SI9620022A - Use of melatonin for treating patients suffering from drug addiction - Google Patents

Abstract

Melatonin is used in the manufacture of a medicament for treating a multidrug addict, or a patient who has symptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug, or for treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug. The invention further relates to a pharmaceutical formulation for the above-stated purposes, which comprises at least one diluent, carrier or adjuvant and as active ingredients a benzodiazepine drug and melatonin.

Description

USE OF MELATONINE FOR SEPARATION FROM ADDICTION

The present invention relates to the use of melatonin in the manufacture of medicaments for the treatment or prevention of addictive and tolerant symptoms and addiction to benzodiazepine drugs, as well as for the treatment of multiple drug addicts and to pharmaceutical preparations for use in such therapies.

Benzodiazepine dependence often occurs in people who have sleep problems and use them to stimulate sleep, and in people who are addicted to multiple drugs and become dependent on benzodiazepines in the process of drug withdrawal to ease their anxiety and cramps. Chronic use of benzodiazepines (when benzodiazepines usually have long half-lives) may, by some unknown mechanism, lead to a tolerable symptom, which is expressed as an ineffective dose increase. Moreover, the abrupt cessation of these drugs is often followed by the repulsive phenomenon or the phenomenon of "withdrawal" that leads to addiction, which has been observed in both animal and human experiments (Greenblatt, DJ, & Shader, RI, Drug Metab. Rev ., 1978, 8: 13-28). In 1990, the US National Hausehold Survey showed that about 8% of hypnotic users had increased the prescribed dose, which was an increase of 25% compared to 1979. Considering the study's finding that 2.6% of the US of the population taking benzodiazepine drugs (compared to 2.4% in 1979), the number of individuals who developed the symptom of tolerance and addiction can be estimated at 560000. All these figures do not include substance use outside medical and social norms and abuse in addicts multiple drugs. To date, no method of abrupt drug withdrawal has been published, followed by effective alternative treatment in patients dependent on benzodiazepine hypnotics, and this problem represents a major obstacle to the rehabilitation and recovery of narcotic addicts.

Melatonin - an indole hormone extract produced at night in the pineal gland - is known to play a major role in regulating the sleep and wake cycle and in regulating sleep. There is also evidence that melatonin can easily increase the efficacy of benzodiazepines, j

see example Cardinali, D.P. et al, Adv. Biochem. Psychopharm., 1986, 42: 155-164; Acuna Castroviejo, D., et al, J. Pineal Res., 1986, 3: 101-102; and Niles, L.P. et al, J. Neural Transm. 70: 117-124. Likewise, melatonin may increase the effect of dye in mice (Guardiola-Lemaitre, B., et al, Pharmacol. Biochem. Behav., 1992, 41, 405-4080). On the other hand, it has been suggested that benzodizepine could in some species, including human potentiate GABA-induced inhibition of melatonin synthesis and secretion (Mclntyre, IM et al, Biol. Psychiat., 1988, 24: 105-108), and nocturnal elevation of melatonin plasma could be prevented by benzodiazepines in humans, which would then lead to distortions in daily melatonin rhythm (Kabuto, M. et al, Endocr. Jap., 1986, 33, 405-414). It has also been observed that prolonged oxazepam treatment alters daily variations in the nocturnal melatonin receptor density in the rat brain, but this effect has not been observed in pinealectomized animals (Anis, Y., et al, J. Neural Transm., 1992, 89 : 155-166).

In connection with the present invention, it has been surprisingly discovered that the use of melatonin in accordance with benzodiazepine drugs may (1) potentially deter the patient from the dependence, addiction or tolerance of such drugs, and (2) in the case of a patient having prescribed benzodiazepine drugs (and these unwanted symptoms have not yet occurred) may prevent these symptoms from occurring.

BACKGROUND OF THE INVENTION

EP-A-513702 describes the use of melatonin and certain melatonin derivatives in the treatment of unbalanced sleep in pre-anesthesia treatment with the possibility of benzodiazepine being present. This document states that benzodiazepine can be used at relatively lower doses to avoid the effects (changes in sleep rhythm, rebound effect and tolerance) associated with the use of large amounts of benzodiazepine or longer use. periods. However, this document does not state that doses of melatonin or derivatives of less than 10 mg may be used for this purpose, nor does it state that melatonin may be useful when a patient has already become addicted, addicted or tolerated with a benzodiazepine drug.

