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WO1998052565A1 - Traitement de la dependance a certaines substances a l'aide de composes d'antagonistes d'opiaces et de serotonine - Google Patents

Traitement de la dependance a certaines substances a l'aide de composes d'antagonistes d'opiaces et de serotonine Download PDF

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Publication number
WO1998052565A1
WO1998052565A1 PCT/US1998/010289 US9810289W WO9852565A1 WO 1998052565 A1 WO1998052565 A1 WO 1998052565A1 US 9810289 W US9810289 W US 9810289W WO 9852565 A1 WO9852565 A1 WO 9852565A1
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WIPO (PCT)
Prior art keywords
person
naltrexone
treatment
alcohol
opioid
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Ceased
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PCT/US1998/010289
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English (en)
Inventor
Suchitra Krishnan-Sarin
Stephanie O'malley
Conor Farren
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Yale University
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Yale University
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Publication date
Application filed by Yale University filed Critical Yale University
Priority to JP55056398A priority Critical patent/JP2002508753A/ja
Priority to AU75824/98A priority patent/AU7582498A/en
Priority to EP98923558A priority patent/EP1011671A1/fr
Priority to CA002290788A priority patent/CA2290788A1/fr
Publication of WO1998052565A1 publication Critical patent/WO1998052565A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • This invention relates to the use of opioid antagonists such as naltrexone or nalmephene with serotonergic medication for substance dependence, to increase abstinence rates, reduce relapse once abstinence has been achieved, and to diminish side effects associated with the use of opiate antagonists.
  • opioid antagonists such as naltrexone or nalmephene with serotonergic medication for substance dependence
  • Dependence is an adaptive biological state induced by chronic drug exposure manifesting itself in various behavioral and physiological responses when drug exposure ceases. Withdrawal from alcohol following chronic use results in the emergence of an abstinence syndrome which reaches its peak intensity within the first few days. Cessation of alcohol consumption has been shown to result in a number of signs and symptoms of withdrawal such as increases in irritability, anxiety, restlessness, impatience, somatic complaints including nausea, insomnia, and tremulousness, and increases in heart rate and blood pressure as well as hallucinations and seizures, all of which are collectively called the alcohol with- drawal syndrome. Similarly, cessation of cocaine and opiate use also results in significant withdrawal symptomatology, while cessation of marijuana use results in a more subtle withdrawal syndrome.
  • naltrexone alone has been found to increase abstinence and reduce relapse to heavy drinking in alcohol dependence, above that of placebo. Abstinence has been increased by naltrexone from approximately 25% to 50% over a 3 month period, and relapse to heavy drinking has been reduced from 50% to 25% over the same period. Following up at 6 months post cessation of naltrexone, there is a tendency for the naltrexone treated subjects to drink less than the non naltrexone group but not to the same extent immediately following treatment. However, not all alcohol dependent individuals benefit from naltrexone therapy and strategies to maximize treatment outcome are needed.
  • naltrexone is approved for the treatment of opiate dependence, it is not considered an effective treatment for most people because compliance is so poor, presumably in part because naltrexone continues provoke subclinical signs and symptoms of opiate withdrawal even in the detoxified opiate addict. A new approach to opiate antagonist therapy that would be more tolerable would be of considerable value.
  • an opioid antagonist such as nalmefene, naloxone, naltrexone, or a mixture of any of these, in combination with a serotonergic medication such as sertraline, fluoxetine, fluvoxamine, paroxetine, or odansetron.
  • Naltrexone is used in one embodiment.
  • This invention is based upon the finding that opioid antagonists in combination with serotonergic medications are useful in alcohol cessation treatments and in marijuana cessation, in cessation of cocaine, opiates and polysub- stance abuse.
  • opioid antagonists alone are employed in treatments for alcoholism or other substance abuse disorders. Any opioid antagonist may be employed; naltrexone and/or related compounds are used in some preferred embodiments, but any other class of opioid antagonists may be used instead or in addition.
  • Naltrexone, 17-(cyclopropyl- methyl)-4,5-epoxy-3, 14-dihydroxymorphinan-6-one is a congener of naloxone, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one, having opiate-blocking activity.
  • Naltrexone related compounds include, but are not limited to, other structurally related opiate antagonists including naloxone, nalmefene (5 ⁇ -17-(cyclo- propylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol), and mixtures thereof. Naltrexone is used in one embodiment; nalmefene, in another.
  • Administration of opioid antagonists or opioid antagonists in conjunction with other compounds can be local or systemic, or a combination of therapies.
  • Systemic administration is preferred in some embodiments.
