BG62876B1 - The application of melatonin for the treatment of patients with medicament addiction - Google Patents

Abstract

The invention relates to the application of melatonin for the prevention and treatment of patients suffering from addiction, resistance or dependence on benzodiazepine medicamentous forms when excessively used and to a pharmaceutical composition designed for such treatment. The daily adminstration dose ranges from 0.01 to 100 mg. In case of the protection of a patient accepting benzodiazepine medicament the daily melatonin quantity should be under 10 mg. 8 claims

Description

Technical field

The invention relates to the use of melatonin for the prevention and treatment of patients suffering from dependence, resistance or addiction to benzodiazepine drugs in their overuse and to a pharmaceutical composition for use in such treatment.

BACKGROUND OF THE INVENTION

Benzodiazepine addiction often develops in people with insomnia who use them to induce sleep, in people who are accustomed to overuse of drugs that, in the process of drug withdrawal, are used to overuse benzodiazepines to relieve anxiety. and convulsions. Moreover, chronic administration of benzodiazepines (when benzodiazepines usually have a long half-life) may cause persistence, resulting in ineffective dose escalation by an unknown mechanism. In addition, the consequences or withdrawal syndrome, which often follows the abrupt discontinuation of these drugs, which is observed in both animals and humans, leads to accustomed drug overuse (Greenblatt, DJ and Shader, RI, Drug Metab. Rev. 1978, 8, 13-28). B 1990 US National Household Survey on the Use of Psychotherapeutic Medications Approximately 8% of sleeping pills increase the prescribed dosage of their own accord, an increase of 25% over those reported in 1979. Given that the review found that 2.6% of the US population accepts benzodiazepine sleeping pills (compared to 2.4% in 1979), the number of people in the US alone who develop resilience and dependence can be estimated at 560,000. involves the use of substances outside social norms and abuse of the direct Erna use of drugs.

There is no known rapid withdrawal method to date, followed by alternative treatment for patients who develop benzodiazepine sleeping pills, and this problem is a major obstacle to rehabilitation and recovery of drug addicts.

Melatonin is known to be a hormone that is an indole derivative produced at night by the pineal gland, playing a major 10 mediator role in the daily waking cycle and in regulating sleep. There are also some indications that melatonin may increase benzodiazepine efficacy (see, e.g., Cardinali, DP. Et al., Adv. Biochem. Psycho15 pharm., 1986, 42, 155-164, Acuna Castroviejo, D., et al., J. Pineal Res., 1986, 3, 101-102; Niles, LPet al., J.Neural Transm., 70, 117-124). Melatonin may also potentiate the anxiolytic effects of diazepam in mice (Guardiola-Lemaitre, 20 B. et al., Pharmacol. Biochem. Behav., 1992, 41, 405-4080). On the other hand, it has been suggested that benzodiazepine may potentiate GABA-induced inhibition of melatonin synthesis and 25 secretion in some species, including humans (McIntyre, IMet al., Biol.Psychiat., 1988, 24, 105-108) and that nocturnal elevation of plasma melatonin can be suppressed by benzodiazepine in humans, resulting in distortion of the 24-hour melatonin rhythm 30 (Kabuto, M. et al., Endocr. Japon., 1986, 33, 405-414). Moreover, chronic oxazepam treatment modifies the 24-hour changes in the melatonin receptor density in the brain of 35 rats at night, and that this effect is not observed in pituitary-eliminated animals (Anis, Y., et al. , J.Neural Transm. 1992, 89, 155-166).

It has been unexpectedly established in accordance with the invention that administration of melatonin together with a benzodiazepine drug may potentiate (1) the patient's dependency, addiction to the drug, or resistance to such drugs, and (2) in the case of patients diagnosed with a benzodiazepine medication (when such undesirable symptoms have not yet been observed) prevent 50 onset of such symptoms.

EP-A-513702 describes the use of melatonin and some of its derivatives in the treatment of sleep disorders and for pre-anesthetic medication, optionally in the presence of benzodiazepine. The description claims that benzodiazepine can therefore be administered in relatively low dosage and thus avoid effects (changes in sleep patterns, side effects and development of resistance) that are reported to be associated with administration of benzodiazepines at high doses or for prolonged periods. This patent does not suggest that doses of melatonin or its derivatives below 10 mg can be used for this purpose, nor that melatonin may be useful if the patient has already become dependent, resistant or accustomed to the benzodiazepine drug.

