks PO), rats (4 weeks IV and up to 26 weeks PO), dogs (4 weeks IV and up to 39 weeks PO), and minipigs (2 weeks IV), behavioral disorders (e.g., reduced locomotor activity, aggressive behavior [rats], sedation, and stiffness), and vomiting (dogs) were observed that are attributed to exaggerated pharmacodynamic (opioid agonistic) effects of cebranopadol. A 13-week oral repeat-dose toxicity study in the Wistar rat revealed a dose-dependent reduction in organ weight in the seminal vesicles, prostate and ovary. Histopathological changes were seen in the testis, epididymis, seminal vesicle, prostate and ovary. However, there was no evidence of an alteration in acinar architecture, associated inflammation, or degenerative processes in these organs. The findings were associated with severely reduced body weights and body weight gain compared with controls. These changes in the accessory sex organs (ASOs) of the rat can be ascribed to a general effect on feeding, body weight gain, debilitation and stress in a very sensitive animal species, i.e., a secondary non-specific effect. Therefore, the effects are considered not to be the result of a specific or direct effect on the reproductive system and its hormonal control mechanisms. In mice and dogs, no treatment-related findings in the ASOs were observed at much higher systemic exposures (10- to 20-fold). After multiple PO dosing up to 13 weeks in Sprague Dawley rats, renal findings were observed that are likely due to urinary retention (a known effect of MOP receptor agonists, resulting from pharmacologic effects on the smooth muscle tone in the urinary bladder, ureter, and external sphincter via opioid receptors) and do not constitute a nephropathy similar to that observed with analgesics (e.g., non-steroidal anti-inflammatory drugs). After 26 weeks multiple PO dosing in Sprague Dawley rats, no histopathological changes occurred in the urinary tract due to a potential development of tolerance to the secondary pharmacological effects via opioid receptors. In addition, the Sprague Dawley rat strain seems more susceptible to this effect since Wistar rats did not show any urinary findings under the same study conditions. In mice, dogs, and minipigs, no treatment-related findings in the urinary tract were observed. Cebranopadol does not pose a genotoxic or phototoxic risk to humans. No effects on mating or fertility in rats and no teratogenic potential in rats and rabbits were detected after PO administration of cebranopadol. In pregnant rats, dose-dependent maternal toxicity was observed without embryotoxic effects. In rabbits, marked maternal toxicity was associated with embryo-fetal toxicity. Cebranopadol did not induce developmental toxicities at doses free of maternal toxicity. Cebranopadol was locally well tolerated and showed no skin sensitizing potential. Cebranopadol induced only minor and NOP receptor-independent opioid-like withdrawal symptoms in mice compared with equi-antinociceptive doses of morphine. In rats, spontaneous or naloxone-precipitated withdrawal from cebranopadol did not result in typical opioid-like withdrawal symptoms. Development of physical dependence was detected in Rhesus monkeys at a dose producing clearly supra-maximal antinociception. In rats, cebranopadol produced a conditioned place preference and a morphine-like discriminative stimulus effect with a full generalization to the morphine cue. The morphine-like cue of cebranopadol was antagonized by naloxone and enhanced by the NOP receptor antagonist J-113397. Further evidence for a contribution of MOP and NOP receptor activity, but not DOP and KOP receptor activity, to the discriminative stimulus effect of cebranopadol was obtained in mechanistic studies using selective agonists and antagonists in generalization tests in animals trained on a cebranopadol cue. Tolerance development to the analgesic effect after repeated administrations was remarkably slower for cebranopadol compared with morphine in neuropathic pain. Clinical Summary Pharmacodynamics The pharmacodynamic effects of cebranopadol increased with ascending doses as assessed using pupillometry and the cold pressor test. The effect of cebranopadol on the pupil diameter developed slowly with a maximum effect at 4 hours to 8 hours after administration of a single dose of cebranopadol. These results indicate an effect of cebranopadol on the MOP receptor. After the administration of cebranopadol, the pain threshold and pain tolerance values in a pain test using transcutaneous electrical stimulation showed a slow and long-lasting increase. The extent of the pharmacodynamic effects (i.e., pupillometry, cold pressor, pain test using transcutaneous electrical stimulation) mirrored the cebranopadol plasma concentration-time profile. The effect of cebranopadol on ventilation was assessed in a single (cebranopadol 600 µg) and a multiple dose trial (up to daily doses of cebranopadol 1600 µg). Both trials showed a trend for a decrease in minute ventilation in the cebranopadol groups caused by a reduction in tidal volume, but not by reduction in respiratory rate as could be expected for classical opioids. This effect appeared to level off with increasing doses and time. The abuse potential of cebranopadol was assessed in a single dose trial comparing cebranopadol 200 µg, 400 µg, and 800 µg with placebo and with hydromorphone 8 mg and 16 mg. Cebranopadol showed statistically significant differences from placebo only at the high dose level (800 μg). No significant subjective effects were observed with cebranopadol 200 μg, whereas only few effects were seen with the cebranopadol 400 μg dose. These results suggest that cebranopadol may have some abuse potential at higher doses, but the abuse potential is limited at the lower doses. All cebranopadol doses had significantly lower effects than hydromorphone immediate release (IR) 16 mg on the Drug Liking visual analog scale (VAS) (at this moment) and these effects occurred later. The abuse potential of hydromorphone and cebranopadol therefore appears to be different. The results of an initial thorough QT trial were inconclusive regarding the pro-arrhythmic potential of cebranopadol according to the Guidance for Industry E14 “Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs” (ICH E14; United States [US] Department of Health and Human Services, Oct 2015). Results of a follow-up thorough QT trial showed a significant effect of cebranopadol on cardiac repolarization at 1600 μg, no effect at 400 μg, and mixed results for the 600 μg and 900 μg dose groups. No other important electrocardiographic effects were observed. Pharmacokinetics In clinical trials with single and multiple oral dosing, plasma concentrations of cebranopadol peaked at ~5 hours post-dose, systemic exposure to cebranopadol increased dose proportionally. The estimated mean operational half-life for cebranopadol (considered to be the relevant parameter for describing the multiple dose pharmacokinetics of longer half-life drugs) was ~24 hours. In line with this observation, an accumulation factor of ~2 was confirmed at steady state conditions after multiple once daily dosing in healthy subjects and subjects with various medical conditions (e.g., cLBP). The mean terminal phase half-life (t1/2,z) ranged from 61.7 hours to 95.8 hours (this half-life is considered to be relevant for the calculation of washout periods after cessation of dosing). The intrinsic pharmacokinetic properties of cebranopadol (the combination of late time to maximum concentration [tmax], broad concentration plateau around maximum concentration [Cmax] and long half-life) allow a once daily administration. The data currently available do not indicate any clinically relevant gender or food effect on systemic exposure to cebranopadol. After a single oral administration of radiolabeled cebranopadol, cumulative excretion was ~71% after 31 days. The majority of the radioactivity was recovered in the feces, with a median recovery of 54% (range: 27% to 77%) in feces, and 17% (range: 8% to 27%) in urine. No radioactivity was recovered in exhaled air. The volume of distribution was high (mean ± standard deviation [SD]: 1832 ± 467 L), and clearance was moderate to high (mean ± SD: 50.4 ± 10.4 L/h). After oral administration of radiolabeled cebranopadol, extensive metabolism of cebranopadol via hydroxylation, demethylation and subsequent secondary conjugation pathways was observed. Cebranopadol only accounted for ~6% and the 3 metabolites M2, M3, and M6, each for <3% exposure of the total radioactivity in plasma, which means that ~15% of the total plasma radioactivity has been identified. There is currently no evidence for a clinically relevant contribution of metabolites to the pharmacodynamic activity of cebranopadol after single dose. However, contribution of metabolites to pharmacological activity cannot be excluded following multiple dose administration of cebranopadol. Currently, no metabolite observed in human plasma was identified as being unique to humans. Adequate exposure to all currently identified metabolites was observed in at least 1 of the species used for nonclinical safety studies. A trial in poor (PMs) and extensive (EMs) CYP2D6 metabolizers did not show substantial differences in the pharmacokinetic parameters of cebranopadol between the 2 groups following an administration of a single oral dose of cebranopadol 400 µg. In CYP2D6 PMs, there was a substantially higher exposure to the metabolite M3 compared with CYP2D6 EMs. The exposure to the metabolites M2 and M6 was lower in CYP2D6 PMs compared with CYP2D6 EMs. In this trial, the safety and tolerability profile were similar in PMs and EMs of CYP2D6. Multiple doses of duloxetine, omeprazole, and paracetamol (likely co-administered medication) did not have clinically relevant effects on the pharmacokinetics of cebranopadol or its main metabolites when administered as single dose. Data in healthy subjects suggest a statistically significant decrease in systemic exposure of approximately 60% to 70% to cebranopadol (i.e., Cmax and the area under the concentration- time curve up to the sampling time 72 hours [AUC0-72h]) after the