  • Systemic administration can be via any method known in the art such as, for example, oral administration of lozenges, tablets, capsules, granules, or other edible compositions; intravenous, intramuscular, or intradermal administration, e.g. , by sterile injections, including depot versions; implants; parenteral administration of fluids, and the like.
  • an antagonist or a compound mixture are typically topically applied to the skin or mucosa in association with a pharmaceutically acceptable carrier in which the antagonist is dispersed or solubilized.
  • Carriers may be aqueous compositions, lotions, creams, ointments, soaps, and the like.
  • the serotonergic medications described can be any one of a number of serotonergic medications including sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, zimeldine, viqualine, fenfluramine, d-fenfluramine, buspirone, gepirone, odansetron and/ or other related compounds.
  • Administration of serotonergic medications or of serotonergic medications in conjunction with other compounds can be local or systemic, or a combination of therapies.
  • Systemic administration is preferred in some embodiments. Systemic administration can be via any method known in the art and summarized above.
  • a serotonergic medication or a compound mixture are typically topically applied to the skin or mucosa in association with a pharmaceutically acceptable carrier in which the antagonist is dispersed or solubilized such as that described for administration of the opioid antagonists described.
  • Carriers may be aqueous compositions, lotions, creams, ointments, soaps, and the like.
  • Naltrexone and/or related compounds are administered to a patient in amounts effective to reduce reinforcement from alcohol, cocaine, marijuana and opiates and polysubstance abuse during detoxification, and/or to prevent relapse after completion of detoxification.
  • the amount of compound necessary to reduce reinforcement and prevent relapse during the therapeutic treatment of withdrawal, or to prevent relapse following detoxification is not fixed per se, and necessarily is dependent upon the severity and extent of substance dependence, the particular compound employed, and the method of administration.
  • the compound is taken orally as a Revia(r)TM tablet.
  • Typical doses vary from about 25 mg to about 100 mg, more narrowly from about 25 mg to about 150 mg daily, more narrowly from about 25 mg to about 100 mg. In one embodiment, smaller doses such as up to about 25 mg are employed. These compounds could be used to prevent relapse to use in alcohol, cocaine, opiate and marijuana abuse and polysubstance abuse.
  • Serotonergic medications can also be administered in combination with opiate antagonists to treat symptoms of withdrawal, and to help treat relapse, and to increase abstinence.
  • Typical doses vary from about 25 mg to 200 mg for sertraline, 10 mg to about 60 mg for fluoxetine, 25 mg to 200 mg for fluvoxamine, 10 mg to 50 mg for paroxetine, 10 mg to 60 mg for citalopram, 15 mg to 120 mg for fenfluramine or d-fenfluramine, and 5 mg to 60 mg of buspirone. These combinations could be used to prevent relapse to heavy use in alcohol, cocaine, opiate, and marijuana abuse and polysubstance abuse.
  • the dependent individual is first placed on the serotonergic compound for a period of time, e.g., 1 to 7 days in one embodiment, and is then begun on naltrexone or the opiate antagonist.
  • the dependent individual is placed on the initial dose of the opioid antagonist for a brief period.
  • Naltrexone treatment may begin at either about 12.5 mg a day with increases up to about 50 mg after a week, or initially at levels of about 50 mg. Lower doses of about 12.5 or 25 mg may also be used throughout the entire treatment.
  • a dose of the serotonergic medication could be added to the naltrexone regime and increased in dose to tolerance for a period from about 3 to 4 to about 12 months, the period of highest risk of relapse following complete detoxification.
  • both compounds are begun simultaneously.
  • the optimal sequence and dose for beginning therapy with naltrexone and the serotonergic compound might be made on the basis of clinical research experience.
  • Alcoholism In alcoholism, opiate antagonists have been shown to reduce alcohol self-administration in monkeys (50% dose-dependent reduction over placebo; Altshuler, et al., Life Sciences, 1980, 26: 679-688) and rats bred for high and low alcohol preference (Froehlich, et ah, Alcohol and Alcoholism, 1987,
  • naltrexone A significant benefit from the opiate antagonist naltrexone has been found in the treatment of alcohol dependent humans over 12 weeks in 2 large outpatient trials. Naltrexone in conjunction with psychotherapy produced a significant rise in complete abstinence from alcohol and a significant fall in relapse to heavy drinking (O'Malley, et al, 1995, 25: 681-689). Although the majority of researchers found that opiate antagonists reduce alcohol preference, not all studies have done so. For example, one researcher found an increase in alcohol consumption in hamsters given a single dose of naltrexone (Ross, et al., Proceedings of the Western Pharmacological Society, 1976, 19: 326-330).
  • the serotonin system has also been implicated in the pathogenesis of alcoholism. Numerous animal studies have suggested a serotonin deficiency in alcohol consuming animals and a large number of human experiments have suggested a serotonergic deficiency in alcoholics relative to non alcoholics (Farren, Journal of Serotonin Research, 1995, 1: 9-26). In general, increased serotonin activity decreases alcohol intake and decreased serotonin function increases alcohol intake.
