Treatment of Substance Use Disorders

Kevin Sevarino

• Publisher: Routledge
• Year: 2013
• eBook ISBN:
  9781135953553
• Topic: Medicine
• Subtopic: Psychiatry & Mental Health

First published in 2002. TREATMENT OF SUBSTANCE USE DISORDERS is a compendium of notable journal articles on the latest advances in the treatment of substance use disorders. This comprehensive resource compiled by the American Academy of Addiction Psychiatry is the first book in the Key Readings in Addiction Psychiatry series. Covering the most current issues concisely, this book serves as a quick guide for mental health professionals specializing in addiction psychiatry. It assembles outstanding contributions from the leading clinical journals in the field on the most recent treatment approaches, both pharmacological and behavioral, for the four major substance categories-alcohol and benzodiazepines, opiates, cocaine, and nicotine. With repeated use and misuse of these substances accounting for the major portion of adverse economic, medical, and social consequences of substance use disorders, this compendium is a valuable reference tool in the treatment of those suffering from substance use disorders. The American Academy of Addiction Psychiatry is seeking ways to turn this intractable problem into one with answers and cures. The American Academy of Addiction Psychiatry is a professional membership organization with approximately 1,000 members in the United States and around the world. The membership consists of health professionals who work with addiction in their practices, faculty at various academic institutions, residents, and medical students.

Chapter 1

Medications for Alcohol, Illicit Drug, and Tobacco Dependence

An Update of Research Findings

Raye Z. Litten, Ph.D.

John P. Allen, Ph.D.

INTRODUCTION

A variety of physiological, psychological, and social factors underlie dependence on psychoactive substances that include alcohol, illicit drugs, and tobacco. While a variety of psychosocial interventions have been developed to assist in resolving these problems, until the past decade or so, little research was undertaken to develop medications that could also assist in treatment of chemically dependent patients. Several medications now appear promising and are likely to significantly influence clinical practice in the future. This article summarizes the state of the knowledge on this topic.

PHARMACOTHERAPY FOR ALCOHOLISM

Progress in development of medications to prevent or reduce drinking is most strikingly illustrated by consideration of two agents, naltrexone and acamprosate. Both have been demonstrated as efficacious and both are currently available for clinical use in a large number of countries. In this section we review research on these agents as well as on disulfiram and the antidepressants fluoxetine and sertraline.

Naltrexone

In December 1994, the opioid antagonist naltrexone (Revia) was approved by the U.S. Food and Drug Administration (FDA) as an adjunct to treatment of alcoholism. Since then, it has been approved in 18 additional countries. Approval of naltrexone was based primarily on two landmark studies (O’Malley & Volpicelli). In the first project, 70 alcohol-dependent male outpatients, recruited from a Veterans Affairs (VA) hospital, were treated with either 50 mg of naltrexone or placebo daily for 3 months (Volpicelli, Alterman, Hayashida, & O’Brien, 1992). Patients also received 4 weeks of intensive abstinence-oriented verbal therapy followed by 8 weeks of aftercare treatment. Those on naltrexone experienced fewer drinking days, were less likely to relapse to heavy drinking, and reported lower craving for alcohol.

In the second investigation (O’Malley et al., 1992), male and female alcohol-dependent patients were treated with 50 mg of naltrexone or placebo daily for 3 months. Again, naltrexone was found to reduce both frequency and quantity of drinking. Interestingly, O’Malley and her colleagues also employed two types of psychosocial intervention and observed a difference in treatment outcome as a conjoint function of drug condition and nature of psychosocial treatment. Subjects treated with naltrexone and supportive therapy emphasizing total abstinence achieved the highest rate of abstinence. Those treated with naltrexone and coping skills therapy were less likely to relapse to heavy drinking if they did sample alcohol.