co-administration with multiple 600 mg doses of rifampicin (a strong CYP3A4 inducer) and a statistically significant increase in systemic exposure of approximately 60% to cebranopadol after the co-administration with multiple 400 mg doses of ketoconazole (a strong CYP3A4 inhibitor). The initiation or discontinuation of strong CYP3A4 inhibitors or inducers should be done with caution if concomitantly used with cebranopadol. As no experience with subjects on hemodialysis treated with cebranopadol exists, these subjects should not be included into clinical trials with cebranopadol. Hepatic impairment did not result in a clinically relevant increase in exposure to cebranopadol following a single oral dose of 200 μg. Therefore, it is expected that dose adjustment for patients with mild and moderate hepatic impairment may not be necessary for single and multiple dosing although individual tolerability should always be considered. Increasing subject renal impairment (mild, moderate, severe) had no effect on the main descriptive pharmacokinetic parameters for cebranopadol and its metabolites M2, M3, and M6. Thus, no dose adjustment for cebranopadol is required in patients with renal impairment. Efficacy One single-dose Phase 2 trial in acute pain and 6 multiple-dose Phase 2 trials in chronic pain that evaluated the efficacy of cebranopadol have been performed. One Phase 3 multiple-dose trial was terminated early for business reasons. In one trial, subjects received a single dose of cebranopadol (200 µg, 400 µg, or 600 µg), morphine sulfate controlled-release (CR) 60 mg, or placebo. The primary endpoint was mean sum of pain intensity from 2 hours to 10 hours after IMP administration (SPI2-10). Morphine sulfate CR 60 mg was less effective than the cebranopadol 400 µg and 600 µg groups for SPI2-10. Morphine sulfate CR 60 mg was as effective as cebranopadol 400 μg and 600 μg for other SPI time windows (e.g., SPI2-12 and SPI2-14). In another trial, subjects with moderate to severe cLBP received cebranopadol in 3 fixed maintenance doses (200 µg, 400 µg, and 600 µg once daily), tapentadol prolonged release (PR) 200 mg twice a day (BID), or placebo. Subjects entered a forced titration phase of up to 2 weeks, during which the dose of IMP was titrated upwards to the allotted fixed maintenance dose. Subjects then stayed for 12 weeks on the fixed dose during the maintenance phase. The primary endpoint was the change from baseline in the weekly average 24 hour pain intensity during the entire 12 weeks of the maintenance phase (European Union [EU] and rest of the world region) and during Week 12 of the maintenance phase (United States [US] region). A statistically significant difference between cebranopadol and placebo (p < 0.05) was apparent for all cebranopadol treatment groups for the primary endpoint. Although not formally tested, the result on the primary endpoint for the tapentadol PR 200 mg BID treatment group was comprised within that of the 2 higher doses of cebranopadol. In another trial (painful diabetic polyneuropathy [DPN]), cebranopadol 80 µg to 200 µg once daily for 5 days showed clinically meaningful differences to placebo in pain reduction in subjects with moderate to severe painful DPN, reaching statistical significance for the cebranopadol 80 µg and cebranopadol 200 µg group when comparing to overall baseline, and for the cebranopadol 100 µg group when comparing to period baseline. Cebranopadol 100 µg demonstrated analgesic effects similar to morphine CR 60 mg for the primary endpoint. Secondary endpoint parameters supported the conclusions drawn from the primary endpoint. In another trial (moderate to severe pain due to osteoarthritis [OA] of the knee), based on change from baseline in the pain intensity scores during the last week of the 4-week treatment period, the 3 active dose groups (75 µg, 200 µg, or 400 µg of cebranopadol once daily for 4 weeks) showed a dose response trend, with 75 µg performing numerically worse than placebo, 200 µg performing numerically better than placebo, and 400 µg performing significantly better than placebo (p < 0.05). In another trial (painful DPN), based on the change from baseline in the pain intensity scores during the last week of the 4-week treatment period, cebranopadol 200 µg once daily for 4 weeks gave a numerically (but not statistically significantly) better pain relief than placebo in subjects with moderate to severe painful DPN whereas the pain reduction in subjects on 25 µg or 75 µg per day did not substantially differentiate from placebo. In another trial (terminated early for business reasons), subjects suffering from chronic persistent cancer pain received cebranopadol film-coated tablets at a dose range of 200 µg to 1000 µg once daily or morphine sulfate PR 30 mg to 150 mg (divided into 2 doses). The primary goal of the trial was to demonstrate non inferiority between the 2 treatment groups with respect to the use of rescue medication. All subjects had a 2-week (16 days) dose titration phase during which their optimum dose within the allowed dose range was achieved and stayed on their individually chosen dose for the entire 4 week maintenance phase. Subjects recorded the amount of used rescue medication on a daily basis in a diary. The primary efficacy endpoint was the average daily use of rescue medication (i.e., morphine sulfate IR) over the last 2 weeks of treatment in the maintenance phase. The primary efficacy analysis for comparing cebranopadol with morphine sulfate PR was performed in Full Analysis Set (FAS) and Per Protocol Set (PPS) populations. The non-inferiority margin was 8 mg. Non-inferiority was demonstrated for cebranopadol versus morphine sulfate PR in both analysis sets for the primary endpoint (FAS: Δ [confidence interval (CI)] = −7.48 mg [−12.05, −2.918], p < 0.0001; PPS Δ [CI] = −4.67 mg [−9.245, −0.099], p < 0.0001; 1 sided tests). This finding was confirmed by sensitivity analyses. In addition, superiority over morphine sulfate PR could be demonstrated for the primary endpoint (FAS: p = 0.0016; PPS: p = 0.0454; 2 sided tests). Another trial was a Phase 2 trial investigating the efficacy of cebranopadol in subjects with painful DPN. Following a forced 2 week titration phase, subjects received target doses of cebranopadol 100 μg, 300 μg, or 600 μg once daily, pregabalin 300 mg BID, or matching placebo for a 6-week maintenance phase. The primary efficacy endpoint was the change from baseline pain to the average 24-hour pain during Week 6 of the maintenance phase of the double-blind treatment period. The difference to placebo in the cebranopadol 600 μg once daily treatment arm was clinically relevant and statistically significant (−1.01 on the numerical rating scale [NRS], p = 0.0153). The cebranopadol 100 μg and 300 μg treatment arms were also better than placebo (reached clinically relevant differences of at least −0.7 points on the NRS over placebo) without reaching statistical significance (p = 0.0621 for 100 µg and p = 0.0564 for 300 µg). A numerical separation between the active treatment arms (cebranopadol 100 μg, 300 μg, and 600 μg once daily, and pregabalin 300 mg BID) and placebo already occurred during the titration phase. A significant dose-response relationship could be established using a multiple comparison procedure combined with a modeling approach (MCP-Mod); an increasing dose of cebranopadol led to an increasing difference to placebo. Although not formally tested, the estimated mean change from baseline of the primary endpoint analysis for pregabalin 300 mg BID was similar to cebranopadol 600 µg, and confirmed in comparison to placebo assay sensitivity of the trial and the clinical relevance of the results. In another trial, subjects with moderate to severe chronic pain due to OA of the knee received cebranopadol in 2 flexible dose ranges (200 µg to 400 μg or 400 µg to 800 μg once daily), oxycodone CR 10 mg to 50 mg BID, or matching placebo in the maintenance phase. All subjects had an up to 3-week dose optimization to their optimum dose within the assigned dose range and stayed on their individually chosen dose for the entire 12 weeks of the maintenance phase. At the discretion of the investigator, they were allowed to stop treatment for up to 4 days or down-titrate under certain circumstances. Although a clinically relevant decrease from baseline in average 24-hour pain intensity was observed with cebranopadol, none of the active treatment groups including oxycodone CR 10 mg to 50 mg was statistically significantly superior to placebo in the change from baseline in average 24-hour pain intensity, neither compared with the entire 12-week maintenance phase nor to the last week of the maintenance phase. Although the trial did not have assay sensitivity on the primary endpoint, results on secondary endpoints (e.g., Patient Global Impression of Change) and post hoc analyses (change from baseline in rescue medication use) support the efficacy of cebranopadol in chronic painful OA. Safety Following oral (0.8 μg to 800 μg) and IV (1 μg) single-dose administration in Phase 1 trials, cebranopadol was safe independent of the galenic formulation (oral and IV solution, liquid- filled capsule, film-coated tablet). Following single oral dosing in healthy subjects, the limit of good tolerability was 800 μg. Following multiple dosing for a 14-day period after titration, the limit of good tolerability was cebranopadol 1600 µg. Higher doses were less well tolerated than lower doses of cebranopadol. The most frequently reported (≥5% of the subjects who took cebranopadol) treatment emergent adverse events (TEAEs) across all Phase 1 trials were nausea, dizziness, headache, constipation, vomiting, somnolence, fatigue, euphoric mood, dry mouth, diarrhea, hiccups, and pruritus. Following single (200 µg to 600 µg) and multiple (25 µg to 800 µg) oral administration of cebranopadol in Phase 2 trials, cebranopadol was safe and well tolerated. The most frequently reported TEAEs (≥5% of the subjects who took cebranopadol) across all Phase 2 trials were nausea, dizziness, vomiting, somnolence, constipation, headache, fatigue, and hyperhidrosis. No clinically relevant or