  • the specific serotonin reuptake inhibitors including fluoxetine, fluvox- amine, citralopram and zimeldine have all been found to reduce alcohol consumption in alcohol preferring lines of rats (Murphy, et al., Alcohol, 1993, 2: 349-352).
  • Sertraline a selective serotonin reuptake inhibitor, has been shown to significantly reduce the intake of alcohol in non-alcohol preferring male rats (Gill, et al., Alcohol, 1988, 5: 349-354).
  • efforts to use serotonergic agents to treat alcohol dependence in humans has met with much less success than that shown in animals.
  • Serotonergic reuptake inhibitors including zimeldine, citralopram, viqualine and fluoxetine have shown very small decreases (9 - 15%) in alcohol consumption in non alcohol dependent humans (Naranjo, et al., Clinical Pharma- cology and Therapeutics 1990, 47: 490-498).
  • serotonin reuptake inhibitors such as fluoxetine, fluvoxamine, and dex-fenfluramine have shown benefit in reducing alcohol consumption (Kranzler, et al., Journal of Substance Abuse Treatment 1993, 10(3): 283-287; Gorelick and Pardes, Alcoholism: Clinical and Experimental Research, 1992, 16(2): 261-265; Romach, et al., Alcoholism: Clinical and Experimental Research, 1996, 20 (Suppl. 2), Abst #520).
  • the serotonergic system has also been investigated with regards to cocaine abuse.
  • Cocaine is a powerful serotonin reuptake inhibitor and chronic cocaine administration results in decreased 5-HT transmission, and this has been suggested as an explanation for the depressive symptoms of acute cocaine with- drawal (Cunningham, et al, Annals of the New York Academy of Sciences, 1992, 654: 117-127).
  • Sertraline has been used, along with fluoxetine, in open label studies of cocaine abusers and has shown promise in decrease of cocaine craving, cocaine use and psychosocial function (Batki, et al, Journal of Clinical Psychopharmacology, 1993, 13: 243-250).
  • Marijuana Cannabis (marijuana) is one of the most widely used drugs throughout the world and currently there are no successful pharmacotherapies to treat marijuana dependence.
  • the psychoactive component of marijuana, tetrahy- drocannabinol (THC) produces a number of pharmacological effects in the CNS similar to those produced by opiates such as morphine including antinociception, hypothermia, respiratory depression, inhibition of locomotor activity and intestinal motility.
  • opioid antagonists have been shown to block some of the pharmacological effects of THC.
  • Preclinical studies have shown that, like alcohol, opiates (morphine) and other drugs of abuse, the reinforcing effects of THC are mediated by release of dopamine in the brain dopamine reward pathway.
  • THC release of dopamine by THC can be blocked by the opioid antagonist naloxone, suggesting a role for the endogenous opioid peptides in modulating THC reinforcement similar to that documented above for alcohol dependence (Chen, et al, Psychopharmacology , 1990, 702: 156-162).
  • THC also suppresses precipitated abstinence in morphine dependent rats and has also been shown to modulate brain opioid receptors (mu and delta) at pharmacologically relevant concentration.
  • results described in the examples below show that a combination of opioid antagonist naltrexone and serotonergic uptake inhibitor sertraline are superior as an alcohol cessation treatment than naltrexone alone. Importantly, these results were obtained in a sample of nondepressed alcoholics. In addition, the results also describe a reduction in side effects of medication in the naltrexone and sertraline combination group. Results described in another example show that naltrexone and the serotonergic uptake inhibitor sertraline led to cessation of marijuana use in two patients.
  • the invention has very important implications for successful treatment of alcohol withdrawal and for successful treatment of long term alcohol dependence.
  • an opioid antagonist such as naltrexone
  • Many individuals do not maintain complete abstinence and then relapse to heavy drinking.
  • Naltrexone and a serotonergic medication together should enhance compliance and be more effective in encouraging abstinence and preventing relapse to heavy drinking.
  • the invention is useful for developing appropriate strategies for using opioid antagonists in combination with other agents in the treatment of alcoholism.
  • opioid antagonists with serotonin agents are useful with other substance abuse disorders involving alterations of the endogenous opioid system and the serotonergic system, or any other disorder, including non substance abuse related disorder, that has these abnormalities.
  • the subjects in both groups were matched according to gender, family history of alcoholism, age, and the number of drinking days in the previous 90, and by the average drinks per drinking occasion.
  • the naltrexone/sertraline group showed greater improvement than the naltrexone alone group. Only 44% of the naltrexone alone group remained abstinent for the duration of the trial, compared with 67% of the naltrexone/sertraline group; 56% of the naltrexone alone group did not relapse to heavy drinking, compared to 78% of the naltrexone/sertraline group; and the number of drinking occasions was higher for the naltrexone group (7.2 vs. 1.9).
  • the invention was made with partial government support under NIH grant numbers K02-AA-00107 and K12-OA-00167. The government has certain rights in the invention.