EP-A-518468 discloses a controlled release dosage form that, in short, releases melatonin according to a profile similar to the plasma profile of a person having a normal endogenous melatonin profile. Dosage forms that optionally contain a profile modifying the melatonin receptor agent such as oxazepine are useful for treating conditions associated with methanonine deficiency or deformity, such as sudden infant death syndrome and migraine. This patent does not disclose the use of melanonin for the prevention or treatment of addiction to benzodiazepines.

DIALOG File Supplier PHIND AN 00302794, 13-03-02, reports that indole-3-pyruvic acid (IPA) increases sleep time in insomnia sufferers, such as benzodiazepine withdrawal and that the effect of IPA on sleep is mainly mediated of increased melatonin turnover in the pineal gland. This patent does not suggest the use of melatonin for the prevention or treatment of addiction to benzodiazepine.

SUMMARY OF THE INVENTION

The invention in one aspect relates to the use of melatonin for the prevention and treatment of patients suffering from a benzodiazepine drug dependence, persistence or habituation by daily administration in the range of 0.01 to 100 mg or in the case of the protection of a patient to whom it is administered benzodiazepine medicine in a daily amount of melatonin less than 10 mg.

According to another aspect, the invention provides a pharmaceutical composition for use in treating patients suffering from a benzodiazepine dependence, resistance or addiction to these benzodiazepine drugs containing at least one diluent, carrier or additive and as active ingredients a benzodiazepine drug and melatonin.

This drug may be a pharmaceutical composition suitable for oral, rectal, parenteral or transdermal administration and containing at least one diluent, carrier or additive, may further be characterized by the following features: (i) represents a unit dosage form, each unit dose contains melatonin, which is in the range of 0.0025-100 mg, (ii) it is a form of controlled release composition, wherein melatonin is preferably released at a predetermined controlled rate, (iii) it also contains at least one melatonin receptor modifier and / or melatonin profile modifier. The medicament also includes a pharmaceutical composition according to the invention comprising at least one benzodiazepine drug such as alprazolam, chlordiazepoxide, chlorazepate, diazepam, flunitrazepam, flurazepam, halazepam, lorazepam, oxazepam, prazepam, triazam and triazam. The pharmaceutical composition containing at least one benzodiazepine drug may further be characterized by one or more of the features (i), (ii) and (iii) as described above.

When administering the invention to treat patients accustomed to excessive drug use, or to patients exhibiting symptoms of dependence, resistance or addiction to drug abuse, the administration of the benzodiazepine drug to the patient is continued, at least initially, and the patient is simultaneously administered melatonin in an amount effective to relieve at least one of the symptoms.

In a preferred embodiment, in such treatment, either the benzodiazepine drug or melatonin may be in the form of a pharmaceutical composition adapted for oral, rectal, parenteral or transdermal administration and containing at least one diluent, carrier or additive. Alternatively, the benzodiazepine drug and melatonin may be administered as such separately prepared, or may be combined into a single pharmaceutical composition comprising the benzodiazepine drug and melatonin.

In connection with the administration of melatonin alone or together with one or more benzodiazepine drugs, administration may be carried out at daily dosage concentrations ranging from 0.01 to 100 mg, which may be administered as a controlled composition release. To illustrate, 1 -2 mg of melatonin as a controlled release formulation can be administered overnight. Melatonin may be administered together with a melatonin receptor modifier or a melatonin profile modifier. Examples of a melatonin receptor modifier are short-acting benzodiazepines such as oxazepam and examples of a melatonin profile modifier are benzodiazepines, beta-blockers, and serotonin uptake inhibitors. Instead of and in addition to using a profile modifier, the melatonin profile may be altered by subjecting the patient to light before, after, or during the administration of melatonin.

The benzodiazepine drugs listed here may give rise to symptoms of dependence, resistance and / or addiction to excessive drug use. Without prejudice to this common part, such drug or drugs may be one or more of, for example, alprazolam, chlordiazepoxide, chlorazepate, diazepam, flunitarazepam, flurazepam, halazepam, lorazepam, oxazepam, prazepam, temazepam, and triazepam, and are indicated.