dose-dependent effects on laboratory parameters and vital signs, including respiratory rate and oxygen saturation, were observed across all clinical trials. The results of an initial thorough QT trial were inconclusive regarding the proarrhythmic potential of cebranopadol according to the Guidance for Industry E14 “Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs” (ICH E14; United States [US] Department of Health and Human Services, Oct 2015). Results of a follow-up thorough QT trial showed a significant effect of cebranopadol on cardiac repolarization at 1600 μg, no effect at 400 μg, and mixed results for the 600 μg and 900 μg dose groups. No other important electrocardiographic effects were observed. Based on the data available from clinical trials, the safety profile of cebranopadol is characterized by the adverse drug reactions (ADRs) nausea, vomiting, constipation, dizziness, somnolence, fatigue, hyperhidrosis, anxiety, decreased appetite, dry mouth, hot flushes, and hiccups. There have been few cases of pregnancy reported in subjects treated with cebranopadol. Healthy children were born. No clinical experience with lactating women treated with cebranopadol is available to date. Clinical Development Existing data for cebranopadol have several limitations. Cebranopadol has never been tested in opioid-dependent patients. Hence, to conclusively determine the therapeutic potential of cebranopadol in OUD patients, critical data are still lacking. These include (1) Identification of therapeutic doses for treating OUD in patients. (2) Evaluation of the safety profile of cebranopadol when it is used in combination with other opioids. (3) Assessment of how to transition opioid-dependent individuals onto cebranopadol. (4) Determination of the efficacy and safety of chronic treatment with cebranopadol in individuals with OUD. The three studies which follow will: Assess Cebranopadol’s Ability to Suppress OUD Withdrawal Signs and Symptoms, Assess the Effects of Cebranopadol on Fentanyl-induced Respiratory Depression (RD) in Opioid-tolerant Adults, and Assess Blockade of Subjective Opioid Effects of Cebranopadol in Adults with Moderate to Severe Opioid Use Disorder. Study 1: Assess Cebranopadol’s Ability to Suppress OUD Withdrawal Signs and Symptoms A randomized, double-blind, multiple ascending dose study determines the ability of cebranopadol to suppress opioid withdrawal signs and symptoms in persons with moderate to severe OUD when transitioned to cebranopadol and identify a dose range for further evaluation. The primary objective of this study is to evaluate the ability of multiple doses of cebranopadol to suppress withdrawal signs and symptoms in adults with moderate to severe OUD. Secondary objectives of this study are: (1) to examine the safety and tolerability of multiple doses of cebranopadol and (2) to assess the pharmacokinetics of multiple doses of cebranopadol. The study involves 4 phases: Screening, Morphine Stabilization, Treatment, and Follow- up. Within approximately 28 days of initiating outpatient screening, subjects are admitted to the clinical research unit (CRU). Following check in to the CRU, subjects are transitioned to an oral immediate-release (IR) opioid, morphine, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to initiating cebranopadol. The last active dose of morphine-IR is administered a minimum of 12 hours before administering the first cebranopadol dose. The Clinical Opiate Withdrawal Scale (COWS) is administered prior to cebranopadol dosing on Day 1 (i.e., a minimum of 12 hr since their last dose of morphine-IR). Up to a maximum of 40 subjects are enrolled and randomized into a maximum of 4 cohorts in the Treatment Phase. Ascending doses of cebranopadol are evaluated in separate cohorts of 10 subjects each; within each cohort, 7 subjects receive multiple doses of cebranopadol and 3 subjects receive multiple doses of matching placebo. The first cohort receives cebranopadol 600 μg or matching placebo; thereafter, dose levels are not fixed and are determined by the Drug Safety Review Committee upon completion of each dosing level. Proposed dose levels include 600, 800, 1200 and 1600 μg. A dose lower than the planned doses may be tested, a dose level may be repeated, or smaller dosing increments may be applied, depending on emerging safety, tolerability, and/or other relevant data, such as available pharmacodynamic data. Subjects receive cebranopadol or placebo once daily for 5 days and remain inpatient in the CRU. Subjects are discharged on Day 5 and a follow-up interview will be conducted on Day 10. Subjects are offered counselling services and referral to treatment while they are in this study. Subjects are required to meet with an addiction counsellor at least once during their stay in clinic. All subjects are informed of treatment options and are encouraged to enter a treatment program upon discharge Pharmacodynamic assessments include COWS, Subjective Opiate Withdrawal Scale (SOWS), visual analog scale (VAS) for craving, and rescue medication use. Safety monitoring include assessments of adverse events (AEs), vital signs, electrocardiograms (ECGs), clinical laboratory tests, physical exams, concomitant medications, and Columbia-Suicide Severity Rating Scale (C-SSRS) results. Blood samples for pharmacokinetic assessments are collected to confirm exposure. Study Title: A Randomized Double-blind Multiple Ascending Dose Study to Assess the Ability of se d
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Within approximately 28 days of initiating outpatient screening, subjects will be admitted to the clinical research unit (CRU). Following check in to the CRU, subjects will be transitioned ls e o 0. ir
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Columbia- Suicide Severity Rating Scale (C--SSRS) results. Blood samples for pharmacokinetic assessments will be collected to confirm exposure. - f n
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Inclusion criteria: 1 Must provide written informed consent prior to the initiation of any protocol- or S . n g
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ii. Post-menopausal (no menstrual period for at least 12 consecutive months without any other medical cause) ve at , or t e
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Subjects with positive urine drug screens for buprenorphine, barbiturates, benzodiazepines or methadone on the day of check in to the CRU or breath he or to d
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15. Subject is an employee of the sponsor or research site personnel directly affiliated with this study or their immediate family member defined as a spouse,
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Safety Endpoints: The following safety endpoints will be evaluated: incidence, severity, and relatedness of .
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Descriptive statistics will be calculated and presented for each time point by treatment for plasma concentrations of cebranopadol. Pharmacokinetic parameters for cebranopadol will be l d
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Study 2: A Randomized, Open-label, Fixed-sequence Crossover Study to Assess the Effects of Cebranopadol on Fentanyl-induced Respiratory Depression (RD) in Opioid-tolerant Adults The effect of cebranopadol on fentanyl-induced RD is critical to understand considering the current mortality rate due to fentanyl overdose (U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 – But Are Still Up 15%. National Center for Health Statistics (2022)). The primary objective of this study is to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by a change in isohypercapnic minute ventilation. Using doses identified in Study 1, the effect of cebranopadol at steady-state concentrations on fentanyl- induced (0.25, 0.35, 0.50 and 0.70 mg/70 kg IV doses) RD are assessed in opioid-tolerant participants (Moss, L.A.-O., et al. Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients. PloS one 17, e0256752 (2022). Minute ventilation after fentanyl dosing is compared with pre-fentanyl baseline (primary outcome), incidence of apnea and requiring verbal stimulation to breathe, and oxygen desaturation (<92%). The secondary objectives of this study are: (1) to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by the secondary outcome measures; (2) to evaluate steady- state plasma cebranopadol concentrations in opioid-tolerant adults; and (3) to examine the safety and tolerability of cebranopadol when co-administered with fentanyl. Study Title: in
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^ To evaluate the effect of cebranopadol on fentanyl-induced respiratory depression in opioid-tolerant adults, as determined by the secondary outcome measures. ) r a re ol a ;
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tolerate a lower fentanyl dose, higher doses will not be administered. Only fentanyl doses the subject tolerated under the placebo condition will be evaluated under the cebranopadol d p r o s
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under development as an oral tablet formulation, the IV route of administration was selected to achieve steady-state concentrations of cebranopadol in a short period of time, which will t 2
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i. Permanently sterile (i.e., both ovaries removed, uterus removed, or bilateral tubal ligation for at least 6 weeks or documented successful f
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Subjects with positive urine drug screens (UDS) for buprenorphine, barbiturates, benzodiazepines, or methadone or positive breath or urine alcohol s - , y ) s). e,
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Investigational Product, Dosage and Mode of Administration: Cb dl l bl I f l i ill b lid i h l bl d he ill 0 - e he t
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^ Incidence of apnea (≥20 sec loss of respiratory activity) ^ Incidence of oxygen desaturation (<92%) G, t e
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The incidence of subjects who experience apnea or oxygen desaturation during cebranopadol treatment at the same fentanyl dose that they experienced apnea or oxygen in l p d t s
