This article was downloaded by: [New York University] On: 29 April 2015, At: 17:56 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Psychoactive Drugs Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ujpd20
Medications in the Treatment of Addictive Disease a
Donald R. Wesson & Walter Ling a
b
University of California San Francisco
b
Los Angeles Addiction Treatment Research Center Published online: 20 Jan 2012.
To cite this article: Donald R. Wesson & Walter Ling (1991) Medications in the Treatment of Addictive Disease, Journal of Psychoactive Drugs, 23:4, 365-370, DOI: 10.1080/02791072.1991.10471608 To link to this article: http://dx.doi.org/10.1080/02791072.1991.10471608
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions
Medications in the Treatment of Addictive Disease!
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Donald R. Wesson, M.D. * & Walter Ling, M.D. ** Abstract-Medication has become an increasingly accepted adjunct to other forms of drug abuse treatmen t. Its acceptance is due in part to clinicians ' frustration in treating crack cocaine abusers and to increasing integration of drug abuse treatment into mainstream medicine . A rapidly growing body ofliterature attests to clinical researchers' interest in pharmacotherapy of substance abuse. Medications can be a useful adjunct to drug abuse treatment in many different ways. The clinical challenge is to decide who should be treated with what medication and at what stage of recovery medications are helpful. This article discusses medications currently in use for treatment of addictive disease, describes some aspects of medication development, and suggests more cost-effective methods of exploring the efficacy of med ications for treatment of drug abuse. Keywords--drug abuse treatment, cocaine, heroin, medication development, methadone maintenance
companies. The design and conduct of such studies proceed according to guidelines! established by the Food and Drug Administration (FDA). Until recently, pharmaceutical companies had little interest in developing medications for treatment of addiction. Pharmaceutical companies have been reluctant to associate their medications that are already approved for other diseases and disorders with treatment of drug addiction and for good reasons. First, they do not want physicians and patients to mentally associate their medication with drug abuse because of the strong negative stereotype of the drug abuser. Second, medications effective in treating symptoms of drug toxicity or withdrawal will inevitably be sold on the street-drug black market Third, medications commonly used by heroin and cocaine abusers will show up as drug mentions in the federal Drug Abuse Warning Network (DAWN), which monitors drug mentions from emergency rooms and other sources. The Drug Enforcement Agency (DEA) and other drug control agencies commonly equate medication mentions by cocaine and heroin abusers with abuse of the medication. Having their medication sold on the street-drug black market or frequent mentions in DAWN could damage the medication's reputation, and it invites the DEA to increase the schedule of the medication. Finally, the so-called addiction market is small from the pharmaceutical industry's perspective. A large potential market is needed to justify investing in the high cost of medication development The average cost of discovery and development of a prescription medication exceeds $200 million (Vagelos 1991). The reluctance of the pharmaceu-
During the past ten years, clinicians have escalated their search for effective medications to treat drug abuse, particularly with relationship to treatments for crack cocaine dependence. While outpatient treatment is the dominant form of treatment, crack cocaine abusers are often difficult to retain in treatment, and they often have much difficulty remaining abstinent. As the focus of this article is medication treatment, neither psychosocial treatment strategies nor the important interface between psychosocial treatments and medication treatments will be covered. It should be understood, however, that medication treatment is almost always an adjunct to psychosocial treatment and rarely is pharmacotherapy alone adequate treatment for a patient who is drug dependent. The search for medication treatments for drug abuse has taken a different course than that taken with other diseases. In the treatment of common medical diseases, clinical trials of new medications are sponsored by pharmaceutical tThis work was supported in part by National Institute on Drug Abuse grant DA 6082 to the Los Angeles Addiction Treatment Research Center administered by Friends Medical Science Research Center, Baltimore, Maryland, and by National Institute on Drug Abuse grant DA 03516 to Merritt Peralta Institute, Oakland, California. - Associate Director, Los Angeles Addiction Treatment Research Center; Associate Clinical Professor, University of California San Francisco. --Director, Los Angeles Addiction Treatment Research Center. Please address reprint requests to Donald R. Wesson, M.D., Los Angeles Addiction Treatment Research Center, 8447 Wilshire Blvd., Suite 409, Beverly Hills, California 90211. Journal ofPsychoactive Drugs
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TABLE I
TABLE II
MEDICATIONS OF ESTABLISHED USEFULNESS IN TREATMENT OF DRUG ABUSE
MEDICATIONS UNDER INVESTIGATION FOR TREATMENT OF DRUG ABUSE
Medications
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FDA -Approved Use Benzodiazepines diazepam (Valium) chlordiazepoxide (Librium) oxazepam (Serax)
Indications
Alcohol withdrawal
Disulfiram (Antabuse)
Prevention of relapse to alcohol abuse
Methadone
Opiate maintenance and detoxification
Naltrexone (Trexan)
Prevention of relapse to opiate abuse
Nicotine gum (Nicorette)
Smoking cessation
Use Established by Clini cal Practice Clonidine (Catapres) oral tablets transdermal patches
Opiate withdrawal
Phen obarbital
Sedative-hypnotic withdrawal
tical industry to chance tarnishing the reputation of an already marketed medication by associating it with drug abuse or to undertake the primary development of a new pharmacotherapy for substance abuse is understandable. Only with nicotine dependence have pharmaceutical companies committed the resources to obtain FDA approval for the indication of smoking cessation. Nicotine gum, Nicorette, is now available, and at least two companies are conducting clinical trials with nicotine transdermal patches. Medications become standard medical practice for treatment of drug abuse (see Table I) in one of two ways. The most common way is that guidelines for use or clinical studies of the medication - such as clonidine for the treatment of opiate withdrawal- are presented at conferences or published in journals. Because most of the medications currently under study for treatment of cocaine abuse are already available for other indications and are not sched uled, addiction medicine specialists - desperate for better treatment strategies, particularly for crack cocaine abusers - tryout the new medications in their practices. In addition, word of medications that are seemingly helpful spreads fast within the drug-abusing subcultures, and addicts themselves often requ est that their physicians treat them with a new medication. The other way that a medication becomes standard medical practice is through FDA approval. Methadone and naltrexone are the only two JOWIU11 of Psychoactiv e Drugs
MedIcations
Indlcatlon(s}
Amantadine Amino acids tryptophan tyrosine
Reduce cocaine cravings Reduce cocaine cravings Reduce cocaine withdrawal symptoms
Antidepressants desipramine doxepin imipramine maprotiline trazodone
Reduce cocaine cravings Reduce cocaine-induced depression
Bromocriptine Buprenorphine
Reduce cocaine cravings Treatment of opiate withdrawal and medical maintenance
Bupropion (Wellbutrin)
Reduce cocaine cravings
Carbamazepine (Tegretol)
Reduce cocaine cravings and relapse
Rupentixol
Reduce cocaine cravings
Gepirone
Reduce cocaine cravings and cocaine withdrawal symptoms
LAAM
Opiate maintenance
Magnesium pemoline
Attention deficit disorders in cocaine abusers
Mazindol (Mazanor, Sanorex)
Reduce cocaine cravings
Methylphenidate (Ritalin)
Attention deficit disorders in cocaine abusers
Naltrexone
Reduce relapse to alc ohol abuse
FDA-apprOVed medications for treatment of opiate dependence. Methadone is administered under special FDA regulations and did not undergo the usual FDA review process. Naltrexone (Trexan) was jointly developed by the National Institute on Drug Abuse (NIDA) and the pharmaceutical industry. In the treatment of alcoholism, disulfiram (Antabuse) is approved by the FDA for preventing relapse, and several benzodiazepines are FDA approved for treating alcohol withdrawal.