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ΕΡ-Α-518468 describes a controlled preparation of a pharmaceutical composition that briefly secretes melatonin according to a profile that simulates a human plasma profile with a normal normal endogenous melatonin profile. Formulations that preferably contain a melatonin modifying receptor profile such as oxazepam are useful for treating conditions that relate to a melatonin deficiency or abnormality, such as sudden childhood death syndrome and migraine. However, this document does not suggest the use of melatonin to prevent or treat benzodiazepine addiction.

In DIALOG File Supplier PHIND. AN 00302794, 13-03-92, indicates that indole-3-pyruvic acid (IPA) prolongs sleep time in non-sleeping subjects undergoing benzodiazepine, and that the effect of IPA on sleep is mainly caused by an accelerated melatonin cycle , in the pineal gland. However, this document does not indicate the use of melatonin to prevent or treat benzodiazepine addiction.

DESCRIPTION OF THE INVENTION

The present invention thus provides for the use of melatonin in the manufacture of medicaments for the treatment of benzodiazepine addicts or for multiple drug addicts, a patient exhibiting symptoms of dependence, tolerance to / or addiction to a benzodiazepine drug, and for the treatment of a patient diagnosed with a condition sensitive relieving the use of the benzodiazepine drug while preventing the patient from experiencing symptoms of dependence, tolerance or addiction to said benzodiazepine drugs, said medicament comprising at least 10 mg of melatonin effective for any of said treatments; said amount should be adjusted for daily use in the range of 0.01-100 mg, provided that said drug is used to treat a patient who has been clinically diagnosed with a condition of susceptibility to the use of a benzodiazepine drug, then said drug is an approved pharmaceutical formulation which does not contain more than 5 mg of melatonin.

Said medicament may be a pharmaceutical formulation adapted for oral, rectal, parenteral or transdermal use, comprising at least one diluent, carrier or adjuvant and further characterized by at least one of the following characteristics: (i) in the form of a single dose, each dose combines a specific an amount of melatonin ranging between 0.0025-100 mg; (ii) in the form of a controlled preparation of a preparation with a predetermined and controlled amount of melatonin; (iii) it also combines at least one melatonin receptor adjuster and / or melatonin profile adjuster. The medicament as well as the pharmaceutical composition of the invention may also contain at least one benzodiazepine drug such as Alprazolam, Chlordiazepoxide, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepam and Triazolam. A preparation that combines at least one benzodiazepine drug may also be characterized by one or more of the characteristics (i), (ii) and (iii) described above.

In the use of the present invention for the treatment of multiple drug addicts or patients suffering from symptoms of dependence, tolerance or dependence on benzodiazepine drugs, the use of the benzodiazepine drug is continued in the patient at least initially and at the same time melatonin is used in an amount effective to relieve at least one of the symptoms listed.

In a particular combination for such treatment, either the benzodiazepine drug or the melatonin in the form of a pharmaceutical composition may be adapted for oral, rectal, parenteral or transdermal use, combining at least one diluent, carrier or adjuvant. Alternatively, the benzodiazepine drug and melatonin may each be used in the formulation ah individually, or combined in a single pharmaceutical formulation comprising both the diazepine drug and melatonin.

Depending on the prescribed dose of melatonin used alone or together with one or more benzodiazepine drugs, administration may be effective with a daily amount ranging from 0.01-100 mg; may be used in the form of a controlled preparation. For illustration, a patient may be prescribed a controlled preparation of 1-2 mg of melatonin at night. Melatonin can be used in conjunction with a melatonin receptor adjuster or a melatonin profile adjuster. Examples of melatonin receptor modifiers are short-term effective benzodiazepines such as Oxazepam; examples of * / melatonin profile tailors are benzodiazepine beta-blockers and seratonin boosters. Instead of, or in addition to, the use of such profile adjusters, the melatonin profile may be altered by exposing the patient to the effect of light before, after and during the use of melatonin.

The benzodiazepine drugs mentioned here can worsen the symptoms of addiction, tolerance and / or addiction. Without bias towards this fact, such drug or drugs may be one or more such as: Alprazolam, Chlordiazepoxide, Clorazepat, Diazepam, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepam and Trazolam.