In an alternative embodiment of the invention for the treatment of said symptoms, the benzodiazepine drug (s) is initially continued to be administered to the patient in conjunction with melatonin, with a daily concentration substantially the same that the patient received prior to initiating treatment with melatonin. In another alternative embodiment of the invention for treating such symptoms, the benzodiazepine drug (a) is administered to the patient in conjunction with melatonin with a progressive decrease in daily concentration compared to that received by the patient prior to initiation of melatonin treatment. In this embodiment, the progressive decrease in the administered daily concentration may continue, for example, until a predetermined stabilized concentration of administration is achieved, or alternatively, for example, until the amount of the benzodiazepine drug administered has reached zero.

In the application of the invention for preventive purposes, for example, for the treatment of patients who have a clinical diagnosis of a condition for susceptibility to relief by administration of a benzodiazepine drug, while preventing the patient from experiencing symptoms of dependence, resistance or accustoming to excessive use of this benzodiazepine drug, the benzodiazepine drug is administered in an amount effective to alleviate this condition, and at the same time to the patient An amount of melatonin is also administered, which is effective in preventing at least one of these symptoms. The various embodiments described above as applicable to the treatment of a patient in a symptom state (s) are applicable, respectively, for preventive purposes, except insofar as they are not applicable on grounds clearly apparent to one of ordinary skill in the art, for example in this particular case of treatment with a benzodiazepine drug is desirable, although it is obvious that the amount of benzodiazepine administered can be reduced in each individual case determined by the treating physician, it cannot be reduced to zero.

As stated above, the invention relates to a pharmaceutical composition comprising at least one benzodiazepine drug and melatonin. Because benzodiazepine medicines are usually administered 1-4 times a day, the daily concentration of 0.01-100 mg of melatonin commonly administered at night, in the same form as benzodiazepine (s), or even when administered separately, can be achieved. for example by administering benzodiazepines as follows:

Days A single dose of benzodiazepine in the range of 1 0.01 - 100 mg 2 0.05 - 50 mg 3 0.033 - 33.3 mg 4 0.025 - 25 mg

Thus, when the pharmaceutical composition of the invention is administered in unit dose form, each unit dose is preferably administered overnight and preferably contains melatonin in the range of 0.0025-100 mg.

The following table lists the amounts of benzodiazepine used to treat those indicated in adults. For further information, such as preservation, half-life, dosage form and appropriate doses for children and infants, see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 7th Edition, 1985 (MacMillan Publishing Co.), passages on the use of benzodiazepines (e.g., pp. 324, 437).

Benzodiazepine Content oral dose per mg mg (per day) Normal daily oral dose * Sedative Hypnotic An anxiolytic Alprazolam 0.75-1.5 Chlordiazepoxide 10-100 (1-3) 50-100 15-40 Clorazepate 3.75-15 (2-4) 15-30 30 Diazepam 5-10 (3-4) 5-10 4-40 Flurazelam 15-30 Halazepam 60-160 Lorazepam 2-4 2-6 Oxazepam 15-30 (3-4) 15-30 30-60 Prazepam 20-40 Temazepam 15-30 __ Triazolam 0.25-0.5 j _________________________ - -

* mg is generally divided into 2-4 single doses, and for further information including parenteral dose concentration, see Goobman & Gilman, loc cit.

The preparation and release profile of the compositions for use according to the invention or its application are illustrated below.

(a) In 7 mm cylindrical punches, 5 tablets are 2540 kg (2.5 t) after dry mixing of the powder materials, namely 2 mg / tablet melatonin (Biosynth Co., Switzerland) and acrylic resin carrier (Rohm Pharma), which is Eudragit® RS 100 (form SR-Ms) or Eudragit ^R RSPO (form SR-Mf), together with other components, as follows: form SR-Ms: Eudragit ”Eudragit * RS 100 48,8%, lactose 50%, melatonin 1.2%; form SR-Mf: RSPO 35.3%, lactose 16.7%, calcium hydrogen phosphate 41.4%, talc

1.3%, magnesium stearate 4%, melatonin 1.3%. SR-Ms and SR-Mf are sustained release formulations.

The usual dosage form (RM) is prepared similar to the SR-Mf composition, but using lactose instead of Eudragit as a carrier.

(B) The possible release profile of the tablets obtained as described in paragraph (a) was investigated for the first time by in vitro dissolution of melatonin in distilled water at 37 ° C. The results in Table A show the% melatonin content (mean of 6 tablets) that was dissolved at the indicated time intervals.