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Concomitant medications will be listed by subject. Sample size estimation:
Figure imgf000097_0001
Subjective Opioid Effects of Cebranopadol in Adults with Moderate to Severe Opioid Use Disorder Using doses identified in Study 1, the effect of cebranopadol in blocking liking of intramuscular (IM) hydromorphone is assessed in a randomized, double-blind, repeat-dose study in non-treatment-seeking participants with moderate to severe OUD (Nasser, A.F., et al. Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder. Journal of clinical psychopharmacology 36, 18-26 (2016); Walsh, S.L., et al. Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry 74, 894-902 (2017)). The primary objective of this study is to evaluate the opioid blocking effects of cebranopadol following administration of IM hydromorphone (6 and 18 mg/70 kg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects, as measured by the Drug Liking visual analog scale (VAS). Blockade of hydromorphone liking by cebranopadol is claimed if the upper bound of the 95% confidence interval of the treatment difference between maximum effect (Emax) scores on Drug Liking VAS (primary outcome) of hydromorphone and placebo is ≤11.8 The secondary objectives of this study are (1) to evaluate the degree of opioid blocking effects of cebranopadol following administration of IM hydromorphone (6 and 18 mg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects in subjects with opioid use disorder (2) to explore the relationship between plasma cebranopadol concentration and blockade of the subjective opioid effects of hydromorphone; (3) to examine the safety and tolerability of cebranopadol when co-administered with hydromorphone. Study Title: A Multiple Dose Opioid Challenge Study to Assess Blockade of Subjective Opioid Effects f n to of
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testing (Days -3 to -1). Prior to beginning the Qualification/Baseline HMO Challenge Session on Day -3, subjects will not receive their late evening or early morning dose of n e ], se ch
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Discussion of Study Design (Including Choice of Control Groups) Subjects with o ioid h sical de endence and moderate to severe o ioid use disorder d, at h e e t ol
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pharmacokinetic profile of cebranopadol, HMO Challenge Sessions will be conducted on Days 2 to 4, Days 8 to 10 and Days 15 to 17 to investigate the onset and magnitude of s ts
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The study will enroll enough subjects to ensure that at least 48 subjects complete the study (24 subjects per treatment group with at least 16 females in total). Replacement subjects t ic as
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b. Non-childbearing potential: i Permanently sterile (ie both ovaries removed uterus removed or ul f
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Subjects who currently meet the criteria for a diagnosis of moderate or severe substance use disorder according to DSM-V criteria for any other substances - , R y )
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Subject has unsuitable or difficult venous access or is unwilling or unable to undergo an IV catheter insertion. e, er bo ts t r, d
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Investigational Product, Dosage and Mode of Administration: ^ Cebrano adol film-coated oral tablet low dose and hi h dose to be determined
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^ Ctrough (plasma concentration level prior to each HMO Challenge Session) Safety Endpoints: de r s
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bound of the treatment difference is ≤11. Effects for cebranopadol low dose will not be claimed unless blocking effects for cebranopadol high dose are established. , t s –
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Concomitant medications will be listed by subject. Sample size estimation:
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Cebranopadol administered orally has a slow onset of action and long half-life. Tmax is 4-6 hr with Thalf of 62-96 hr (Lambert, D.G., Bird, M.F. & Rowbotham, D.J. Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. British journal of anaesthesia 114, 364-366 (2015)). Plasma concentrations are closely correlated with pharmacodynamic effect (Göhler, K., et al. Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study. J Clin Psychopharmacol 39, 46-56 (2019)), and the slow onset and decline in the drug’s effects may contribute to its lower abuse potential. The first industry-sponsored Phase 1 oral human abuse potential (HAP) study demonstrated that at therapeutic doses (200 and 400 µg), cebranopadol did not result in clinically relevant drug liking using the visual analog scale (VAS) of drug liking (Koch, E.D., et al. Cebranopadol, a Novel First-in-Class Analgesic Drug Candidate: First Experience With Cancer- Related Pain for up to 26 Weeks. Journal of pain and symptom management 58, 390-399 (2019)). The first study compared 3 doses (200, 400 and 800 µg) of cebranopadol to 2 doses (8 and 16 mg) of hydromorphone and placebo. Cebranopadol administration did not increase subjective drug liking greater than placebo, whereas an equi-analgesic dose of hydromorphone (8 mg; positive control) produced significantly more drug liking than 800 µg of cebranopadol (Göhler, K., et al. Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study. J Clin Psychopharmacol 39, 46-56 (2019)). At twice the maximum planned therapeutic dose for analgesia, some liking was seen at 5 hr post-dose, but at levels significantly below the roughly equianalgesic dose of 16 mg hydromorphone and comparable to 8 mg hydromorphone. For some secondary endpoints, 800 µg of cebranopadol was similar to 8 mg hydromorphone. Results of secondary endpoints, including desire to take the drug again, revealed hydromorphone 8 mg was significantly preferred. Hydromorphone 16 mg was significantly preferred to all doses of cebranopadol across all measures (Göhler, K., et al. Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study. J Clin Psychopharmacol 39, 46-56 (2019)). Subjects rated the negative effects 800 µg of cebranopadol higher than hydromorphone 8 and 16 mg (24.5 vs 13.2 and 20.1, respectively), likely due to the high rate of nausea (19.6%) and vomiting (15.2%) seen at this supratherapeutic dose. A second single-dose, randomized, double-blind, placebo- and active-controlled crossover trial of oral human abuse potential study (de Guglielmo, G., Martin-Fardon, R., Teshima, K., Ciccocioppo, R. & Weiss, F. MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats. Addict Biol 20, 643-651 (2015)) participants was conducted by Park Therapeutics to evaluate the abuse potential of two more supratherapeutic doses (600 µg and 1000 µg) of cebranopadol in recreational opioid users. Studies of Respiratory Depression The potential for cebranopadol to produce respiratory depression was assessed in two clinical trials (Scholz, A., Bothmer, J., Kok, M., Hoschen, K. & Daniels, S. Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain. Pain Physician 21, E193-E206 (2018)), which showed that it produces less respiratory depression than full MOP agonists and suggested that the respiratory depression ceiling seen in animal studies is also the case in humans. In the first trial (Schlolz, et al., 2018), cebranopadol 600 µg (oral) was compared to fentanyl IV. cebranopadol lowered the mean respiratory rate from ≈17 breaths per minute to ≈13 bpm over a period of 6 hours which was dramatically different than the change (≈17 bpm to <10 bmp) produced by fentanyl over the course of <0.5 hours. More importantly, PK/PD modeling predicted that cebranopadol would not produce apnea at any dose in contrast to fentanyl. This respiratory depression ceiling is determined in an ongoing trial (NCT05491785) as part of pain development program. In the second study, cebranopadol was titrated to much higher doses (up to 1600 µg daily) in a one-month inpatient study. Doses above 600 µg did not produce significantly more respiratory depression than seen with 600 µg, seeming to support the finding of the single dose study. A study is ongoing to evaluate the respiratory drive by measuring ventilatory response to hypercapnia (maximum decrease in minute ventilation). In this randomized, double-blind, four- period, six-treatment, placebo controlled partial crossover study, a number of parameter associated with respiratory function is analyzed in approximately 30 adult (18-45 years) completer participants after the administration of cebranopadol, oxycodone and placebo. Other measures include, but are not limited to, expired minute volume, respirator rate (breaths/min), flow rates, tidal volume, end tidal CO2 and peripheral oxygen saturation. Example 5: Safety and effectiveness of cebranopadol in an alternative treatment for OUD The following studies 1 to 5 below are designed to evaluate: (1) Identification of therapeutic doses for treating OUD in patients. Compared to healthy subjects, this patient population, due to chronic exposure to opioids, may experience opioid receptor reorganization leading to tolerance development. Hence, the therapeutic dose of cebranopadol may be different (possibly higher) than those proven efficacious in patients with pain. (2) Evaluation of the safety profile of cebranopadol when it is used in combination with other opioids. (3) Measurement of the abuse liability of cebranopadol by non-oral routes of administration. (4) Assessment of how to transition opioid-dependent individuals onto cebranopadol. (5) Determination of the efficacy and safety of chronic treatment with cebranopadol in individuals with OUD. (6) Non-oral abuse potential and safety in combination with other opioids. To address these gaps in the development program of cebranopadol for treatment of OUD, several clinical experiments are proposed below. Preparatory to these clinical studies there is a limited number of experiments to be conducted in animal models to help determining the therapeutic dose range of cebranopadol in OUD patients and to evaluate its safety if taken in combination with illicit opioids (i.e., fentanyl). 