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Abstract

L'invention porte sur un traitement de la dépendance de patients vis à vis de l'alcool, de la marijuana, de la cocaïne, des opiacés, consistant à leur administrer une combinaison d'une quantité efficace d'un antagoniste des opiacés tel que la nalméfène, la naloxone, la naltréxone ou un de leurs mélanges, et une médication sérotonergique de sertraline, de fluoxétine, de paroxétine, de fluvoxamine ou d'odansétron. L'administration d'une quantité efficace d'un antagoniste des opiacés seule aide à prévenir les rechutes une fois la désintoxication achevée, tandis que l'adjonction de la médication sérotonergique accroît l'efficacité des antagonistes des opiacés, tout en en réduisant les effets secondaires et en contribuant à atténuer les effets du sevrage.
PCT/US1998/010289 1997-05-20 1998-05-19 Traitement de la dependance a certaines substances a l'aide de composes d'antagonistes d'opiaces et de serotonine Ceased WO1998052565A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP55056398A JP2002508753A (ja) 1997-05-20 1998-05-19 オピエート拮抗薬及びセロトニン化合物を使用する薬物依存治療
AU75824/98A AU7582498A (en) 1997-05-20 1998-05-19 Substance dependence treatment using opiate antagonists and serotonin compounds
EP98923558A EP1011671A1 (fr) 1997-05-20 1998-05-19 Traitement de la dependance a certaines substances a l'aide de composes d'antagonistes d'opiaces et de serotonine
CA002290788A CA2290788A1 (fr) 1997-05-20 1998-05-19 Traitement de la dependance a certaines substances a l'aide de composes d'antagonistes d'opiaces et de serotonine