In one alternative combination, in the use of the invention for the treatment of the above-mentioned symptoms, the benzodiazepine drug (s) is initially continued to be administered to the patient in accordance with melatonin at a daily dose substantially the same as that obtained at baseline. treatment with melatonin. In another alternative combination of use of the invention in the treatment of such symptoms, the benzodisepine drug (s) is administered to the patient in accordance with melatonin in a progressively reduced daily dose compared to the initiation of treatment with melatonin. In this combination, the progressive decrease in daily amount in use can be continued until a predetermined stable amount is reached, or alternatively, until the amount of benzodiazepine drug used is zero.

When using the invention for preventive purposes, e.g. in the treatment of a patient who has a clinical diagnosis of susceptibility to benzodiazepine, while simultaneously avoiding symptoms of dependence, tolerance, or addiction to said benzodiazepine drug, the benzodiazepine drug is prescribed in an amount that effectively alleviates the said condition, while the amount of melatonin that is effective in preventing at least one of these symptoms is also prescribed according to the patient. The various combinations described above as useful in treating a patient with said symptoms are also consistently useful for preventive purposes, except when they are not useful for reasons known to the person skilled in the art, e.g. on this occasion, treatment with the benzodiazepine drug is desirable to achieve the predetermined amount of benzodiazepine used, while it may not be reduced to zero in any case specified by the physician.

However, according to the preventive application of the invention, it is not only the use of a benzodiazepine drug consistent with melatonin at a conventional daily dose to achieve a particular purpose, but also as an alternative to similar use of such drugs at a lower daily dose, which is conventionally prescribed to the patient to alleviate said condition.

As mentioned above, the invention also relates to a pharmaceutical composition comprising at least one benzodiazepine drug and melatonin. Because benzodiazepine drugs are usually prescribed 1 to 4 times a day, a daily dose of 0.01-100 mg of melatonin, typically used at night, in the same formulation as benzodiazepine (s), or even when prescribed separately, can be achieved by use. benzodiazepines as follows:

Days Benzodiazepine dose in range 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 preparation is made in unit dosage form, it is preferable that each dose be prescribed at night and include an amount of melatonin in the range 0.0025100 mg.

The following table shows the amount of melatonin used in the treatment of these conditions in adults. For further information on reservations, half-life, uses and appropriate dosing in children, see Goodman & Gilman's 'The Pharmacological Basis of Therapeutics', Seventh Edition, 1985 (MacMillan Publishing Co.), excerpts relating to the use of benzodiazepines (as on pages 352, 437).

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Benzodiazepine Oral dose content in mg (daily) Normal daily oral dose Sedative Hypnotic A tranquilizer Alprazolam 10-100 (1-3) 0.75-1.5 Chlordiazepoxide 3.75-15 (2-4) 50-100 15-40 Clorazepat 5-10 (3-4) 15-30 30 Diazepam 5-10 4-40 Flurazepam 15-30 Halazepam 60-160 Lorazepatn 2-4 2-6 Oxazepam 15-30 (3-4) 15-30 30-60 I'm blank 20-40 Temazepam 15-30 Triazolam 0.25-0.5

* mg; usually divided into 2-4 unit doses; for further information including parenteral dosage areas, see the previously cited edition of Goodman & Gilman.

The preparation and fabrication of profiles of preparations for use in accordance with the invention or its applications are described below.

(a) Compressed in a 7 mm cylindrical press at 2540 kg (2.5 tonnes) after dry mixing of the following powdered materials: 2 mg per tablet of melatonin (Biosynth Co., Switzerland) and acrylic resin carrier (Rohm Pharma) Eudragit® RS 100 (SR-Ms formulation) or Eudragit® RSPO (SR-Mf formulation), among other components, in the following ratio:

SR-Ms formulation: Eudragit® RS 100 48.8%, lactose 50%, melatonin 1.2% SR-Mf formulation: Eudragit® RSPO 36.3%, lactose 16.7%, calcium hydrogen phosphate 41.4%, talc 1.3%, magnesium stearate 4%, melatonin 1.3%. SR-Ms and SR-Mf are accepted formulations of the preparation.

The conventional dosage unit (RM) formulation was prepared similar to the SR-Mf formulation but using lactose instead of Eudragit® as a carrier.

(b) The possible profile of the tablets prepared as described in paragraph (a) was first investigated in a test tube (in vitro) with a solution of melatonin in distilled water at 37 ° C. The results in Table A show% of the amount of melatonin (mean of 6 tablets) dissolved at the indicated time intervals.