1: Determine the effects of cebranopadol on intravenous (IV) fentanyl self- administration and fentanyl-induced respiratory depression in opioid-dependent rats. We have demonstrated in preclinical models that cebranopadol exhibits low abuse potential, does not produce respiratory depression (RD), and following acute administration reduces opioid conditioned place preference (CPP) and short access (2-hrs) self-administration (SA). These studies support our hypothesis that cebranopadol has an improved safety margin compared to other opioids, yet questions remain. In this preclinical study, we test the hypothesis that acute cebranopadol significantly reduces long access (12 hrs) fentanyl SA and RD, and these effects are maintained during repeated administration. This study completes the final preclinical safety and efficacy studies needed to initiate clinical studies in OUD patients. General Methodology and Statistics: Male Wistar rats (bw 250-300 at the beginning of experiment) are used in these studies. Rats surgically implanted with a permanent catheter into the jugular vein are be trained to operant fentanyl SA as described previously (de Guglielmo, G., et al. Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat. Addict Biol 18, 644-653 (2013)). The effect of cebranopadol on fentanyl SA is analyzed by a one-way within-subject analysis of variance (ANOVA). ANOVA is followed by the Newman– Keuls test, when appropriate. Statistical significance is set at p<.05. All data are expressed as the mean ± standard deviation (SD). With data from 10 rats per group, we have at least 80% power to detect a true reduction in mean values in a treatment arm compared to controls using a two-sided test with a 1.7% type I error. These power calculations assume a within-group coefficient of variation of 10%. Experiment 1.1: Effect of acute cebranopadol on LA fentanyl self- administration (SA). Rats are trained to self-administer fentanyl (2.5 μg/infusion) in 1 hr sessions on an FR 1 schedule 5 days/week until a stable baseline is reached (Wade, C.L., Vendruscolo, L.F., Schlosburg, J.E., Hernandez, D.O. & Koob, G.F. Compulsive-like responding for opioid analgesics in rats with extended access. Neuropsychopharmacology 40, 421-428 (2015)). Sessions then change to 12 hr long-access (LgA) conditions until escalation of fentanyl intake is obtained, defined as a significant increase in average fentanyl infusions earned during the 1st hour of the final two LgA sessions compared to average infusions during the 1st hour of the first two LgA sessions (Schulteis, G., Ahmed, S.H., Morse, A.C., Koob, G.F. & Everitt, B.J. Conditioning and opiate withdrawal. Nature 405, 1013-1014 (2000)). Significant escalation occurs after 1 week of LgA training. But, to evoke neuroplastic changes maintaining stable escalation presumed to underlie the transition to an addiction-like state, LgA to continue for 2 weeks before drug tests (Wade, C.L., Vendruscolo, L.F., Schlosburg, J.E., Hernandez, D.O. & Koob, G.F. Compulsive-like responding for opioid analgesics in rats with extended access. Neuropsychopharmacology 40, 421-428 (2015); Schulteis, G., Ahmed, S.H., Morse, A.C., Koob, G.F. & Everitt, B.J. Conditioning and opiate withdrawal. Nature 405, 1013-1014 (2000); Vendruscolo, L.F., et al. Escalation patterns of varying periods of heroin access. Pharmacol Biochem Behav 98, 570-574 (2011)). a) Fentanyl-Maintained FR Responding. Following completion of LgA training, rats according to a Latin-square design rats are treated with cebranopadol (0, 12.5, 25, 50, µg/kg, o.s.) given 1.5 hr before access to fentanyl. Doses and administration time are based on preliminary results (FIG.5A and 5B) and published work (Linz, K., et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349, 535-548 (2014); de Guglielmo, G., et al. Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats. J Pharmacol Exp Ther 362, 378-384 (2017); Shen, Q., Deng, Y., Ciccocioppo, R. & Cannella, N. Cebranopadol, a Mixed Opioid Agonist, Reduces Cocaine Self- administration through Nociceptin Opioid and Mu Opioid Receptors. Front Psychiatry 8, 234 (2017); Kleideiter, E., Piana, C., Wang, S., Nemeth, R. & Gautrois, M. Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic. Clin Pharmacokinet 57, 31-50 (2018)). At the completing tests of cebrtanopadol on fentanyl SA, rats are re- trained to fentanyl SA for 3 days, but on day 4 they receive cebranopadol (no fentanyl SA) and tail vein plasma samples are taken at 1.5, 5, and 12 hr after cebranopadol administration for PK analysis. A naïve control group are included to compare cebranopadol PK in fentanyl-exposed vs non-exposed rats. b) Fentanyl-Maintained PR Performance. To establish the effects of cebranopadol (0, 1.25, 25, 50 µg/kg, o.s.) on the motivation to expend effort to obtain fentanyl, breakpoints (BP) for fentanyl-reinforced responding (defined as the final ratio completed to obtain a dose of the substance (de Guglielmo, G., Martin-Fardon, R., Teshima, K., Ciccocioppo, R. & Weiss, F. MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats. Addict Biol 20, 643-651 (2015); Roberts, D.C. & Bennett, S.A. Heroin self-administration in rats under a progressive ratio schedule of reinforcement. Psychopharmcology (Berl) 111, 215-218 (1993))) will be established on a PR schedule. A new group of rats are trained to SA fentanyl under LgA conditions. Once stable LgA SA is established, rats are tested under the PR schedule as previously described (Wade, C.L., Vendruscolo, L.F., Schlosburg, J.E., Hernandez, D.O. & Koob, G.F. Compulsive-like responding for opioid analgesics in rats with extended access. Neuropsychopharmacology 40, 421-428 (2015)). Drug dose effects are tested using a Latin- square design, with tests separated by 3 days during which SA baseline are re-established. Design and sample sizes: cebranopadol self-administration (FR1/PR): N = 10/group × 2 (FR1/PR) = 20 + 10 naïve group. Total N=30 Experiment 1.2: Effect of chronic Cebranopadol on LA fentanyl SA. a) Fentanyl-Maintained FR1 Responding. After acquisition of escalated LgA fentanyl SA as described above, rats are divided into 2 groups and tested in a between-subjects design with one dose of cebranopadol or vehicle for 12 consecutive days. Drug doses are selected based on results of Exp.1.1, using the most efficacious dose not leading to non-specific effects (i.e., inactive lever responses) (Shen, Q., Deng, Y., Ciccocioppo, R. & Cannella, N. Cebranopadol, a Mixed Opioid Agonist, Reduces Cocaine Self- administration through Nociceptin Opioid and Mu Opioid Receptors. Front Psychiatry 8, 234 (2017); Kallupi, M., et al. Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption. Addict Biol 23, 585-595 (2018); Sorge, R.E., Rajabi, H. & Stewart, J. Rats maintained chronically on buprenorphine show reduced heroin and cocaine seeking in tests of extinction and drug-induced reinstatement. Neuropsychopharmacology 30, 1681-1692 (2005)). On the 13th day (12 hr after completion of the final fentanyl SA session), rats receive a final dose of cebranopadol, and plasma samples are collected at 1.5, 5, and 12 hr after cebranopadol administration. A fentanyl-naïve group is included to compare the PK parameters of chronic cebranopadol in fentanyl- vs non-fentanyl-exposed rats. b) Fentanyl-Maintained PR Performance. Similarly to experiment 1.1 another group of rats is trained and tested to evaluate the effect of chronic cebranopadol on fentanyl-maintained PR. Design and sample sizes: cebranopadol self-administration (FR1/PR): N = 10/group × 2 (FR1/PR) = 20 + 10 naïve group. Total N=30. Experiment 1.3: Effect of cebranopadol on fentanyl-induced respiratory depression (RD): whole-body plethysmography measurement of ventilatory parameters. Rats implanted with a permanent IV catheter are trained to LgA fentanyl SA as described in Exp.1.1, Twenty-four hours after the last fentanyl SA session, rats are placed in a whole-body plethysmography (DSI, St Paul, MN, USA) for 60 min to acclimatize to the chambers and to allow true resting ventilatory parameters to be established. At this point animals are treated with cebranopadol (0, 12.5, 25, 50 µg/kg, o.s), and 90 min later they receive an IV bolus injection of fentanyl (75 μg/kg, IV) or vehicle. The following ventilatory parameters are recorded: breathing frequency (fr), tidal volume (Vt), minute ventilation (Ve), inspiratory time (Ti), expiratory time (Te), peak inspiratory (PIF) and peak expiratory (PIF) flows using classical protocols described in the literature (Baby, S.M., et al. Bilateral carotid sinus nerve transection exacerbates morphine- induced respiratory depression. Eur J Pharmacol 834, 17-29 (2018); Henderson, F., et al. Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats. Respir Physiol Neurobiol 191, 95-105 (2014); Jenkins, M.W., et al. Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia. Sci Rep 11, 6985 (2021)). Body weight differences are taken into account to adjust the recorded parameters. To determine the effect of cebranopadol alone and on fentanyl-induced RD, these paraments are measured at baseline, following cebranopadol alone, and after the fentanyl challenge. To determine if and in which direction the effect of cebranopadol may be affected by a history of fentanyl SA a group of opioid-naïve rats implanted with an IV permanent catheter is tested in parallel. Cebranopadol is tested in a Latin square counter-balanced design. At least 3-4 days are allowed between drug tests during which LgA fentanyl SA is re-established. Design and sample sizes: Measurement of ventilatory parameters following cebranopadol: N = 10/group × 2 (naive/LgA fentanyl) × 2 (veh/fentanyl challenge). Total N = 40/group. Expected Outcomes, Potential Pitfalls, and Alternative Approaches: Significant reduction of fentanyl intake and attenuation of fentanyl breakpoint by cebranopadol will confirm its efficacy in attenuating the motivation for opioids. This finding will be particularly significant if at the efficacious doses cebranopadol reduces fentanyl-induced respiratory depression. Stable sensitivity to the inhibitory actions of repeated cebranopadol administration on fentanyl- motivated behaviors will document that no significant tolerance develops to chronic treatment with this drug. 2: Determine the IV abuse potential of cebranopadol. In this study we conduct an IV HAP trial as that is a preferred route of use by individuals with OUD. The design is a single-dose, randomized, double-blind, placebo- and active-controlled crossover study to evaluate the abuse potential of cebranopadol compared to oxycodone and placebo when administered intravenously in healthy non-dependent recreational opioid users. The study consists of two parts: Dose Escalation Phase (Part A) and Main Study (Part B). Experiment 2.1: Dose Escalation Phase (Part A) The Dose Escalation Phase utilizes a randomized, double-blind, placebo-controlled, dose escalation design in up to 4 separate cohorts of subjects. Because the safety and tolerability of administering single IV doses of cebranopadol using a 1-min infusion rate have not yet been evaluated, the Dose Escalation Phase evaluates the safety and tolerability of potential cebranopadol doses to be used in the subsequent Main Study using this infusion rate. The Dose Escalation Phase consists of 3 phases: Screening, Treatment and Follow-up. Subjects participate in an outpatient medical Screening visit (Visit 1), a 3-day Treatment visit (Visit 2), and an outpatient safety Follow-Up visit (Visit 3). Within 28 days of the Screening visit, eligible subjects are admitted to the clinical research unit (CRU) on Day-1 of the Treatment visit. At least 12 hr prior to first study drug administration, a Naloxone Challenge Test are performed to confirm that subjects are not opioid dependent. Escalating cebranopadol doses are evaluated in separate cohorts of 8 subjects each, randomized in a 3:1 fashion, such that 6 subjects receive a single dose of IV cebranopadol and 2 subjects receive a single dose of IV placebo within each cohort. Within each cohort, safety and pharmacodynamic data is collected up to 12 hr post-dose. Safety monitoring includes assessments of adverse events (AEs), vital signs, 12-lead electrocardiogram (ECG), clinical laboratory results, physical exams, concomitant medications and continuous pulse oximetry/ telemetry monitoring for at least 4 hr after study drug administration. Pharmacodynamic assessments includes subjective effects visual analog scales (VAS) (for example, Alertness/Drowsiness VAS, Any Effects VAS, Drug Liking VAS, etc.) and pupillometry. Following dosing in each cohort, the sponsor and investigator reviews unblinded safety and pharmacodynamic data prior to initiating the next cohort. If the sponsor and investigator interpret that the data from a cohort are insufficient to make a determination to escalate the dose, an additional cohort of 8 new subjects may be added to repeat a dose level or evaluate an alternative dose. Once a maximum tolerated dose (MTD) is identified, the Dose Escalation Phase is concluded. If the MTD is not identified as part of the Dose Escalation process, the highest evaluated dose is considered as the maximum feasible dose for evaluation in the Main Study. Subjects are discharged after completing assessments on Day 2 or, if medically necessary, subjects may remain in the CRU at the discretion of the investigator or designee. All subjects who participate in the Treatment visit return within 3 to 7 days of discharge for a Follow-Up visit. To ensure that all subjects in the Main Study have not had previous exposure to cebranopadol, subjects who participate in the Dose Escalation Phase are not be eligible to participate in the Main Study. Experiment 2.2: Main Study (Part B) The Main Study consists of 4 phases: Screening, Qualification, Treatment and Follow- Up. Subjects participate in an outpatient medical Screening visit (Visit 1), an inpatient visit (Visit 2) that comprises a 3-day Qualification Phase, a Treatment Phase that comprises four 2-day treatment periods (Visits 3 through 6), and an outpatient safety Follow Up visit (Visit 7). Within 28 days of the Screening visit, eligible subjects are admitted to the CRU on Day -1 for the Qualification Phase. The Qualification Phase comprise a Naloxone Challenge Test and a Drug Discrimination Test. At least 12 hr prior to first study drug administration in the Drug Discrimination Test, a Naloxone Challenge Test are performed to confirm that subjects are not opioid dependent. During the Drug Discrimination Test, subjects receive IV oxycodone (0.07 mg/kg) or matching placebo administered over 1 minute in a randomized, double blind, crossover manner, with each study drug administration separated by approximately 24 hours, to ensure that they can discriminate and show positive subjective effects of oxycodone. Subjects who do not meet Drug Discrimination Test Criteria are discharged from the CRU at approximately 24 hours after the second period. Subjects who do meet the Drug Discrimination Test criteria may remain in the CRU for the first treatment period of the Treatment Phase. A washout interval of approximately 24 hours is required between last study drug administration in the Qualification Phase and first study drug administration in the Treatment Phase. Following confirmation of eligibility in the Qualification Phase, subjects are randomized to 1 of 6 treatment sequences according to a 4 × 4 Williams square in the Treatment Phase. Subjects receive each of the following 3 treatments, administered IV over 1 min, in a randomized, double-blind, crossover manner following an overnight fast: cebranopadol low dose (as determined by Part A); cebranopadol high dose (as determined by Part A); Oxycodone 0.07 mg/kg; Placebo (saline infusion). Each study drug administration is separated by at least 14 days. Serial pharmacodynamic evaluations are conducted up to 24 hr after each study drug administration. Safety monitoring includes assessments of AEs, vital signs, clinical laboratory results, 12-lead ECG, physical exams, concomitant medications and continuous pulse oximetry/telemetry monitoring for at least 4 hr after study drug administration. Pharmacodynamic assessments includes subjective effects VAS (including the primary measure of Drug Liking) and pupillometry as an objective measure. Subjects are discharged at approximately 24 hr after each study drug administration. Subjects return within 3 to 7 days following the last study drug administration for a Follow-Up visit. For the Dose Escalation Phase, approximately 8 subjects per cohort are enrolled and randomized in a 3:1 fashion (cebranopadol: placebo), for a total of up to approximately 32 randomized subjects (4 cohorts). For the Main Study, approximately 40 subjects are randomized to 1 of 4 sequences, using a 4 × 4 Williams square, to ensure that a minimum of 36 subjects complete the planned treatments. Replacement subjects may be added at the discretion of the sponsor, in agreement with the investigator. The primary endpoint is an assessment of the visual analog scale (VAS) rating for Drug Liking “at this moment”. Other data collected includes VAS ratings for any drug effects, bad drug effects, euphoria (“high”), take drug again, and overall drug liking. Data on adverse effects, PK, and demographics are also collected. 3: Assess the ability of cebranopadol to suppress opioid withdrawal. A randomized, double-blind, multiple ascending dose study determines the ability of cebranopadol to suppress opioid withdrawal signs/symptoms in persons with moderate to severe OUD when transitioned to cebranopadol and identify a dose range for further evaluation. The primary objective of this study is to evaluate, in adults with moderate to severe OUD, the ability of multiple doses of cebranopadol to suppress withdrawal signs and symptoms; secondary objectives of this study are: (1) to examine the safety and tolerability of multiple doses of cebranopadol and (2) to assess the pharmacokinetics of multiple doses of cebranopadol. Experiment 3.1: Escalating dose study. This is a randomized, double-blind, multiple ascending dose study to evaluate the opioid withdrawal suppressing effects of cebranopadol in patients with moderate or severe OUD. The study involves 4 phases: Screening, Morphine Stabilization, Treatment, and Follow-up. Within approximately 28 days of initiating outpatient screening, subjects are admitted to the clinical research unit (CRU). Following check in to the CRU, subjects are transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to initiating cebranopadol. The last active dose of morphine-IR is administered a minimum of 12 hr before administering the first cebranopadol dose. The Clinical Opiate Withdrawal Scale (COWS) is administered prior to cebranopadol dosing on Day 1 (i.e., a minimum of 12 hr since their last dose of morphine-IR). Up to a maximum of 40 subjects are enrolled and randomized into a maximum of 4 cohorts in the Treatment Phase. Ascending doses of cebranopadol are evaluated in separate cohorts of 10 subjects each; within each cohort, 7 subjects receive multiple doses of cebranopadol and 3 subjects each receive multiple doses of matching placebo. The first cohort receives cebranopadol 600 μg or matching placebo; thereafter, dose levels are not fixed and are determined by the Drug Safety Review Committee (DSRC) upon completion of each dosing level. Proposed dose levels include 800, 1000 and 1200 μg. A dose lower than the planned doses may be tested, a dose level may be repeated, or smaller dosing increments may be applied, depending on emerging safety, tolerability, and/or other relevant data, such as available pharmacodynamic data. Subjects receive cebranopadol or placebo once daily for 5 days and remain inpatient in the CRU. Pharmacodynamic assessments include COWS, Subjective Opiate Withdrawal Scale (SOWS), visual analog scale (VAS) for craving, and rescue medication use. Safety monitoring includes assessments of AEs, vital signs, ECGs, clinical laboratory tests, physical exams, concomitant medications, and Columbia- Suicide Severity Rating Scale (C SSRS) results. Blood samples for pharmacokinetic assessments are collected to confirm exposure. To avoid risk of withdrawal, patients are titrated onto and stabilized on buprenorphine/naloxone before leaving the study on day 30. The abrupt discontinuation of cebranopadol could potentially result in withdrawal symptoms at the end of study protocol. Subjects are assessed for WD symptoms and transitioned to an appropriate treatment at the investigators’ discretion. D.2 Transition The next phase of this proposal is considered successful when the following milestones have been met: (1) In rats, demonstration that cebranopadol significantly reduces IV fentanyl SA and does not worsen fentanyl-induced RD (Aim 1); (2) In humans, determination of a range of doses for safe use in OUD demonstrated by: a) lower Emax drug liking compared with oxycodone (positive control) when administered IV in recreational opioid users (Aim 2); b) Attenuation of withdrawal signs/symptoms upon discontinuation of the participants’ opioid (Aim 3). D.3 Phase Overview The next phase of this proposal demonstrates the therapeutic efficacy of cebranopadol in decreasing opioid use with low risk of withdrawal or abuse in a Phase 2 placebo-controlled inpatient trial. The results of this study determine whether cebranopadol can meaningfully reduce illicit opioid use under real world conditions. 