Table A

Time, h 1 2 4 6 8 10 Melatonin,% released from: SR-Ms 12 29 62 84 90 100 SR-Mf 32 51 76 88 100 RM 93 96 100

(c) The in vivo profile of SR-Mf tablets prepared as described in paragraph (a) shall be examined by oral administration twice to healthy men (age 36) at 10 am, ie when circulating. no melatonin was detected. The amount of in vivo melatonin released is determined by radioimmunoassay of its major metabolites, 6-sulfatoxymelatonin, in the urine. The amount of 6-sulfatoxymelatonin reflects the level of the hormone in the blood. The results of Table B show that melatonin is defined as% of the total amount of melatonin administered (mean of 2 tablets).

Table C

In vivo release of melatonin from SR-Mf

Time, h 1 2 4 6 8 10 % Release at intervals 10, 7 25.7 40,6 14,0 7.0 1.9 Cumulative release,% 10.7 36,4 77.0 91,0 98.0 99,9

It is noted that the release of melatonin in vitro, illustrated in Table A, provides only an approximate indication of the in vivo release profile due to the known phenomenon of the active compound being absorbed by the tissues in the early stage of release. The amount of melatonin in sustained release formulations can be varied, for example, to 0.5, 1 or 5 mg / tablet, without prejudice to the type of release found for tablets containing 2 mg / tablet of melatonin.

To the extent that melatonin analogues that substantially resemble the function of melatonin in the human body are known in the art, it should be appreciated that such analogues are considered to be the obvious chemical equivalents of melatonin in this context.

According to the invention, one or more benzodiazepines may be included in the composition in the amounts described herein.

Examples of carrying out the invention

The invention is illustrated by the following examples.

Example 1. The reciprocal effects of chronic administration of benzodiazepine and melatonin on brain melatonin and benzodiazepine receptors and the ability of melatonin to reverse these effects were investigated. Male rats were maintained daily for 14 h light day: 10 h dark (light 05.00 h, cold white fluorescence) at 24 ° C ± 2 ° C. Food and drinking water are provided unlimited. Animals (2 months of age) are divided into 4 groups of 5 animals each. In one group (CON) animals are injected

i.p. daily at 16.00 h with vehicle (200 l saline). Those in the second group (VAL) are injected daily, i.p. at 16 h with diazepam (1 mg in 200 μΐ vehicle, Roche). Animals in the third group (MEL) were injected daily at 16.00 h with vehicle and this group's drinking water contained melatonin (4 mg dissolved in 100 μΐ) ethanol and diluted to Ιμΐ). Animals in group IV (VAI / MEL) were injected daily at 16.0 h with diazepam (1 mg in 200 μΐ vehicle), and the drinking water of this group contained melatonin (4 mg diluted with 100 μл ethanol and diluted to Ιμΐ). After 21 days, treatment was stopped and the animals weighed. Mean body weights in the VAL (247 ± 20 g) and VAL / MEL (239 ± 30 g) groups were found to be slightly lower than those in CON (292 ± 30 g) or MEL (285 ± 30) g) groups.

Animals were decapitated between 1819.00 h the next day (at this time 2- ¹²⁵ 1- iodomelatonin density in medulla pons was maximal), brains were rapidly removed and crude synaptosomal pellets were prepared as described, and melatonin receptors were examined , as described by Laudon, M. and Zisapel, N .. FEBS Lett., 1986, 197, 9-12. Benzodiazepine receptors are assayed by measuring ³ H-flunitrazepam ( ³ H-FNZ) and ³ H-RO 15-1788 binding as described by Amiri, Z. et al., Brain Res., 1991, 553, 155-158 . The coupling parameters are calculated from the equilibrium coupling data. In _tach values indicate the specific binding of 2- ¹²³ 1 iodomelatonin, ³ H-FNZ or ³ H-RO 151788 at saturation and Kd values are visible dissociation constants. The binding parameters of the different groups were compared with the analysis of variants and then StudentNewman-Keul's multiple comparison test. Differences are considered significant if P <0.05. Daily injection of diazepam (1 mg ip at 16.00 h) in male rats for 3 weeks markedly reduced the density of binding 2- ^{| 25} 1-iodomelatonin sites in medulla pons (Table 1), where benzodiazepine binding was unaffected. significantly (Table 2). If melatonin receptors are associated with the control of the wake-up cycle, the results indicate that chronic administration of benzodiazepines leads to a delay in the regulation of melatonin mechanisms and is a consequence of physiological activities. Melatonin given orally via drinking water for 3 weeks significantly increased the ³ H-RO 15-1788 binding in medulla pons (Tables 2,3), without affecting 2- ^{| 25} 1-iodomelatonin binding. The increase in density at the benzodiazepine binding site and the apparent Kd in medulla pons induced by melatonin treatment is consistent with the increase previously observed in rat cerebral cortex and indicates that it is mediated by opioid peptide mediators (Gomar, M. D. et al., Neuroendocrinology 1993, 4, 987-990). The fact that this increase persists even in animals treated with diazepam may exclude competition between melatonin and benzodiazepines on bienzodiazepine binding sites.