Table A

Time (hours) 1 2 4 6 8 10 melatonin (%) obtained 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) was investigated by oral administration twice in a healthy male (age 36 years) at 10 o'clock in the morning when the rate of melatonin circulation was undetectable. The amount of melatonin secreted in vivo was determined by radioimmunoassay of its major metabolite, 6-sulfatoxymelatonin in the urine. The amount of urine 6-sulfatoxymelatonin shows very well in the amount of hormone in the blood. The results of Table B show melatonin determined as a percentage of all melatonin consumed. (mean of two tablets).

Table B

In vivo distributed melatonin from SR-Mf

Time (hours) 1 2 4 6 8 10 % elimination at intervals 10.7 25.7 40.6 14.0 7.0 1.9 cumulative elimination % 10.7 36.4 77.0 91.0 98.0 99.9

It is reported that the amount of in vitro excreted melatonin shown in Table A provides only approximate indications of the in vivo secreted profile, due to the known phenomenon of active components absorbed by tissue at an early stage of excretion.

The amount of melatonin in the permanently eliminated formulations may be changed to 0.5, 1 or 5 mg / tablet without affecting the elimination pattern observed in tablets containing 2 mg of melatonin per tablet.

The melatonin analogues thus found, which mimic well the function of melatonin in the Human Body, are to be considered in this context as the chemical equivalents of melatonin.

According to the present invention, one or more benzodiazepines may be combined in the above preparation in the amount described herein. The invention will now be described by way of example.

EXAMPLE 1

The reciprocal effects of chronic use of benzodiazepine and melatonin on brain melatonin and benzodiazepine receptors and the ability of melatonin to reverse these effects were examined. Male rats were exposed to 14 hours of light daily (beginning at

5 am; cool white fluorescent light) and 10 hours of darkness at 24 ± 2 ° C. They got their food and drinking water together. Animals (2 months old) were divided into 4 groups of 5 specimens. Animals in the first group (CON) were injected daily with a preparation (200 pl, saline) at 4:00 pm. Animals in the second (VAL) group were injected with diazepam (1 mg in 200 μΐ of the preparation; Roche) daily at 4:00 pm. Animals in the third group (MEL) were injected daily at 4:00 pm; The drinking water of this group contained melatonin (4 mg dissolved in 100 μΐ ethanol and diluted to 1 liter). Animals in group 4 (VAL / MEL) were injected with daizepam (1 mg per 200 μΐ of the preparation) daily at 4:00 pm; The drinking water of this group contained melatonin (4 mg dissolved in 100 μ! ethanol and diluted to 1 liter). After 21 days, the experiment was stopped, the animals weighed. The mean body weights in the VAL group (274 ± 20 g) and the VAL / MEL group (239 ± 30 g) were found to be slightly lower than those in CON (292 ± 30 g) or MEL (285 ± 30 g) groups.

Lives were beheaded between 6pm and 7pm the next day (at this time, the density of 2- I-iodomelatonin in medulla pons is expected to be highest); their brains were quickly removed and coarse synaptic circuits prepared as described and melatonin receptors evaluated as described by Laudon, M. and Zisapel, N., FEBS Lett., 1986, 197: 9-12. Benzodiazepine receptors were evaluated by measuring ³ H-flunitrazepam ( ³ H-FNZ) and ³ H-RO 15-1788 bound as described by Amiri, Z. et al, Brain Res., 1991, 533: 155-158. The binding parameters were calculated by equilibrium binding data. Bmax values represent specific binding of 2- ¹²⁵ I-iodomelatonin, ³ H-FNZ or ³ H-RO 15-1788 at saturation, and Kd values are likely dissociation constants. The binding parameters of different groups were compared by analysis of variance followed by Student-Nevvman-Keul test for multiple comparisons. Differences were considered significant if P <0.05. Three-week daily injections of diazepam (1 mg at 4:00 pm) in male rats significantly reduced the density of 2- I-iodomelatonin binding sites in the medulla-pons (Table 1), while benzodiazepine bonds were not significantly affected (Table 2). If melatonin receptors are linked to the control of the sleep and wake cycle, then the results suggest that chronic use is manifested in the decline of the melatonin response mechanism and, consequently, of psychic activity.