4: Determine the effects of cebranopadol on fentanyl-induced respiratory depression (RD) in opioid-tolerant participants. The effect of cebranopadol on fentanyl-induced RD is critical to understand considering the mortality rate due to fentanyl (U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 – But Are Still Up 15%. National Center for Health Statistics (2022)). Using doses identified in the dose-escalation study (Study 3), the effect of cebranopadol at steady-state concentrations on fentanyl-induced RD (0.25, 0.35, 0.50 and 0.70 mg/70 kg IV) is assessed in opioid-tolerant participants (Moss, L.A.-O., et al. Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients. PloS one 17, e0256752 (2022)). Hypothesis: The primary objective of this study is to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by change in isohypercapnic minute ventilation. The secondary objectives of this study are: (1) to evaluate the effect of cebranopadol on fentanyl- induced RD in opioid-tolerant adults, as determined by the secondary outcome measures; (2) to evaluate steady-state plasma cebranopadol concentrations in opioid-tolerant adults; and (3) to examine the safety and tolerability of cebranopadol when co-administered with fentanyl. Experiment 4.1 This is a randomized, open-label, fixed-sequence crossover study to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults. The study involves 4 phases: Screening, Morphine Stabilization, Treatment, and Follow-up. Within approximately 28 days of initiating outpatient Screening, subjects are admitted to the clinical research unit (CRU). Following check-in to the CRU, subjects are transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to the first treatment period. Prior to the first treatment period, subjects do not receive their late evening or early morning doses of morphine-IR; therefore, the last active dose of morphine- IR is administered a minimum of 12 hr before first administration of study drug (placebo). Subjects receive placebo and cebranopadol, administered IV, in an open-label, fixed-sequence following an overnight fast. Subjects receive placebo in Period 1 and cebranopadol in Period 2. A washout period of 48 hr separates each treatment period. Subjects receive maintenance morphine- IR during the washout period, with the last morphine-IR dose administered a minimum of 12 hr before administration of cebranopadol. Subjects are randomized to receive 1 of 3 cebranopadol doses in Period 2. Cebranopadol is administered IV to achieve steady-state plasma concentrations based on doses identified in the MAD study (Study 3)); the placebo infusion rate and duration are matched. Escalating IV fentanyl doses of 0.25, 0.35, 0.50, and 0.70 mg/70 kg are administered over 90 sec at 120, 180, 240, and 300 min after the start of the cebranopadol /placebo infusion. Isohypercapnic ventilation is measured during cebranopadol /placebo infusion for approximately 360 min using the dynamic end-tidal forcing technique. Minute ventilation (L/min), respiratory rate (breaths/min), oxygen saturation (SpO2), tidal volume (L), end-tidal PCO2 (kPa; PEiCO2) and end tidal PO2 (kPa; PEiO2) are collected at baseline and during study drug administration. Pulse oximetry continuously monitors oxygen saturation (SpO2) up to 8 hr postdose. Safety monitoring include assessments of AEs, vital signs, clinical laboratory results, 12-lead ECG, physical exams, concomitant medications. Pharmacokinetic samples are collected up to 8 hr postdose in Period 2. Subjects are discharged on Day 3 and a follow-up visit is conducted on Day 7. Given the long half-life of cebranopadol, it might be operationally more feasible to administer it after placebo so that the treatment period can be shortened and there is only 1 morphine stabilization period. If a subject does not tolerate a lower fentanyl dose, higher doses are be administered. Only fentanyl doses the subject tolerated under the placebo condition is evaluated under the cebranopadol condition. 5: Evaluate the ability of cebranopadol to block the subjective effects of hydromorphone. Using doses identified in Study 3, the effect of cebranopadol in blocking liking of oral hydromorphone is assessed in a randomized, double-blind, repeat-dose study in non-treatment- seeking participants with moderate to severe OUD (Nasser, A.F., et al. Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder. Journal of clinical psychopharmacology 36, 18-26 (2016); Walsh, S.L., et al. Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry 74, 894-902 (2017)). Blockade of hydromorphone liking by cebranopadol is claimed if the upper bound of the 95% confidence interval of the treatment difference between Drug Liking Emax (primary outcome) of hydromorphone and placebo is ≤11 (Chen, L. & Bonson, K.R. An equivalence test for the comparison between a test drug and placebo in human abuse potential studies. Journal of biopharmaceutical statistics 23, 294-306 (2013)). The primary objective of this study is to evaluate the opioid blocking effects of cebranopadol following administration of IV hydromorphone (6 and 18 mg/70 kg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects in subjects with moderate or severe OUD, as measured by the Drug Liking visual analog scale (VAS). The secondary objectives of this study are (1) to evaluate the degree of opioid blocking effects of cebranopadol following administration of IV hydromorphone (6 and 18 mg/70 kg) compared to administration of 0 mg hydromorphone (placebo) on subjective opioid effects in subjects with opioid use disorder, as determined by the secondary outcome measures; (2) to explore the relationship between plasma cebranopadol concentration and blockade of the subjective opioid effects of hydromorphone; (3) to examine the safety and tolerability of cebranopadol when co-administered with hydromorphone. Experiment 5.1 This is a randomized, double-blind, repeat-dose Phase 2 study to evaluate the onset and degree of multiple doses of cebranopadol in blocking the effects of a mu opioid agonist (hydromorphone) in non-treatment volunteers with moderate or severe OUD. The study involves 4 phases: Screening, Qualification, Treatment, and Follow-up. Within approximately 28 days of initiating outpatient screening, subjects are admitted to a clinical research unit (CRU) for the Qualification Phase. Following check in to the CRU, subjects are transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to the Qualification/Baseline Hydromorphone Challenge Session, which consists of 3 consecutive days of testing (Days -3 to -1). Prior to beginning the Qualification/Baseline Hydromorphone Challenge Session on Day -3, subjects do not receive their late evening or early morning dose of morphine-IR; thus, the last active dose of morphine- IR is administered a minimum of 12 hr before administration of each of the Hydromorphone Challenge doses. Following the 3-day Qualification/Baseline Hydromorphone Challenge Session (Days -3 to -1), eligible subjects are randomized in a 1:1 ratio to 1 of 2 groups to receive cebranopadol low dose or high dose stratified by gender (cebranopadol doses and timing of administration relative to last morphine-IR dose to be determined based on results of a dose escalation study). The COWS is administered prior to cebranopadol dosing on Day 1 (i.e., minimum of 12 hr since their last dose of morphine-IR). In order to be dosed on Day 1, subjects must have a COWS score ≥8. Subjects receive cebranopadol once daily for 17 days and remain inpatient in the CRU for a total of up to about 4 weeks. Three Hydromorphone Challenge Sessions are conducted on Days 2 to 4, Days 8 to 10, and Days 15 to 17 to evaluate the onset and degree of opioid blocking effects of cebranopadol. Each Hydromorphone Challenge Session consists of 3 doses of hydromorphone IV (doses of 0 mg [placebo], 6 and 18 mg/70 kg) administered on 3 consecutive days in randomized order, with one dose of hydromorphone administered each day. Eligible subjects are randomized in a 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences according to two 3 × 3 William squares. Safety and pharmacodynamic evaluations are conducted following each dose of hydromorphone over about 4 hr post-dose or longer, if medically necessary. Blood samples for measurement of plasma cebranopadol concentrations are also be collected pre-dose on each day of the Hydromorphone Challenge Sessions. Subjects are discharged on Day 17, after all assessments and procedures are completed following the last Hydromorphone Challenge Session, and the Investigator deems it is safe. A follow-up phone interview is conducted on Day 22. The degree of hydromorphone dose tolerability is determined based on the site-specific study Investigator’s review of the subject’s oximetry data, vital