Two recently completed studies have indicated that patient compliance is an important component in naltrexone treatment. In a replication of their first naltrexone study, but with non-VA alcoholic males and females and receiving less intense psychosocial intervention, Volpicelli et al. (1997) reported generally modest effects for assignment to naltrexone in reducing number of days drinking and proclivity to relapse to excessive drinking. Nevertheless, among compliant patients (i.e., those who took medication or placebo at least 90% of the time), naltrexone appeared quite effective. Naltrexone-compliant patients drank on 3% of study days, while equally compliant placebo patients drank on 11 % of study days. More than half of the placebo-compliant patients returned to heavy drinking, contrasted with only 14% of the naltrexone-compliant group. No differences in drinking outcome measures emerged between less compliant naltrexone- and placebo-treated groups.

Chick et al. (Litten & Fertig, 1996) completed a 3-month trial of naltrexone in the United Kingdom. Following detoxification, alcohol-abusing and alcohol-dependent patients received either 50 mg of naltrexone or placebo daily in the context of traditional outpatient therapy. Although neither frequency nor quantity of drinking distinguished the groups, patients who remained in the study and were adjudged compliant on the basis of correct pill count on at least 80% of return visits benefitted from naltrexone. The naltrexone-compliant group experienced a 40% decrease in number of drinking days and a 50% reduction in total number of drinks consumed. In addition, they reported less craving for alcohol than did the compliant placebo-treated group.

In a safety trial with naltrexone administered up to 1 year, the agent appeared well tolerated and nonelicitive of severe adverse effects. The most common side effects were nausea and headaches (Croop, Faulkner, & Labriola, 1997; Litten). In addition, there was no evidence of hepatic injury, an important finding since both alcohol and naltrexone are metabolized by the liver.

To explore the possibility that other opioid antagonists might also aid in reducing drinking, Litten and Fertig (1996) conducted a 3-month, placebo-controlled trial with the opioid antagonist nalmefene. Results of the study indicated that patients treated with nalmefene were less prone to return to heavy drinking than were placebo-treated subjects. Thus, it appears that opioid antagonists other than naltrexone may also have promise in reducing drinking.

Acamprosate

Encouraged by earlier studies suggesting efficacy of acamprosate (Campral) for alcoholic patients (Gerra et al., 1992; Lhuintre et al., 1985, 1990), Lipha Pharmaceuticals recently conducted 11 independent multisite double-blind, placebo-controlled studies in nine European countries, recruiting over 4,000 alcohol-dependent patients. Analyses of pooled data indicated that alcohol-dependent patients treated with acamprosate for 6 to 12 months enjoyed abstinence rates, on average, twice those of placebo-treated patients (Mann, Chabac, Lehert, Potgieter, & Sass, 1995).

Several of the country-specific studies have recently been published. Paille et al. (1995) conducted a 31-site trial of acamprosate with 538 alcohol-dependent patients in France. Subjects were administered either 1.3 g or 2.0 g of acamprosate or placebo daily and also were given traditional supportive psychotherapy. Following 1 year of treatment, both acamprosate groups revealed higher rates of continuous sobriety (significant at 6 months, but not at 12 months) and treatment retention than the placebo group.

Sass, Soyka, Mann, and Zieglgansberger (1996) performed a 12-site study in Germany with 272 alcoholic patients. Subjects were administered either 1332 mg of acamprosate for body weight below 60 kg or 1998 mg of acamprosate for body weight above 60 kg or placebo daily. All received counseling or psychotherapy according to customary practice of the participating site. Following 48 weeks of treatment, 43% of acamprosate-treated patients who finished the study had maintained continuous abstinence, versus 25% of placebo-treated subjects. Amazingly, 48 weeks after treatment ceased, 40% of acamprosate-treated patients still remained abstinent, as compared with 17% of the placebo group.

Whitworth et al. (1996) conducted a 1-year, multicenter study of acamprosate in Austria. Four hundred and fifty-five alcohol-dependent patients were randomly administered one of two dose levels of acamprosate as a function of body weight as described above, or placebo daily. At study conclusion, 18% of acamprosate-treated subjects sustained abstinence, versus 7% of placebo-treated patients.