The daily administration of both diazepam and melatonin increased the ³ H-RO 15-1788 binding in medulla pons and reversed the diazepam induced inhibition of 2- ¹²⁵ l-iodomelatonin binding in this area (Table 1.2). These results are surprising as previously demonstrated (Ansis, Y. et al., At melatonin binding sites in hamster brain: effect of melatonin. Molec. Cell. Endocrinol., 1989, 67, 121-128, OakninBendahan , S. et al., J.Basic Clin. Phisil. Pharmacol., 1992, 3, 253-268) and was also confirmed in this study, the administration of melatonin by injection in the morning or evening or orally through drinking water does not affect density or 24-hour changes in melatonin binding sites in most areas of the brain, including medulla pons. Moreover, pituitary removal does not eliminate the one-hour changes in 2- ^{| 25} 1-iodomelatonin binding sites, although it affects their phase position (Oaknin-Bendaham et al., 1992, ibid). Thus, the change in the density of melatonin binding sites may not be due to the auto-regulation of the melatonin receptor.

In the cerebral cortex, melatonin slightly reduces ³ H-RO 15-1788 and ³ HFNZ binding.

Treatment with diazepam did not significantly affect ³ H-RO 15-1788 and Ή-FNZ binding, but prevented a decrease in mediator melatonin (Table 2.3). These data indicate, first, that the effects of melatonin on the benzodiazepine binding sites are more local than the general suppression or facilitated binding, and second, that melatonin replacement therapy may counteract some of the deleterious effects of chronic benzodiazepine treatment.

Table 1 shows the equilibrium binding parameters of 2- ¹²⁵ 1-iodomelatonin binding sites in synaptosomal preparations in the medulla pons region of treated and untreated diazepam and / or melatonin rats, expressed with mean and SD values of Kd (in nM) and B _tach (in pmol / mg protein). The values indicated in the same way in Table 1 should not differ significantly. (Codes of the same meaning are also used in Tables 2 and 3 below).

TABLE 1

GROUP Kd ± sd Bmaxisd CON 0.87 + 0.2 a 7.9 + 1.0 a MEL 1.16 + 0.3 a 7.7 + 1.0 a VAL 0.98 + 0.21 a 5.1 + 0.5 b VAL / MEL 2.27 + 0.75 b 12.5 + 2.0 c

Table 2 shows the equilibrium binding parameters of ³ H-RO 15-1788 binding sites in synaptosomal preparations from the medulla pons area of treated and untreated rats with diazepam and / or melatonin, expressed as mean and SD values of Kd (in nM) and Bmax (in pmol / mg protein).

TABLE 2

GROUP Kd ± sd Bmax ^ Sd | CON 2.3 + 0.4 a 310 + 22 a MEL 2.8 + 0.2 a 476 + 26 b VAL 2.5 + 0.4 a 295 + 34 a VAL / MEL 2.6 + 0, 5 a 375 + 87 b

Table 3 shows the effects of diazepam or melatonin on Ή-FNZ and ³ H-RO 15-1788 binding in rat cortex membranes, expressed as mean and SD values (in pmol / mg protein).

TABLE 3

GROUP ³ H-FNZ ^j H7R0 15-1788 CON 1 935131 a 1354 + 48 a MEL 765178 b 1060 + 26 b VAL 870 + 22 a 1264 + 99 a VAL / MEL 980 + 16 a 1362 + 155 a

Example 2. This example illustrates the surprising effect of melatonin to facilitate the very rapid elimination of resistance to benzodiazepine drugs.