Melatonin given orally in drinking water for three weeks significantly increased the binding of ³ H-RO 15-1788 in medulla pons (Table 2.3), while the binding of 2- ¹²⁵ I-iodomelatonin remained unchanged. The increase in the density of benzodiazepine binding sites and apparent Kd in the medulla pons induced by the melatonin experiment is compatible with the previously observed increase in rat cortex, which was seen as binding to opioid peptides (Gomar, MD et al, Neuroendocrinnology 1993, 4: 987- 990). The fact that this increase also persists in animals given diazepam is thought to outweigh the competition between melatonin and benzodiazepines for occupying benzodiazepine binding sites.

Daily administration of both diazepam and melatonin increases ³ H-RO 15-1788 bonds in medulla pons and obes diazepam-induced reduction of 2- ¹²⁵ I-iodomelatonin bonds in this area (Tables 1,2). These results are striking, as shown (Anis, Y; mlatonin binding sites in the hamster brain; influence of melatonin. Mole. Whole. Endocrinol., 1989, 67: 121-128; Oaknin-Bendahan, S., J. Basic Ciin. Physiol Pharmacol., 1992, 3: 253-268) and is also confirmed in this study, the use of melatonin through morning or evening injection, and oral administration with drinking water does not affect the density or daily variation in melatonin binding sites in most areas in brain, including medulla-pons. Moreover, pinealectomy does not eliminate daily variations in the 2- ¹²⁵ Iodomelatonin melatonin binding sites, although it does affect their phase position (Oaknin-Bendahan, 1992, ibid). These changes in the density of melatonin binding sites are not at the expense of autoregulation of receptors by melatonin.

In the cerebral cortex, it slightly reduces ³ H-RO 15-1788 and ³ H-FNZ bonds. The use of diazepam did not significantly affect ³ H-RO 15-1788 and ³ H-FNZ bonds, but prevented a decrease in mean melatonin (Table 2.3). These data suggest, first, that the effects of melatonin on benzodiazepine binding sites are localized rather than a general reduction or assist in bond formation, and second, that melatonin replacement therapy may prevent some adverse effects in benzodiazepine therapy.

Table 1 shows the balance of binding parameters of 2- ¹²⁵ I-iodomelatonin binding sites and synaptosomal preparations from the medulla-pons region of rats treated with melatonin and / or diazepam or nothing, in terms of meanings and SD values of Kd (in nM) and Bmax ( in gmol / mg protein). The values indicated by the characters in Table 1 are not significantly different. (Codes of the same meaning are also used in Tables 2 and 3, below.)

Table 1

GROUP Kd ± sd Bmax ± sd 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 ± 0.5b VAL / MEL 2.27 ± 0.75 b 12.5 ± 2.0 c

Table 2 shows the equilibria of the binding parameters of ³ H-RO 15-1788 binding sites in synaptosomal preparations from the medulla-pons region of rats given diazepam and / or melatonin or nothing, in terms of meanings and SD values of Kd (in nM) and Bmax (in μηιοΐ / mg protein).

Table 2

GROUP Kd ± sd Bmax ± sd CON 2.3 ± 0.4 a 310 ± 22a 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 the ³ H-RO 15-1788 and ³ HFNZ bonds in the membranes of rat cerebral cortex, in terms of meanings and SD values (in μιηοΐ / mg protein).

Table 3

GROUP ³ H-FNZ ³ H-RO 15-1788 CON 935 ± 31a 1345 ± 48 a MEL 765 ± 78 b 1060 ± 26b VAL 870 ± 22a 1264 ± 99 a VAL / MEL 980 ± 16 a 1362 ± 155 a

EXAMPLE 2

This example demonstrates the striking action of melatonin in the very rapid acceleration of lowering tolerance of benzodiazepine medications. Thirty-four (43) women; married, with two children; has suffered from uneven sleep over the last ten (10) years, accompanied by severe and persistent migraine attacks. The exact neurological evaluation was negative. Psychiatric or organic problems were also excluded. Throughout all these years, she has been treated with benzodiazepines, tricyclic antidepressants and neuroleptic drugs, as well as biofeedbacks and the relaxation method, all with no visible improvements. For the last four years, she has been taking 4-8 mg of Lorazepam every night.