MEDICATIONS CURRENTLY BEING STUDIED Many different medications are being studied for treatment of addictive disease. Table II lists medications whose clinical investigations have been reported in the substance abuse literature. Most of the studies are designed 366
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Wesson & Ling
TABLE III THERAPEUTIC USES OF MEDICATIONS IN TREATMENT OF DRUGABUSE Therapeutic Purpose
Drug or Abuse
Example(s)
Heroin
Methadone, clonidine
Facilitating Abstinence To reduce acute drug withdrawal symptoms To medically maintain patient
Heroin
Methadone, buprenorphines, LAAM·
To decrease drug craving
Cocaine Heroin
Desipramine": brornocryptine" Methadone, buprenorphine": LAAM·
To block the drug's reinforcing effects
Heroin
Naltrexone (Trexan)
To reduce prolonged withdrawal syndrome
Heroin Benzodiazepine
Antidepressants
To decrease drug craving
Cocaine Heroin
Desipramine'; bromocryptine" Naltrexone
To alter the drug's reinforcing effects
Alcohol Heroin
Disulfiram (Antabuse), naltrexone" Naltrexone
To treat underlying psychopathology that predisposes to relapse
Alcohol Heroin Cocaine
Antidepressant treatment of depression
To treat drug-induced psychopathology (e.g., panic attacks induced by stimulant abuse)
Cocaine
Desipramine
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Preventing Relapse
• Investigational use
and carried out by addiction specialists, sometimes with grants from NIDA. NIDA's Medications Development Division has been encouraging pharmaceutical companies to pursue clinical trials of medications that have potential usefulness for the treatment of drug abuse. One study of gepirone (an analogue of buspirone) for cocaine withdrawal has been completed. Currently, studies of bupropion (Wellbutrin) for treatment of cocaine dependence are underway,and studies with other medications are being planned. In the development of some new medications (e.g., buprenorphine, depo-naltrexone), many of the functions of a pharmaceutical company have been assumed by NIDA's MedicationsDevelopment Division.For example, it has become the sponsor for a major, multicenter study of buprenorphine. With consultation and collaboration with grantees, the pharmaceutical industry, the FDA, and various contractors, the Medications Development Divisionwill develop the necessary informationto prepare a New Drug Application (NDA) for submission to the FDA, seeking to add opiate dependency as an indication for buprenorphine.
Journal ofPsychoactive Drugs
POTENTIAL USES OF MEDICATIONS Medications would be clinically useful if they improved the percentage of patients who recover, decreased the cost of recovery or decreased the time needed for recovery. Table III summarizes some of the ways that medications may be useful in treatment of drug abuse. The therapeutic uses of medications can be categorized into two functions: to help patients stop abusing drugs and to help patients prevent relapse to drug use. As indicated in Table III, some medication strategies, such as those to decrease craving, may apply to both stopping drug use and preventing relapse.
Treatment or Acute Drug Withdrawal The relative importance of pharmacotherapy of withdrawal varies for different drug groups: sedative-hypnotics, opiates, and stimulants. With sedative-hypnotic withdrawal (e.g., alcohol, barbiturates, benzodiazepines), medication is often a medical necessity. For opiates, medication treatment relieves unpleasant, but not life-threatening, symptoms and sometimes facilitates patients' entry into more definitive treatment. For stimulants, treatment 367
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tients' return of symptoms with protracted withdrawal symptoms.
of withdrawal may reduce symptoms, but medication is not medically necessary. Acute Sedative-hypnotic Withdrawal. After a sedative-hypnotic drug has been taken for weeks to months at larger than the therapeutic dose, abrupt discontinuation of the medication can produce seizures, psychosis or even death. Protocols for treating withdrawal from sedativehypnotics are available (Smith & Wesson 1970). When the withdrawal protocols are appropriately applied, the medically severe sequelae of sedative-hypnotic withdrawal are avoided. Opiate Withdrawal. The intensity of withdrawal symptoms can be severe, and unmedicated withdrawal is unusual in a medical or drug abuse treatment clinic setting. Withdrawal is usually accomplished by a graded reduction of methadone, which is the currently FDA-approved medication for treatment of opiate withdrawal. Alternatively, clonidine, an antihypertensive medication, can be used. Although clonidine is not FDA approved for drug withdrawal, its therapeutic utility in treatment of opiate withdrawal is well established in the clinical literature , and the use of clonidine for treating opiate withdrawal has become standard clinical practice. Protocols for use of clonidine in treatment of opiate withdrawal are available (Ling & Wesson 1990).