Finally, a 6-month multisite trial of acamprosate was conducted in the Netherlands, Belgium, and Luxembourg, employing 262 alcohol-dependent patients (Geerlings, Ansoms, & van den Brink, 1997). Dosage was adjusted to body weight as described above. Patients treated with acamprosate maintained continuous abstinence longer (45 vs. 15 days), experienced more days abstinent (61 vs. 45 days), and were more likely to be abstinent during the 6 months of treatment (20% vs. 10%) than the placebo-treated group.

Acamprosate is well tolerated and seems to have no serious adverse effects, the most common side effect being diarrhea (Paille et al., 1995; Sass, Soyka, Mann, & Zieglgansberger, 1996; Whitworth et al., 1996). Acamprosate appears to interact with the glutamate receptor (Spanagel & Zieglgansberger, 1997), although its precise mechanism of action is still under investigation.

Disulfiram

Naltrexone and disulfiram (Antabuse) are the only two medications to date approved by the FDA for treatment of alcoholism. Although disulfiram has been available for approximately 50 years, few well-designed studies have been conducted. The most rigorously controlled study was performed by Fuller et al. (1986). In this 1-year, 9-site veteran hospital study, 605 alcohol-dependent patients received either 250 mg of disulfiram per day, 1 mg of disulfiram (placebo) per day, or no disulfiram. No differences were observed among groups in total abstinence, time to first drink, and employment or social stability. However, among subjects who did drink, those who had been on 250 mg of disulfiram drank on fewer days than did those on the 1 mg disulfiram or no disulfiram. Overall, medication compliance was rather low in this study.

Several previous studies have suggested that disulfiram might enhance treatment outcome if compliance-enhancing strategies are employed (Allen & Litten, 1992). Illustrative of this, Chick et al. (1992) conducted a supervised trial in which 200 mg of disulfiram or vitamin C intake was observed daily by an informant. Following 6 months of treatment, patients treated with disulfiram engaged in drinking on fewer days and consumed less alcohol than did the placebo-treated group. In addition, gamma-glutamyl transpeptidase (GGT), a biochemical marker reflecting alcohol consumption, was reduced in disulfiram-treated subjects. In contrast, GGT levels in placebo subjects were elevated.

Finally, recent studies have shown that disulfiram may curb both alcohol and cocaine use in individuals suffering abuse of each substance (Carroll et al., 1993; Higgins, Budney, Bickel, Hughes, & Foerg, 1993). Carroll and colleagues are conducting a rigorous study of disulfiram in this population.

Fluoxetine and Sertraline

Selective serotonin reuptake inhibitors (SSRIs) seem to have potential for treating alcoholics suffering comorbid depression. In the past, only a few well-designed pharmacotherapy trials had been conducted with this population. More recent rigorously controlled studies (Mason, Kocsis, Ritvo, & Cutler, 1996; McGrath et al., 1996) have now shown that the tricyclic antidepressants de-sipramine and imipramine are helpful in reducing depressive symptoms and likely, to some extent, drinking.

Cornelius et al. (1997) recently completed the first double-blind trial of the SSRI fluoxetine (Prozac) with patients comorbid for alcohol dependence and major depression. Fifty-one patients received between 20 and 40 mg of fluoxetine or placebo daily, as well as standard weekly treatment of supportive psychotherapy and psychiatric sessions. Following 12 weeks of treatment, fluoxetine-treated subjects enjoyed more pronounced improvement in depression than did the placebo group. Furthermore, number of drinking days was significantly reduced by 48% and number of drinks per occasion decreased by 56% in fluoxetine-treated patients. Several well-designed studies are currently underway with the SSRI sertraline (Zoloft) in depressed alcoholics, including a 12-site trial by Pfizer. Brady, Sonne, and Roberts (1995) have also initiated a trial of sertraline with alcoholics evidencing posttraumatic stress disorder.