A 43-year-old woman married with two children suffering from insomnia at the onset of sleep for the past 10 years, accompanied by frequent and severe migraines. Detailed neurological examination is negative. Psychiatric and other problems are also dismissed. For these years, the woman has been treated with benzodiazepine, tricyclic antidepressants and neuroleptic drugs, as well as physiotherapy and relaxation methods without visible relief. For the past year she has used 4-8 mg lorazepam every night. A thorough physiological study at Sileep Laboratory of Tel Aviv University did not reveal any significant pathology. The quality of sleep was examined by tracking an actigraph that automatically measures the way of falling asleep in the bed by a small device attached to the wrist of the hand. The follow-up is logged on three consecutive days and shows upset sleep: decreased performance, long sleep latency, and many episodes of waking. Urine was collected every 3 h (for 36 h) and tested for the major metabolite of melatonin: 6-sulfatoxymelatonin, as an indicator of the daily secretion of melatonin into the plasma. The results show that the excretion level of 6-sulfatoxymelatonin is lower than for individuals of the same age and lacks the typical daily rhythm (Table 4).

Oral administration of a controlled-release composition containing melatonin in the form of tablets containing 1 mg of melatonin (Neurim Pharmaceuticals, Israel) is started in order to correct the deficiency and disorder of the melatonin rhythm. It is given daily at one tablet at 8.30 in the afternoon. The patient is required to reduce the number of benzodiazepine tablets taken each night. Surprisingly, for a period of two days the patient stopped using benzodiazepine sleeping pills altogether and stated that insomnia had decreased significantly. In addition, her headache also gradually diminishes. Repeated monitoring of the activigr after 3 weeks of treatment showed a marked improvement in sleep.

Treatment was discontinued and urine collected every 3 h (36 h) for 2 weeks and examined for 6-sulfatoxymelatonin. The results (Table 4) show an increase in the amount and a clear nighttime peak for 6-sulfatoxymelatonin in the urine. After 5 months of use, the patient still maintains quality of sleep and barely suffers from a headache. After 6 months without treatment, the quality of sleep begins to deteriorate and melatonin therapy resumes.

This case report shows a potential breakthrough in the relief of many patients whose quality of life is impaired by the habit of overuse of benzodiazepine sleeping pills. Moreover, administration of exogenous melatonin serves as a means of rapid and asymptomatic withdrawal of benzodiazepine from resistant patients.

Table 4

6-Sulfatoxymelatonin in the urine of benzodiazepine-dependent patients before and after melatonin therapy (pg / h)

Time Before treatment After treatment 15,00 0.3 0.11 18,00 0.16 0.45 21,00 0.18 0.11 Ί i -4 24,00 3.00 0.13 0.23 1,24 0.74 ή 6,00 0.23 0.36 9,00 0.22 0.21 ^P 12,00 0.13 0.01 and 15.00 L 0.22 0.04

Example 3. This example demonstrates the effects of long-term administration of melatonin in the treatment of insomnia in patients dependent on a benzodiazepine drug.

Two volunteers, Y.L., a man of 80 years, and E.L., a woman of 73, each suffered many years of insomnia and frequent waking at night, accompanied by difficulty in recovering from sleep afterwards. Both were found to have low melatonin secretion by determining the amount of metabolite 6-sulfatoxymelatonin in the urine. Both patients took 1-2 mg of flunitrazepam orally before going to bed each night.

Each patient was relieved from flunitrazepam by gradually reducing the dose and concomitantly administering melatonin orally (2 mg melatonin daily as a controlled release formulation) over a 2-month period. From the end of this period, each patient continued to take melatonin in the same form and at the same dosage concentration for 2 years.

Each patient subjectively reported good sleep and a significant improvement in sleep quality. Specifically, patient E.L. reported an improvement in sleep quality at the beginning of the withdrawal period, and Y.L. noted a similar effect about 2 weeks into the opt-out period. Each patient reported a decrease in daytime fatigue within days of the start of the withdrawal period, and indicated that melatonin did not cause any residual fatigue in the morning or any unpleasant sensation. No side effects were reported by both patients.