A thorough psychological assessment at the Tel Aviv University Sleep Lab revealed no major pathologies. Sleep quality was assessed by actigraphic tracking, which automatically monitors nighttime sleep-wake patterns with a small device attached to the wrist. Tracking was recorded for 3 consecutive days and showed an altered sleeping pattern: decreased performance, long sleep latency, and numerous wake-ups. Urine was taken every 3 hours (within 36 hours) and tested for the major melatonin metabolite: 6-sulfatoxymelatonin as an indicator for the daily secretion of melatonin plasma. The results showed that the elimination rates of 6-sulfatoxymelatonin were lower than they should have been for older, married individuals, and lacked the typical circadian rhythm (Table 4).

Oral administration of a controlled-formulation melatonin preparation in the form of tablets containing 1 mg of melatonin (Neurim Pharmaceuticals, Israel) was introduced to correct the deficiency and deformity of the melatonin rhythm. 1 tablet was given daily at 8:30 in the evening. The patient was asked to gradually reduce the number of benzodisepine tablets taken each night. Surprisingly, within 2 days the patient completely stopped using benzodiazepine hypnotics and claimed that her insomnia had improved visibly. In addition, her headaches gradually subsided. Repeated actigraphic tracking showed a marked improvement in the sleeping pattern after three weeks of treatment.

Treatment was discontinued after 2 weeks, then re-taken urine for 3 hours (within 36 hours) and tested for 6-sulfatoxymelatonin. The results (Table 4) indicated an increase in the amount of urinary 6-sulfatoxymelatonin and a clear nighttime peak. A follow-up examination after 5 months confirmed that the patient was still maintaining her sleep quality and was barely suffering from headaches. At 6 months, without treatment, the quality of sleep began to deteriorate and melatonin therapy was repeated.

This case points to a potential achievement in the relief of many patients whose quality of life has been impaired by benzodiazepine hypnotics. The use of exogenous melatonin may primarily serve as a means of withdrawal from benzodiazepines in dependent patients, which is rapid and does not cause any symptoms.

Table 4: Urinary 6-sulfatoxymelatonin in a benzodiazepine-dependent patient before and after melatonin therapy (pig / hour)

Time before therapy after therapy 15.00 0.3 0.11 18.00 0.16 0.45 21.00 0.18 0.11

24.00 0.13 1.24 3.00 0.23 0.74 6.00 0.23 0.36 9.00 0.22 0.21 12.00 0.13 0.01 15.00 0.22 0.04

EXAMPLE 3

This example shows the consequences of long-term use of melatonin in the treatment of insomnia in a patient dependent on benzodisepine drugs.

Two volunteers, Y.L., an eight-year-old (80) man, and E.L, a seventy-three-year-old (73) woman, suffered many years of insomnia and / or constant nighttime awakening, which was associated with difficulty falling asleep again. Both were found to be low in melatonin, determining the amount of metabolite 6-sulfatoxymelatonin in the urine. Both patients took 1-2 mg of flunitrazepam orally each night before going to bed.

Flunitrazepam was withdrawn from each patient by dramatically reducing the amount and simultaneously administering melatonin (2 mg controlled-dose melatonin) orally over two months. At the end of this time, patients continued to use melatonin in the same form and amount for about two years.

Each patient personally reported a good sleep onset as well as a marked improvement in sleep quality. In particular patient E. L, observed an improvement in sleep quality at the beginning of the discharge period, Y. L. observed similar effects, approximately two weeks after the start of the discharge. Both patients reported decreased fatigue during the day, several days after the start of the discharge period, and also showed that melatonin did not cause fatigue in the morning, nor a feeling of a night out. No patient reported any side effects.

EXAMPLE 4

This double-blind case study is a cross-sectional and randomized study designed to demonstrate the possibility of alternative melatonin therapy for improving sleep in chronic elderly benzodisepine drug users.

The average age group of 78 (SD = 9.7) consisted of eight men and five women, all of whom complained of long-term insomnia, all using different benzodiazepines, to induce sleep. Urine was taken approximately every 4 hours for 15 hours, and the overnight excretion of 6-sulfatoxymelatonin, the major urinary metabolite of melatonin, was analyzed and duplicated by RIA. Urine analysis of patients showed low and delayed 6-sulfatoxymelatonin excretion (<14 pg / night compared with 25 μg / minute in young adults). The study protocol consisted of two treatment periods of 3 weeks each, with a one-week cleaning period between the two periods. During the treatment periods, patients were given orally either 2 mg of controlled-release melatonin tablets or placebo two hours before bedtime. Five patients continued melatonin treatment, two months after the end of the experimental periods.