Future Directions

In spite of recent, important successes in trials of pharmacologic agents, a variety of critical research questions remain unresolved. For example, what is the optimal dose and duration of treatment for naltrexone? What is the physiological basis by which acamprosate diminishes? Would a combination of medications, such as naltrexone and acamprosate, acting on different neuroreceptors of the brain, be more effective than either singly? Since psychosocial interventions are recommended in conjunction with medications, which psychosocial therapy should be used with particular medications and how should the two treatment strategies be integrated? Can specific pharmacologic-psychosocial treatments be matched to different subtypes of alcohol-ics? Will the medications prove helpful for nondependent, but abusing, patients? Since patient compliance in taking the medication and attending psychotherapy appears to be a key factor in favorable outcome, how can it be fostered? Finally, a host of more fundamental questions surrounding treatment of alcoholics with comorbid psychiatric disorder remain. For instance, how does treatment of either alcoholism or psychiatric disorder affect outcome of the other condition? Also, what sequence of treatment for alcohol and psychiatric problems is optimal?

PHARMACOTHERAPY FOR TREATMENT OF COCAINE ADDICTION

Over the past decade, extensive research has been conducted on pharmacologic agents to treat cocaine dependency. Unfortunately, no medication has consistently demonstrated efficacy in well-controlled trials. A wide range of drugs has been explored, including stimulants, antidepressants, cocaine antagonists, dopaminergic agents, serotonergic medications, opioid agents, and anticonvulsants (Litten, Allen, Gorelick, & Preston, 1997; Mendelson & Mello, 1996). In spite of the lack of success to date, pharmacotherapy studies continue to address this very serious problem. Experimental agents currently under investigation include desipramine pergolide, a dopamine agonist; risperidone, a dopamine/serotonin antagonist; flupenthixol, a neuroleptic; mazindol, a dopamine reuptake inhibitor; methylphenidate and pemoline, dopamine stimulants; nefazadone, antidepressant and serotonin and norepinephrine reuptake inhibitor and 5-HT₂ antagonist; phenytoin, an anticonvulsant; baclofen, a GABAergic agent; amantadine, a dopamine agonist; buprenorphine, a mixed opioid agonist-antagonist; propranolol, a beta-adrenergic antagonist; and memantine, a noncompetive N-methyl-D-aspatate (NMDA) antagonist (Herman, Vocci, Bridge, & Litten, 1996).

Three recent discoveries from basic science may refine the focus of further pharmacotherapy research on cocaine dependence (Leshner, 1996). First, the research team of Giros, Jaber, Jones, Wightman, and Caron (1996) has successfully disabled the gene responsible for transport of dopamine in mice. When administered cocaine, these “knockout” mice did not respond to psychostimulatory effects of cocaine. Volkow et al. (1997) also recently demonstrated an association between the subjective effects of cocaine and blockage of the dopamine transporter in humans. Developing a medication ...

Table of contents

• Front Cover
• Half Title
• Title Page
• Copyright
• Contents
• Series Introduction
• Introduction
• 1. Medications for Alcohol, Illicit Drug, and Tobacco Dependence: An Update of Research Findings
• 2. The Pharmacotherapy of Relapse Prevention Using Anticonvulsants
• 3. Current Developments in Psychosocial Treatments of Alcohol and Substance Abuse
• 4. Drug Therapy for Alcohol Dependence
• 5. Alcoholism Treatment and Medical-Care Costs from Project MATCH
• 6. Use of Anticonvulsants in Benzodiazepine Withdrawal
• 7. Pharmacologic Treatment of Heroin-Dependant Patients
• 8. Methadone versus L-alpha-acetylmethadol (LAAM) in the Treatment of Opiate Addiction: A Meta-Analysis of the Randomized, Controlled Trials
• 9. Old Psychotherapies for Cocaine Dependence Revisited
• 10. New Treatments for Smoking Cessation
• Permission Acknowledgments
• Index