signs, behavior, and physical demeanor. Due to safety concerns surrounding fentanyl administration, hydromorphone has been chosen as the opioid challenge condition. Subjects with opioid physical dependence and moderate to severe OUD (DSM-5) are enrolled in this study. Because this is the intended population, results from this study are directly applicable to the therapeutic use of cebranopadol in clinical practice (i.e., determine the ability of cebranopadol to block illicit opioid effects, which is one dimension of opioid maintenance treatment). These subjects are also likely to provide meaningful ratings of subjective opioid effects based on their prior opioid use experience. For ethical and safety reasons, non-dependent opioid users are not be included, as they are less likely to tolerate repeated administration of the higher cebranopadol doses and because it would be unethical to produce opioid dependence in an opioid abuser who has avoided developing physical dependence themselves. In addition to the requirement that subjects are “history-qualified” (i.e., history of regular opioid use), this study uses a pharmacologic qualification to ensure that subjects who meet the drug use history criteria can also distinguish and demonstrate “liking” of the subjective euphoric experience of both doses of hydromorphone compared to placebo. Therefore, the pharmacologic qualification procedure provides more objective confirmation of drug use history and ensures that subjects can respond appropriately in a laboratory setting as well as tolerate the doses of fentanyl. Studies with opioid-dependent subjects have used a wide array of opioid maintenance drugs/doses to stabilize subjects. In the current study, all subjects are stabilized on a 30 mg dose QID of short-acting morphine prior to enrollment in the Treatment Phase to ensure that any opioids that the subject may have recently used are washed out, as well as to establish a consistent schedule of opioid administration and to shorten the duration of the opioid washout period prior to administration of the Qualification/Baseline Hydromorphone Challenge Session. Overall, the Morphine-IR stabilization phase ensures sufficient opioid washout of opioids used prior to check in and a similar level of physical dependence among the subjects prior to the Qualification/Baseline Hydromorphone Challenge that ensures that subjects are not uncomfortable as a result of opioid withdrawal and allow for a baseline measurement of the Drug Liking Emax of hydromorphone from which the active cebranopadol can be compared for determination of its efficacy to block this effect of hydromorphone. In this study, randomization is used to avoid bias in the assignment of treatment for all the Hydromorphone Challenge Sessions and in the assignment of subjects cebranopadol treatment groups during the Treatment Phase. If there is an additional safety concern with the randomization protocol, it is possible to have the hydromorphone doses administered in ascending order, but with placebo randomly interspersed. Prior to the Hydromorphone Qualification Phase, subjects are randomized to 1 of 6 challenge sequences, according to two 3 x 3 William squares (ABC, ACB, BAC, BCA, CAB, CBA), and receive one dose of fentanyl daily over 3 consecutive days, including 2 doses of hydromorphone and 1 dose of placebo. This approach has previously been shown to be is sensitive to identifying dose-related agonist effects, while ensuring that both subjects and staff remain blinded to the dose of hydromorphone or placebo being administered, thereby reducing the risk of potential expectancy effects. As an additional precaution, subjects are housed in inpatient research units for the duration of the study both for safety monitoring and to ensure that the subjects do not use other illicit opioids while enrolled in the study, as this may affect the Hydromorphone Challenge Session results. Randomization increases the likelihood that known and unknown subject attributes (e.g., demographics and baseline characteristics) are evenly balanced across dose groups and enhance the validity of statistical comparisons across dose groups. It is not possible to include a placebo control group (cebranopadol placebo) in the current study because the enrolled population is physically dependent on opioids and would go into opioid withdrawal with placebo administration. Therefore, this study includes a baseline Hydromorphone Challenge Session to establish the frequency and magnitude of changes in clinical endpoints that may occur in the absence of cebranopadol. Impact: Achieving these multiple programmatic aims significantly advance the field by establishing the safety and preliminary efficacy of cebranopadol, a novel MOP/NOP agonist for treatment of OUD. REFERENCES 1. Bell, J. & Strang, J. Medication Treatment of Opioid Use Disorder. Biological psychiatry 87, 82-88 (2020). 2. 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Sci Rep 11, 6985 (2021). All patents, patent publications, and other publications listed in this specification are incorporated herein by reference, including US Provisional Patent Application No.63/485,139, filed February 15, 2023, US Provisional Patent Application No.63/578,894, filed August 25, 2023, and International Patent Application No. PCT/US2023/083697, filed December 12, 2023. While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

CLAIMS: 1. A method for preventing and/or treating opioid use disorder (OUD) in a human patient being treated for pain, said method comprising treating the human patient with a pharmaceutical composition comprising at least one cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate.
2. The method of claim 1, wherein the composition provides an immediate release profile for the cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate.
3. The method of claim 2, wherein the composition comprises cebranopadol in its free base form.
4. The method of claim 1, wherein the composition is delivered once daily.
5. The method of claim 1, wherein the composition is delivered no more than once a day for three to 14 days.
6. A composition useful in treating a human patient being treated for pain and having or being susceptible to opioid use disorder, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, administrable to the subject.
7. The composition of claim 6, wherein the composition is administered daily at a dose in an amount of about 10 μg to about 2000 μg cebranopadol.
8. The composition of claim 6 or 7, wherein the cebranopadol is a free base.
9. The composition of any one of claims 6 to 8, wherein at least 80% of the cebranopadol is in crystal form A.
10. Use of cebranopadol in treating a human patient having opioid use disorder, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate.
11. Use of claim 10, wherein the composition is administered daily at a dose in an amount of about 10 μg to about 2000 μg cebranopadol.
12. Use of claim 10 or claim 11, wherein the cebranopadol is a free base.
13. Use of any one of claims 10 to 12, wherein at least 80% of the cebranopadol is in crystal form A.
14. The composition of any one of claims 6 to 9, or use of any one of claims 10 to 13, wherein subject is being treated for pain.
15. The composition of any one of claims 6 to 9, or use of any one of claims 10 to 13, wherein the pain is chronic, acute, central, peripheral, neuropathic, and/or nociceptive pain.
16. The composition of any one of claims 6 to 9, or use of any one of claims 10 to 13, wherein the pain is visceral pain, skeletal pain, and/or nervous pain.
17. The composition of any one of claims 6 to 9, or use of any one of claims 10 to 13, wherein the pain is associated with tissue damage following surgery.
18. The composition of any one of claims 6 to 9, or use of any one of claims 10 to 13, wherein the pain is associated with hyperalgesia.
19. The composition of any one of claims 6 to 9, or use of any one of claims 10 to 13, wherein the pain is associated with opioid-induced hyperalgesia.
20. A method for reducing the risk of apnea and/or oxygen desaturation in a human patient receiving pain treatment, said method comprising administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol.
21. An immediate release cebranopadol composition for use in reducing the risk of apnea and/or decrease in oxygen desaturation in a human in need of pain treatment, said method comprising administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol
22. Use of cebranopadol in preparing a medicament for use in reducing the risk of apnea and/or decrease in oxygen desaturation in a patient in need of pain treatment, said method comprising administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol.
23. The method according to claim 20, composition of claim 21, or use of claim 22, wherein the patient has impaired lung function.
24. The method according to claim 20, composition of claim 21, or use of claim 22, wherein the patient has asthma, chronic obstructive pulmonary disease (COPD), pneumonia, chronic or acute bronchitis, emphysema, cystic fibrosis, interstitial lung disease (ILD), pulmonary embolism, pleural effusion, mesothelioma, tuberculosis, acute respiratory distress syndrome (ARDS), neuromuscular disorders, obesity hypoventilation syndrome, or lung cancer.
25. The method of claim 20, composition of claim 21, or use of claim 22, wherein the cebranopadol prevents apnea in a patient receiving pain treatment in the first two hours post- dosing of an immediate release cebranopadol composition independent of dose.
26. The method of claim 20, composition of claim 21, or use of claim 22, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate.
27. The method of claim 20, composition of claim 21, or use of claim 22, wherein the composition is administered daily at a dose in an amount of about 10 μg to about 2000 μg cebranopadol.
28. The method of claim 20, composition of claim 21, or use of claim 22, wherein the cebranopadol is a free base.
29. The method of claim 20, composition of claim 21, or use of claim 22, wherein at least 80% of the cebranopadol is in crystal form A.
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