Medical Maintenance During the early 196Os,Dole and Nyswander (1967) found that some heroin abusers' social functioning improved if they were maintained on methadone. They introduced methadone maintenance as a treatment for heroin dependence in 1965. In the intervening 26 years, numerous studies have shown that heroin addicts maintained on methadone use less heroin, decrease criminal activity, and suffer fewer medical complications. Nevertheless, methadone maintenance remains controversial (Kim 1988). Methadone maintenance has been the subject of recent reviews (Martin, Payte & Zweben 1991; Zweben & Payte 1990). There is renewed interest and effort in making LAAM (l-alpha-acetylmethadol) available for treatment of opiate dependency. NIDA's Medications Development Division - working in collaboration with a contractor, Biometic Research Institute - recently presented to an FDA advisory committee a summary of available research on LAAM. It was favorably received , and there is now a plan to complete the NDA process. Some additional clinical studies should be completed in 1992, which will allow the NDA to be submitted by the end of that year.
Treatment of Protracted Withdrawal States Protracted withdrawal syndromes have been described for alcohol, heroin, methadone, and many sedative-hypnotics. Theory holds that protracted withdrawal symptoms make patients in early abstinen ce more vulnerable to relapse and that symptomatic treatment of protracted withdrawal may reduce the proportions of patients who relapse to drug abuse. Some patients who are being withdrawn from chronic benzodiazepine abuse or from chronically administered therapeutic doses of benzodiazepines have a prolonged and severe withdrawal syndrome that is poorly managed with conventional treatment. It is not always possible to prospectively predict which patients will develop the severe protracted withdrawal syndrome. Most patients can take benzodiazepines within the therapeutic range for months to years and abruptly discontinue the benzodiazepine without serious difficulty. Other patients, however, develop a prolonged withdrawal syndrome lasting six to 12 months. Case studies suggest that patients who have a past history of alcohol or other drug abuse are at higher risk of developing the prolonged withdrawal syndrome (Smith & Wesson 1983). Because benzodiazepines are prescribed to treat chronic anx iety and insomnia, stopping the medication in patients with these conditions produces a reemergen ce of symptoms that were suppressed by the benzodiazepine . The prolonged withdrawal syndrome was not recognized for many years because physicians often confused pa Journal of Psychoactive Drugs
To Decrease Drug Craving Drug craving is oft en presumed to be the proximal cause of drug use. Much medication development, particularly medication for treatment of cocaine dependence, has as its primary or secondary effect the reduction of drug craving. As noted in Table III, reducing drug craving may be important in facilitating patients to stop drug use (particularly when treated as outpatients) or in preventing relapse after abstinence is achieved. Many of the medications that are under investigation (see Table II) have as their intended therapeutic effect the reduction of craving. To Block the Drug's Reinforcing Effects Opiate antagonists (e.g., naltrexone) have no effect unless an opiate is ingested, in which case the opiate's mood-altering or analgesic effects are blocked . By blocking the receptor site to which the opiate normally attaches, naltrexone effectively prevents relapse by preventing impulsive drug use. Naltrexone is a prime example of a medication with high pharmacological efficacy, but low clini cal efficacy. Because naltrexone produces no mood-enhancing effects for the user, and for some it produces side effects, only opiate abusers who are highly motivated for opiate abstinence or opiate abusers who are coerced (e.g., condition of probation or parole) will continue taking it.
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To Treat Underlying Psychopathology The high prevalence of psychiatric comorbidity among drug abusers leads organized psychiatry to opine that "psychiatrists have a critical role to play in the diagnosis and treatment of patients with substance abuse disorders" (Group for the Advancement of Psychiatry 1991). The self-medication hypothesis (i.e., addicts use drugs or find certain drugs appealing to self-medicate underlying psychopathology) is commonly believed by psychiatrists. Actual estimates of the prevalence of psychopathology among drug users vary widely, but there is little doubt that a significant number of drug abusers have psychopathology, particularly depression that predates the development of addiction . Lemere (1991) noted that of 292 primary cocaine addicts undergoing inpatient treatment, " ... 22% had abused cocaine while seeking relief from preaddictive dysphoria and depression and 13% had become addicted while seeking to enhance the euphoria that they had always enjoyed because of a hypomanic personality trait." Researchers at Yale have noted that depression predicts cocaine abuse among methadone maintenance patients and hypothesized that "pharmacotherapy of depression in these patients may not only reduce psychosocial morbidity, but may also impact on subsequent cocaine abuse...." (Kosten, Morgan & Kosten 1990). Much pharmacotherapy in clinical practice and research is driven by the self-medication hypothesis.
Side Effects
'" tj ~
tIl
"
"0
in
....o
.~
"
>
"
Vl'--_-==::::.-
Therapeutic Response
:J
~ tIl
....o "0 " a
"c00
.
:8 Dose -----.
Figure 1. The relationship between side effects, therapeutic response and dose . As the dose is increased beyond the peak in the therapeutic response curve, side effects overshadow the therapeutic effects.
To Treat Drug-Induced Psychopathology Chronic drug abuse can produce changes in the number of neurotransmitter receptors , changes in receptor sensitivity, and alterations in brain chemistry. The biochemical and receptor perturbations, which may take days or even months to return to normal , may explain the protracted withdrawal syndromes that occur in newly abstinent drug abusers. To the extent that abstinent drug abusers turn to drugs to self-medicate protracted withdrawal symptoms, effective pharmacotherapy of the symptoms with nondependence-producing medications may assist in patients remaining drug abstinent. In some cases, chronic drug abuse induces new illnesses that can be effectively treated with medication. For example, chronic abuse of amphetamine or cocaine may up-regulate noradrenergic receptor sensitivity, which manifests clinically as panic attacks in some individuals. Antidepressants may down-regulate noradrenergic receptor sensitivity.