Example 4. This example, referred to as an arbitrary, double-blind cross-over study, illustrates the ability of melatonin replacement therapy to improve sleep maintenance in adult patients receiving a chronic benzodiazepine drug.

The average age group of 78 years (S.D. = 9.7) consists of 8 men and 5 women, all of whom complain of prolonged insomnia and use various benzodiazepines to induce sleep. Urine was collected approximately every 4 h for 15 h and overnight excretion of 6-sulfatoxymelatonin, the major metabolite of melatonin in urine, was analyzed two-step by RIA. Urine testing in these patients showed low and delayed excretion of 6-sulfatoxymelatonin (<14 pg per night compared with 25 pg per minute in young adults).

The study protocol consists of two treatment periods of three weeks each, with a one-week wash interval between the two treatment periods. During the treatment periods, patients are given orally 2 mg melatonin in controlled-release tablets or placebo 2 hours before bedtime. Five patients continued treatment with melatonin for a period of 2 months after the start of the experimental period.

Patients' sleep was objectively examined at the end of each treatment period for 3 consecutive nights using an actigraph worn on the wrist of the arm. Motion registration was analyzed using the Neurim algorithm to determine sleep latency, sleep efficiency, total sleep time, wake-up wake-up time, and number of wake-ups as a mean of three nights for each subject. Six Wilcoxon-matched and matched pairs were analyzed, with 10 finding statistically significant differences in parameters between the melatonin and placebo-matched pairs. The results are shown in Table 5.

Table 5

Effect on sleep parameters and substitution of benzodiazepine drugs with melatonin

Parameter After 3 weeks of treatment with After + 2 months treatment with melatonin Melatonin Placebo Sleep efficiency 82% 75% 85% (z = -2.82, ρ = 0.005) Sleep latency 17 min 39 min 7 min (z = -2.12, ρ = 0,03) Waking up after 59 min 76 min 42 min the onset of sleep (-2 = -2.00, ρ = 0,04) Number of wakes 11 17 10 (ζ = -2.70, ρ = 0.007) Total Sleep Time 386 min 375 min 348 min (ζ = -0.57, ρ = 0.58)

From the above results, it can be concluded that melatonin therapy may improve the initiation and maintenance of sleep using a benzodiazepine drug in elderly patients with low endogenous melatonin release. The beneficial effects of melatonin treatment increase over time, indicating that a reorganization of the daily system has occurred.

Claims (8)

Claims 1. The use of melatonin for the prevention and treatment of patients suffering from ben40 zodiazepine dependence, persistence or habituation by daily administration in the range of 0.01 - 100 mg or in the case of the protection of a patient to whom benzodiazepine is administered daily of melatonin less than 10 mg. Use according to claim 1, wherein the melatonin is included in a controlled release pharmaceutical composition. Use according to claims 1 and 2, wherein the controlled release pharmaceutical composition contains melatonin in 50 amount adapted for daily administration in the range of 0.01 - 5 mg. Use according to claims 1 to 3, wherein the pharmaceutical composition is suitable for oral, rectal, parenteral or transdermal administration and comprises at least one diluent, carrier or additive. Use according to claim 4, wherein the pharmaceutical composition is further characterized by at least one of the following features: (I) is a unit dosage form, each of which contains, including in the case of protection, melatonin, in the range of 0.0025-100 mg when the formulation is not controlled-release and 0.0025-5 mg when the formulation is a controlled release; (Ii) when in the form of a controlled release formulation, melatonin is preferably released at a predetermined controlled rate; (III) also contains at least one melatonin receptor modifier and / or a melatonin profile modifier. Use according to claims 1 to 5, wherein the pharmaceutical composition also includes at least one benzodiazepine drug, which is preferably alprazolam, chlordiazepoxide, chlorazepate, diazepam, flunitrazepam, flurazepam, halazepam, lorazepam, oxazepam, prazepam and triazepam, triazamam. Use according to claims 1 to 6, wherein the treatment involves administering the benzodiazepine drug (a) together with melatonin, the benzodiazepine drug being administered in a daily amount which progressively decreases until a predetermined stabilized daily amount of the benzodiazepine drug (a) is reached. The use according to claims 1 to 6, wherein the treatment comprises administering the benzodiazepine drug (s) together with melatonin, the benzodiazepine drug being administered in a daily amount which progressively decreases until the patient's total withdrawal of the benzodiazepine drug (s) is achieved .