Patients' sleep was objectively analyzed at the end of each treatment period, three consecutive nights, using a wrist actigraph. Motion records were analyzed using the Neurim algorithm to determine latency, sleep efficiency, total sleep time, wake-up and wake-up times, as averages of three nights for each patient. Six identical pairs of Wilcoxon prescribed-rate analyzes revealed statistically significant differences in sleep parameters between melatonin and placebo treatment.

Table 5: Effects on sleep parameters of benzodiazepine drug replacement with melatonin.

Parameters after three weeks treatment after + two months of treatment with melatonin placebo melatonin efficiency 82% 75% 85% sleep (z = -2.82, p = 0.005) latency 17 min. 39 min. 7 min. sleep (z = -2.12, p = 0.03) awakening honey 59 min. 76 min. 42 min. sleep (z = -2.00, p = 0.04) number 11 17 10 awakening (z = -2.70, p = 0.007) total time 386 min 375 min. 348 min. sleep (z = -0.57, p = 0.58)

From the above results, it is concluded that replacement melatonin therapy can improve the onset and maintenance of sleep; in benzodiazepine treatment, elderly patients have a low endogenous melatonin response. The usefulness of melatonin treatment increases over time, suggesting that the circadian system has re-established.

Claims (9)

1. The use of melatonin in the manufacture of medicaments for the treatment of benzodiazepine addiction in addicts, or for a patient exhibiting symptoms of, dependence on, or addiction to a benzodiazepine drug, or for the treatment of a patient diagnosed clinically with a condition susceptible to the use of a benzodiazepine drug while preventing the patient from experiencing symptoms of dependence, tolerance or addiction with said benzodiazepine drug, wherein said medicament comprises at least an amount of melatonin effective for any of said treatments; said amount should be adjusted for daily use in the range of 0.01-100 mg, provided that said drug is used to treat a patient who has been clinically diagnosed with a condition of susceptibility to the use of a benzodiazepine drug, then maintained for said drug approved pharmaceutical formulation containing no more than 5mg of melatonin. Use of melatonin according to claim 1 in the manufacture of medicaments for the treatment of benzodiazepine addictions in multiple drug addicts or patients with symptoms of dependence, tolerance or benzodiazepine drug addiction. Use according to claim 2, wherein said medicament is an accepted form of medicament containing no more than 5 mg of melatonin. Use of melatonin according to claim 1, in the manufacture of an accepted form of medicament for the treatment of a patient who has been clinically diagnosed with a condition of susceptibility to benzodiazepine drug, while at the same time preventing the patient from symptoms of dependence, tolerance or addiction to said benzodiazepine a drug according to which said medicament contains at least an amount of melatonin effective for any of said treatments; this amount should be adjusted for daily use in the range of 0.01-5 mg. Use according to any one of claims 1 to 4, wherein said medicament comprises a pharmaceutical preparation adapted for oral, rectal, parenteral or transdermal use and comprising at least one diluent, carrier or adjuvant. Use according to claim 5, wherein said pharmaceutical formulation is further characterized by at least one of the following characteristics: (i) in the form of a single dose, each dose combines a certain amount of melatonin moving in the range 0.0025-100 mg when the formulation is not a sustained approved formulation and in the range 0.0025-5 mg, the named formulation being maintained confirmed formulation (ii) when said formulation is sustainably validated, a formally controlled formulation according to which melatonin is confirmed at a predetermined controlled dose; (iii) it also includes at least one melatonin receptor adjuster and / or adjuster of the melatonin profile. Use according to any one of claims 1-6, wherein said formulation also contains at least one of the benzodiazepine drugs, such as Alprazolam, Chlordiazepoxide, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepam and Triazolam. Use according to any one of claims 1 to 7, when the said treatment involves the use of a benzodiazepine drug (drug) concomitantly with melatonin, the benzodiazepine drug (drug) is used in a daily dose which progressively decreases until a predetermined stable dose is achieved. use of benzodiazepine drug (drug). Use according to any one of claims 1 - 7, when the said treatment involves the use of a benzodiazepine drug (drug) concomitantly with melatonin, the benzodiazepine drug (drug) is used at a daily dose which progressively decreases until the patient has reached complete abstinence from the benzodiazepine drug . z? . · '~ T ~.