Finding the Right Dose One of the major problems in medication development for treatment of substance abuse is the general lack of dose-ranging and dose-comparison studies. This is true even for well-established medications. After 25 years of clinical use of methadone maintenance, for example, there is still controversy about the most effective dose. Before undertaking multicenter clinical trials of a new medication, the "best apparent dose" should be known (Schmidt 1988) . Even when medications are borrowed from treatment of other diseases (e.g., desipramine), it should not be automatically assumed that the same dose of desipramine used to treat depression will also be the best dose for reducing cocaine craving. Study designs for exploring the dose-response relationship include the titration studies (Shih, Gould & Hwang 1989) and dose-comparison studies. In dose -titration studies, each patient's dose of medication is increased stepwise over time while the patient's dependent variable (e.g ., amount of drug use, drug craving) is measured. For a therapeutic efficacy trial, the dependent measure must be relatively constant over time so that the effect of differing doses of medication can be assessed. Efficacy cannot be unequivocally established in a study of this design
FUTURE RESEARCH The methodology and technology for conducting clinical trials of new medications for treatment of drug dependence is still developing. Fully appreciating the limitations of previous studies may facilitate more successful med ication development in the future. Journal ofPsychoactive Drugs
_
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Treatment of Addictive Disease
because the dependent variable may be affected by timein-treatment or some other extraneous variable. The strengths of carefuIly controIled dose titration are that researchers can measure subjects' responses to differing doses of medication over time, delineate the types of patients who apparenl1y respond to the medication, and establish with considerable precision the side-effect profile of the medication and subjects' tolerance of medication side effects at various doses. If an effect to the medication is present, it is likely to be observed with this design. Moreover, subjects find the design acceptable because they are assured of receiving active medication. The importance of dose ranging is illustrated in Figure I. Medications, such as antidepressants, have a minimum therapeuti c dose. If patients receive less than the minimum therapeutic dose, they will not have an antidepressant effect; however, they may have some medication side effects. As the do se is in creased, therapeutic re sponse increase s and the intensity of sid e effects increases. As the dose is increased, a dosage is eventually reached above whi ch further increases do not increase therapeutic response. Side effec ts continue to increase and eventually they overshadow the therapeutic benefit. Further increa se in dose result'> in decreasing therapeutic response. It is important to establish the shape of the curve before fixeddose trials are undertaken. The investigator should pick a dose that is as near as pos sible to the peak for most patients to maximize the chances of demonstrating efficacy. If the fixed dose chosen for placebo-controlled efficacy trial is over the peak to the right, the results of the trial may result in rejecting an efficacious medication. Dose comparison studies use independent, parallel
groups. Subjects are randomly assigned to a fixed dose of medication and one measures the proportion of subjects that respond to each dosage level. CONCLUSION Medication treatment of drug abuse can be an irnportant adjunct to psychosocial treatment, and pharmacotherapy may attract and retain some drug abu sing patients in treatment who would otherwise be untreatable. Current treatment approaches can be improved if clinicians are clear with themselves and their patients about what they want to accomplish with pharmacotherapy. Clinical trials of new medication can be improved by additional attention to dose-ranging studies and clear outcome mea sures that are linked to the intended indication or purpo se of the medication. NOTES
1. Usually, the FDA will not consider a study to be "pivotal" unless it is conducted using Good Clinical Practice Guidelines, which specify documentation requirements for clinical trials that far exceed what most clinicians or clinical researchers would deem necessary. The purpose of the extensive documentation is to allow FDA auditors to verify the data and to make judgments about the conduct of the study, often several years after it is completed. Th e technical aspects of an NDA are oul1ined in the 1988 FDA publication Guidelines for the Format and Conduct of the Clinical and Statistical Secti ons of New Drug Applications.
REFERENCES Schmidt, R. 1988. Dose-finding studi es in clinical drug developme nt. European Journal ofClinical Pharmacol ogy Vol. 34 : 15-19. Shih, W.J.; Gould, A.L. & Hwang , I.K . 1989. The analysi s of titrati on studies in phase III clinical trials . Stat istics in Medicine Vol. 8: 583 591. Smith , D.E. & Wesson, D.R. 1983 . Bcn zod iazep ine dependency syn dromes. Journal 0/ Psychoa ctive Drugs Vol. 15(1-2): 85-95 . Smith, D.E. & Wesson, D.R. 1970. A new method for treatment of barbiturate depend ence. Journal of the American Medical Association Vol. 213(2): 294 -295. Vagelos, P.R. 1991. Are prescript ion drug prices high? Science Vol. 252: 1080-1084 . Zwebcn, lE. & Payte , J.T. 1990. Methadone maintenance in the treatment of opioid depend ence: A current perspective . Western Journal 0/ Medi cine Vol. 152: 588-599.
Dole, V. & Nyswander, M. 1967. Heroin addiction: A metabolic disease. Archi ves of General Psychiatry Vol. 120: 19-24. Group for the Advan cement of Psych iatry Committee on Alcohol ism and the Addictions. 1991. Substance abuse disorders : A psychiatric priority. Am erican Journal ofPsychiatry Vol. 148(10): 1291-1300. Kim, T.F. 1988. Methadone maintenance treatment remains controversial even after 23 years of experience. Journal of the American Medical Associati on Vol. 260(20): 2970ff. Kosten, T.R.; Morgan, C. & Kosten, T.A. 1990. Depressive symptoms during buprenorph ine treatment of opioid abu sers . Journal 0/ Substan ce Abuse Treatm ent Vol. 7: 51-54 . Ling, W. & Wesson, D.R. 1990 . Drugs of abuse--opiate s. Western Journal 0/ Medicine Vol. 152: 565 -572. Martin, J.; Payte, J.T. & Zwebcn, J.E. 1991. Methadone maintenance treatment : A primer for physicians . Journal ofPsychoactive Drugs Vol. 23(2) : 165-176 .