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US4616297P 1997-05-20 1997-05-20
US60/046,162 1997-05-20

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AU (1) AU7582498A (fr)
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068080A3 (fr) * 2000-03-15 2002-07-04 Wolfgang Sadee Antagonistes neutres et utilisation de ces derniers dans le traitement de l'abus des drogues
US6454789B1 (en) 1999-01-15 2002-09-24 Light Science Corporation Patient portable device for photodynamic therapy
JP2002541202A (ja) * 1999-04-09 2002-12-03 サザン・リサーチ・インスティテュート 注入可能ナルトレキソン微細球体組成物、並びにヘロイン及びアルコールの摂取量を減少させるためのその使用
WO2004078177A1 (fr) * 2003-03-07 2004-09-16 Toray Industries Inc. Medicament contre la dependance aux drogues et aux substances toxiques
RU2428984C1 (ru) * 2010-05-24 2011-09-20 Общество с ограниченной ответственностью "Урал Крафт" Способ купирования алкогольной абстиненции
US9278094B2 (en) 2013-01-30 2016-03-08 Pharmorx Therapeutics, Inc. Treatments for depression and other diseases with a low dose agent
CN106456634A (zh) * 2014-04-22 2017-02-22 大塚制药株式会社 布雷帕唑和纳美芬的组合及其用于治疗物质有关的病症的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5114976A (en) * 1989-01-06 1992-05-19 Norden Michael J Method for treating certain psychiatric disorders and certain psychiatric symptoms
US5486362A (en) * 1991-05-07 1996-01-23 Dynagen, Inc. Controlled, sustained release delivery system for treating drug dependency

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5114976A (en) * 1989-01-06 1992-05-19 Norden Michael J Method for treating certain psychiatric disorders and certain psychiatric symptoms
US5486362A (en) * 1991-05-07 1996-01-23 Dynagen, Inc. Controlled, sustained release delivery system for treating drug dependency

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6454789B1 (en) 1999-01-15 2002-09-24 Light Science Corporation Patient portable device for photodynamic therapy
JP2002541202A (ja) * 1999-04-09 2002-12-03 サザン・リサーチ・インスティテュート 注入可能ナルトレキソン微細球体組成物、並びにヘロイン及びアルコールの摂取量を減少させるためのその使用
JP2010031036A (ja) * 1999-04-09 2010-02-12 Brookwood Pharmaceuticals Inc 注入可能ナルトレキソン微細球体組成物、並びにヘロイン及びアルコールの摂取量を減少させるためのその使用
WO2001068080A3 (fr) * 2000-03-15 2002-07-04 Wolfgang Sadee Antagonistes neutres et utilisation de ces derniers dans le traitement de l'abus des drogues
US6713488B2 (en) 2000-03-15 2004-03-30 Sadee Wolfgang Neutral antagonists and use thereof in treating drug abuse
WO2004078177A1 (fr) * 2003-03-07 2004-09-16 Toray Industries Inc. Medicament contre la dependance aux drogues et aux substances toxiques
RU2428984C1 (ru) * 2010-05-24 2011-09-20 Общество с ограниченной ответственностью "Урал Крафт" Способ купирования алкогольной абстиненции
US9278094B2 (en) 2013-01-30 2016-03-08 Pharmorx Therapeutics, Inc. Treatments for depression and other diseases with a low dose agent
CN106456634A (zh) * 2014-04-22 2017-02-22 大塚制药株式会社 布雷帕唑和纳美芬的组合及其用于治疗物质有关的病症的用途
US11642341B2 (en) 2014-04-22 2023-05-09 Otsuka Pharmaceutical Co., Ltd. Combination of brexpiprazole and nalmefene and use thereof for treating substance-related disorders

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AU7582498A (en) 1998-12-11
CA2290788A1 (fr) 1998-11-26
JP2002508753A (ja) 2002-03-19
EP1011671A1 (fr) 2000-06-28

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