Journal
0/ Psychoactive Drugs
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\bl. 23(4), Oct -Dec 1991
Journal of Psychoactive Drugs Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ujpd20
Medications in the Treatment of Addictive Disease a
Donald R. Wesson & Walter Ling a
b
University of California San Francisco
b
Los Angeles Addiction Treatment Research Center Published online: 20 Jan 2012.
To cite this article: Donald R. Wesson & Walter Ling (1991) Medications in the Treatment of Addictive Disease, Journal of Psychoactive Drugs, 23:4, 365-370, DOI: 10.1080/02791072.1991.10471608 To link to this article: http://dx.doi.org/10.1080/02791072.1991.10471608
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions
Medications in the Treatment of Addictive Disease!
Downloaded by [New York University] at 17:56 29 April 2015
Donald R. Wesson, M.D. * & Walter Ling, M.D. ** Abstract-Medication has become an increasingly accepted adjunct to other forms of drug abuse treatmen t. Its acceptance is due in part to clinicians ' frustration in treating crack cocaine abusers and to increasing integration of drug abuse treatment into mainstream medicine . A rapidly growing body ofliterature attests to clinical researchers' interest in pharmacotherapy of substance abuse. Medications can be a useful adjunct to drug abuse treatment in many different ways. The clinical challenge is to decide who should be treated with what medication and at what stage of recovery medications are helpful. This article discusses medications currently in use for treatment of addictive disease, describes some aspects of medication development, and suggests more cost-effective methods of exploring the efficacy of med ications for treatment of drug abuse. Keywords--drug abuse treatment, cocaine, heroin, medication development, methadone maintenance
companies. The design and conduct of such studies proceed according to guidelines! established by the Food and Drug Administration (FDA). Until recently, pharmaceutical companies had little interest in developing medications for treatment of addiction. Pharmaceutical companies have been reluctant to associate their medications that are already approved for other diseases and disorders with treatment of drug addiction and for good reasons. First, they do not want physicians and patients to mentally associate their medication with drug abuse because of the strong negative stereotype of the drug abuser. Second, medications effective in treating symptoms of drug toxicity or withdrawal will inevitably be sold on the street-drug black market Third, medications commonly used by heroin and cocaine abusers will show up as drug mentions in the federal Drug Abuse Warning Network (DAWN), which monitors drug mentions from emergency rooms and other sources. The Drug Enforcement Agency (DEA) and other drug control agencies commonly equate medication mentions by cocaine and heroin abusers with abuse of the medication. Having their medication sold on the street-drug black market or frequent mentions in DAWN could damage the medication's reputation, and it invites the DEA to increase the schedule of the medication. Finally, the so-called addiction market is small from the pharmaceutical industry's perspective. A large potential market is needed to justify investing in the high cost of medication development The average cost of discovery and development of a prescription medication exceeds $200 million (Vagelos 1991). The reluctance of the pharmaceu-
During the past ten years, clinicians have escalated their search for effective medications to treat drug abuse, particularly with relationship to treatments for crack cocaine dependence. While outpatient treatment is the dominant form of treatment, crack cocaine abusers are often difficult to retain in treatment, and they often have much difficulty remaining abstinent. As the focus of this article is medication treatment, neither psychosocial treatment strategies nor the important interface between psychosocial treatments and medication treatments will be covered. It should be understood, however, that medication treatment is almost always an adjunct to psychosocial treatment and rarely is pharmacotherapy alone adequate treatment for a patient who is drug dependent. The search for medication treatments for drug abuse has taken a different course than that taken with other diseases. In the treatment of common medical diseases, clinical trials of new medications are sponsored by pharmaceutical tThis work was supported in part by National Institute on Drug Abuse grant DA 6082 to the Los Angeles Addiction Treatment Research Center administered by Friends Medical Science Research Center, Baltimore, Maryland, and by National Institute on Drug Abuse grant DA 03516 to Merritt Peralta Institute, Oakland, California. - Associate Director, Los Angeles Addiction Treatment Research Center; Associate Clinical Professor, University of California San Francisco. --Director, Los Angeles Addiction Treatment Research Center. Please address reprint requests to Donald R. Wesson, M.D., Los Angeles Addiction Treatment Research Center, 8447 Wilshire Blvd., Suite 409, Beverly Hills, California 90211. Journal ofPsychoactive Drugs
365
\bl. 23(4), Oct-Dec 1991
Wesson & Ling
Treatment of Addictive Disease
TABLE I
TABLE II
MEDICATIONS OF ESTABLISHED USEFULNESS IN TREATMENT OF DRUG ABUSE
MEDICATIONS UNDER INVESTIGATION FOR TREATMENT OF DRUG ABUSE
Medications
Downloaded by [New York University] at 17:56 29 April 2015
FDA -Approved Use Benzodiazepines diazepam (Valium) chlordiazepoxide (Librium) oxazepam (Serax)
Indications
Alcohol withdrawal
Disulfiram (Antabuse)
Prevention of relapse to alcohol abuse
Methadone
Opiate maintenance and detoxification
Naltrexone (Trexan)
Prevention of relapse to opiate abuse
Nicotine gum (Nicorette)
Smoking cessation
Use Established by Clini cal Practice Clonidine (Catapres) oral tablets transdermal patches
Opiate withdrawal
Phen obarbital
Sedative-hypnotic withdrawal
tical industry to chance tarnishing the reputation of an already marketed medication by associating it with drug abuse or to undertake the primary development of a new pharmacotherapy for substance abuse is understandable. Only with nicotine dependence have pharmaceutical companies committed the resources to obtain FDA approval for the indication of smoking cessation. Nicotine gum, Nicorette, is now available, and at least two companies are conducting clinical trials with nicotine transdermal patches. Medications become standard medical practice for treatment of drug abuse (see Table I) in one of two ways. The most common way is that guidelines for use or clinical studies of the medication - such as clonidine for the treatment of opiate withdrawal- are presented at conferences or published in journals. Because most of the medications currently under study for treatment of cocaine abuse are already available for other indications and are not sched uled, addiction medicine specialists - desperate for better treatment strategies, particularly for crack cocaine abusers - tryout the new medications in their practices. In addition, word of medications that are seemingly helpful spreads fast within the drug-abusing subcultures, and addicts themselves often requ est that their physicians treat them with a new medication. The other way that a medication becomes standard medical practice is through FDA approval. Methadone and naltrexone are the only two JOWIU11 of Psychoactiv e Drugs
MedIcations
Indlcatlon(s}
Amantadine Amino acids tryptophan tyrosine
Reduce cocaine cravings Reduce cocaine cravings Reduce cocaine withdrawal symptoms
Antidepressants desipramine doxepin imipramine maprotiline trazodone
Reduce cocaine cravings Reduce cocaine-induced depression
Bromocriptine Buprenorphine
Reduce cocaine cravings Treatment of opiate withdrawal and medical maintenance
Bupropion (Wellbutrin)
Reduce cocaine cravings
Carbamazepine (Tegretol)
Reduce cocaine cravings and relapse
Rupentixol
Reduce cocaine cravings
Gepirone
Reduce cocaine cravings and cocaine withdrawal symptoms
LAAM
Opiate maintenance
Magnesium pemoline
Attention deficit disorders in cocaine abusers
Mazindol (Mazanor, Sanorex)
Reduce cocaine cravings
Methylphenidate (Ritalin)
Attention deficit disorders in cocaine abusers
Naltrexone
Reduce relapse to alc ohol abuse
FDA-apprOVed medications for treatment of opiate dependence. Methadone is administered under special FDA regulations and did not undergo the usual FDA review process. Naltrexone (Trexan) was jointly developed by the National Institute on Drug Abuse (NIDA) and the pharmaceutical industry. In the treatment of alcoholism, disulfiram (Antabuse) is approved by the FDA for preventing relapse, and several benzodiazepines are FDA approved for treating alcohol withdrawal.
MEDICATIONS CURRENTLY BEING STUDIED Many different medications are being studied for treatment of addictive disease. Table II lists medications whose clinical investigations have been reported in the substance abuse literature. Most of the studies are designed 366
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TABLE III THERAPEUTIC USES OF MEDICATIONS IN TREATMENT OF DRUGABUSE Therapeutic Purpose
Drug or Abuse
Example(s)
Heroin
Methadone, clonidine
Facilitating Abstinence To reduce acute drug withdrawal symptoms To medically maintain patient
Heroin
Methadone, buprenorphines, LAAM·
To decrease drug craving
Cocaine Heroin
Desipramine": brornocryptine" Methadone, buprenorphine": LAAM·
To block the drug's reinforcing effects
Heroin
Naltrexone (Trexan)
To reduce prolonged withdrawal syndrome
Heroin Benzodiazepine
Antidepressants
To decrease drug craving
Cocaine Heroin
Desipramine'; bromocryptine" Naltrexone
To alter the drug's reinforcing effects
Alcohol Heroin
Disulfiram (Antabuse), naltrexone" Naltrexone
To treat underlying psychopathology that predisposes to relapse
Alcohol Heroin Cocaine
Antidepressant treatment of depression
To treat drug-induced psychopathology (e.g., panic attacks induced by stimulant abuse)
Cocaine
Desipramine
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Preventing Relapse
• Investigational use
and carried out by addiction specialists, sometimes with grants from NIDA. NIDA's Medications Development Division has been encouraging pharmaceutical companies to pursue clinical trials of medications that have potential usefulness for the treatment of drug abuse. One study of gepirone (an analogue of buspirone) for cocaine withdrawal has been completed. Currently, studies of bupropion (Wellbutrin) for treatment of cocaine dependence are underway,and studies with other medications are being planned. In the development of some new medications (e.g., buprenorphine, depo-naltrexone), many of the functions of a pharmaceutical company have been assumed by NIDA's MedicationsDevelopment Division.For example, it has become the sponsor for a major, multicenter study of buprenorphine. With consultation and collaboration with grantees, the pharmaceutical industry, the FDA, and various contractors, the Medications Development Divisionwill develop the necessary informationto prepare a New Drug Application (NDA) for submission to the FDA, seeking to add opiate dependency as an indication for buprenorphine.
Journal ofPsychoactive Drugs
POTENTIAL USES OF MEDICATIONS Medications would be clinically useful if they improved the percentage of patients who recover, decreased the cost of recovery or decreased the time needed for recovery. Table III summarizes some of the ways that medications may be useful in treatment of drug abuse. The therapeutic uses of medications can be categorized into two functions: to help patients stop abusing drugs and to help patients prevent relapse to drug use. As indicated in Table III, some medication strategies, such as those to decrease craving, may apply to both stopping drug use and preventing relapse.
Treatment or Acute Drug Withdrawal The relative importance of pharmacotherapy of withdrawal varies for different drug groups: sedative-hypnotics, opiates, and stimulants. With sedative-hypnotic withdrawal (e.g., alcohol, barbiturates, benzodiazepines), medication is often a medical necessity. For opiates, medication treatment relieves unpleasant, but not life-threatening, symptoms and sometimes facilitates patients' entry into more definitive treatment. For stimulants, treatment 367
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tients' return of symptoms with protracted withdrawal symptoms.
of withdrawal may reduce symptoms, but medication is not medically necessary. Acute Sedative-hypnotic Withdrawal. After a sedative-hypnotic drug has been taken for weeks to months at larger than the therapeutic dose, abrupt discontinuation of the medication can produce seizures, psychosis or even death. Protocols for treating withdrawal from sedativehypnotics are available (Smith & Wesson 1970). When the withdrawal protocols are appropriately applied, the medically severe sequelae of sedative-hypnotic withdrawal are avoided. Opiate Withdrawal. The intensity of withdrawal symptoms can be severe, and unmedicated withdrawal is unusual in a medical or drug abuse treatment clinic setting. Withdrawal is usually accomplished by a graded reduction of methadone, which is the currently FDA-approved medication for treatment of opiate withdrawal. Alternatively, clonidine, an antihypertensive medication, can be used. Although clonidine is not FDA approved for drug withdrawal, its therapeutic utility in treatment of opiate withdrawal is well established in the clinical literature , and the use of clonidine for treating opiate withdrawal has become standard clinical practice. Protocols for use of clonidine in treatment of opiate withdrawal are available (Ling & Wesson 1990).
Medical Maintenance During the early 196Os,Dole and Nyswander (1967) found that some heroin abusers' social functioning improved if they were maintained on methadone. They introduced methadone maintenance as a treatment for heroin dependence in 1965. In the intervening 26 years, numerous studies have shown that heroin addicts maintained on methadone use less heroin, decrease criminal activity, and suffer fewer medical complications. Nevertheless, methadone maintenance remains controversial (Kim 1988). Methadone maintenance has been the subject of recent reviews (Martin, Payte & Zweben 1991; Zweben & Payte 1990). There is renewed interest and effort in making LAAM (l-alpha-acetylmethadol) available for treatment of opiate dependency. NIDA's Medications Development Division - working in collaboration with a contractor, Biometic Research Institute - recently presented to an FDA advisory committee a summary of available research on LAAM. It was favorably received , and there is now a plan to complete the NDA process. Some additional clinical studies should be completed in 1992, which will allow the NDA to be submitted by the end of that year.
Treatment of Protracted Withdrawal States Protracted withdrawal syndromes have been described for alcohol, heroin, methadone, and many sedative-hypnotics. Theory holds that protracted withdrawal symptoms make patients in early abstinen ce more vulnerable to relapse and that symptomatic treatment of protracted withdrawal may reduce the proportions of patients who relapse to drug abuse. Some patients who are being withdrawn from chronic benzodiazepine abuse or from chronically administered therapeutic doses of benzodiazepines have a prolonged and severe withdrawal syndrome that is poorly managed with conventional treatment. It is not always possible to prospectively predict which patients will develop the severe protracted withdrawal syndrome. Most patients can take benzodiazepines within the therapeutic range for months to years and abruptly discontinue the benzodiazepine without serious difficulty. Other patients, however, develop a prolonged withdrawal syndrome lasting six to 12 months. Case studies suggest that patients who have a past history of alcohol or other drug abuse are at higher risk of developing the prolonged withdrawal syndrome (Smith & Wesson 1983). Because benzodiazepines are prescribed to treat chronic anx iety and insomnia, stopping the medication in patients with these conditions produces a reemergen ce of symptoms that were suppressed by the benzodiazepine . The prolonged withdrawal syndrome was not recognized for many years because physicians often confused pa Journal of Psychoactive Drugs
To Decrease Drug Craving Drug craving is oft en presumed to be the proximal cause of drug use. Much medication development, particularly medication for treatment of cocaine dependence, has as its primary or secondary effect the reduction of drug craving. As noted in Table III, reducing drug craving may be important in facilitating patients to stop drug use (particularly when treated as outpatients) or in preventing relapse after abstinence is achieved. Many of the medications that are under investigation (see Table II) have as their intended therapeutic effect the reduction of craving. To Block the Drug's Reinforcing Effects Opiate antagonists (e.g., naltrexone) have no effect unless an opiate is ingested, in which case the opiate's mood-altering or analgesic effects are blocked . By blocking the receptor site to which the opiate normally attaches, naltrexone effectively prevents relapse by preventing impulsive drug use. Naltrexone is a prime example of a medication with high pharmacological efficacy, but low clini cal efficacy. Because naltrexone produces no mood-enhancing effects for the user, and for some it produces side effects, only opiate abusers who are highly motivated for opiate abstinence or opiate abusers who are coerced (e.g., condition of probation or parole) will continue taking it.
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To Treat Underlying Psychopathology The high prevalence of psychiatric comorbidity among drug abusers leads organized psychiatry to opine that "psychiatrists have a critical role to play in the diagnosis and treatment of patients with substance abuse disorders" (Group for the Advancement of Psychiatry 1991). The self-medication hypothesis (i.e., addicts use drugs or find certain drugs appealing to self-medicate underlying psychopathology) is commonly believed by psychiatrists. Actual estimates of the prevalence of psychopathology among drug users vary widely, but there is little doubt that a significant number of drug abusers have psychopathology, particularly depression that predates the development of addiction . Lemere (1991) noted that of 292 primary cocaine addicts undergoing inpatient treatment, " ... 22% had abused cocaine while seeking relief from preaddictive dysphoria and depression and 13% had become addicted while seeking to enhance the euphoria that they had always enjoyed because of a hypomanic personality trait." Researchers at Yale have noted that depression predicts cocaine abuse among methadone maintenance patients and hypothesized that "pharmacotherapy of depression in these patients may not only reduce psychosocial morbidity, but may also impact on subsequent cocaine abuse...." (Kosten, Morgan & Kosten 1990). Much pharmacotherapy in clinical practice and research is driven by the self-medication hypothesis.
Side Effects
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tIl
"
"0
in
....o
.~
"
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"
Vl'--_-==::::.-
Therapeutic Response
:J
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....o "0 " a
"c00
.
:8 Dose -----.
Figure 1. The relationship between side effects, therapeutic response and dose . As the dose is increased beyond the peak in the therapeutic response curve, side effects overshadow the therapeutic effects.
To Treat Drug-Induced Psychopathology Chronic drug abuse can produce changes in the number of neurotransmitter receptors , changes in receptor sensitivity, and alterations in brain chemistry. The biochemical and receptor perturbations, which may take days or even months to return to normal , may explain the protracted withdrawal syndromes that occur in newly abstinent drug abusers. To the extent that abstinent drug abusers turn to drugs to self-medicate protracted withdrawal symptoms, effective pharmacotherapy of the symptoms with nondependence-producing medications may assist in patients remaining drug abstinent. In some cases, chronic drug abuse induces new illnesses that can be effectively treated with medication. For example, chronic abuse of amphetamine or cocaine may up-regulate noradrenergic receptor sensitivity, which manifests clinically as panic attacks in some individuals. Antidepressants may down-regulate noradrenergic receptor sensitivity.
Finding the Right Dose One of the major problems in medication development for treatment of substance abuse is the general lack of dose-ranging and dose-comparison studies. This is true even for well-established medications. After 25 years of clinical use of methadone maintenance, for example, there is still controversy about the most effective dose. Before undertaking multicenter clinical trials of a new medication, the "best apparent dose" should be known (Schmidt 1988) . Even when medications are borrowed from treatment of other diseases (e.g., desipramine), it should not be automatically assumed that the same dose of desipramine used to treat depression will also be the best dose for reducing cocaine craving. Study designs for exploring the dose-response relationship include the titration studies (Shih, Gould & Hwang 1989) and dose-comparison studies. In dose -titration studies, each patient's dose of medication is increased stepwise over time while the patient's dependent variable (e.g ., amount of drug use, drug craving) is measured. For a therapeutic efficacy trial, the dependent measure must be relatively constant over time so that the effect of differing doses of medication can be assessed. Efficacy cannot be unequivocally established in a study of this design
FUTURE RESEARCH The methodology and technology for conducting clinical trials of new medications for treatment of drug dependence is still developing. Fully appreciating the limitations of previous studies may facilitate more successful med ication development in the future. Journal ofPsychoactive Drugs
_
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because the dependent variable may be affected by timein-treatment or some other extraneous variable. The strengths of carefuIly controIled dose titration are that researchers can measure subjects' responses to differing doses of medication over time, delineate the types of patients who apparenl1y respond to the medication, and establish with considerable precision the side-effect profile of the medication and subjects' tolerance of medication side effects at various doses. If an effect to the medication is present, it is likely to be observed with this design. Moreover, subjects find the design acceptable because they are assured of receiving active medication. The importance of dose ranging is illustrated in Figure I. Medications, such as antidepressants, have a minimum therapeuti c dose. If patients receive less than the minimum therapeutic dose, they will not have an antidepressant effect; however, they may have some medication side effects. As the do se is in creased, therapeutic re sponse increase s and the intensity of sid e effects increases. As the dose is increased, a dosage is eventually reached above whi ch further increases do not increase therapeutic response. Side effec ts continue to increase and eventually they overshadow the therapeutic benefit. Further increa se in dose result'> in decreasing therapeutic response. It is important to establish the shape of the curve before fixeddose trials are undertaken. The investigator should pick a dose that is as near as pos sible to the peak for most patients to maximize the chances of demonstrating efficacy. If the fixed dose chosen for placebo-controlled efficacy trial is over the peak to the right, the results of the trial may result in rejecting an efficacious medication. Dose comparison studies use independent, parallel
groups. Subjects are randomly assigned to a fixed dose of medication and one measures the proportion of subjects that respond to each dosage level. CONCLUSION Medication treatment of drug abuse can be an irnportant adjunct to psychosocial treatment, and pharmacotherapy may attract and retain some drug abu sing patients in treatment who would otherwise be untreatable. Current treatment approaches can be improved if clinicians are clear with themselves and their patients about what they want to accomplish with pharmacotherapy. Clinical trials of new medication can be improved by additional attention to dose-ranging studies and clear outcome mea sures that are linked to the intended indication or purpo se of the medication. NOTES
1. Usually, the FDA will not consider a study to be "pivotal" unless it is conducted using Good Clinical Practice Guidelines, which specify documentation requirements for clinical trials that far exceed what most clinicians or clinical researchers would deem necessary. The purpose of the extensive documentation is to allow FDA auditors to verify the data and to make judgments about the conduct of the study, often several years after it is completed. Th e technical aspects of an NDA are oul1ined in the 1988 FDA publication Guidelines for the Format and Conduct of the Clinical and Statistical Secti ons of New Drug Applications.
REFERENCES Schmidt, R. 1988. Dose-finding studi es in clinical drug developme nt. European Journal ofClinical Pharmacol ogy Vol. 34 : 15-19. Shih, W.J.; Gould, A.L. & Hwang , I.K . 1989. The analysi s of titrati on studies in phase III clinical trials . Stat istics in Medicine Vol. 8: 583 591. Smith , D.E. & Wesson, D.R. 1983 . Bcn zod iazep ine dependency syn dromes. Journal 0/ Psychoa ctive Drugs Vol. 15(1-2): 85-95 . Smith, D.E. & Wesson, D.R. 1970. A new method for treatment of barbiturate depend ence. Journal of the American Medical Association Vol. 213(2): 294 -295. Vagelos, P.R. 1991. Are prescript ion drug prices high? Science Vol. 252: 1080-1084 . Zwebcn, lE. & Payte , J.T. 1990. Methadone maintenance in the treatment of opioid depend ence: A current perspective . Western Journal 0/ Medi cine Vol. 152: 588-599.
Dole, V. & Nyswander, M. 1967. Heroin addiction: A metabolic disease. Archi ves of General Psychiatry Vol. 120: 19-24. Group for the Advan cement of Psych iatry Committee on Alcohol ism and the Addictions. 1991. Substance abuse disorders : A psychiatric priority. Am erican Journal ofPsychiatry Vol. 148(10): 1291-1300. Kim, T.F. 1988. Methadone maintenance treatment remains controversial even after 23 years of experience. Journal of the American Medical Associati on Vol. 260(20): 2970ff. Kosten, T.R.; Morgan, C. & Kosten, T.A. 1990. Depressive symptoms during buprenorph ine treatment of opioid abu sers . Journal 0/ Substan ce Abuse Treatm ent Vol. 7: 51-54 . Ling, W. & Wesson, D.R. 1990 . Drugs of abuse--opiate s. Western Journal 0/ Medicine Vol. 152: 565 -572. Martin, J.; Payte, J.T. & Zwebcn, J.E. 1991. Methadone maintenance treatment : A primer for physicians . Journal ofPsychoactive Drugs Vol. 23(2) : 165-176 .
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