Overview

The pharmacotherapy for alcohol dependence was selected as an evidence report topic by the Agency for Health Care Policy and Research (AHCPR) because of its timeliness, the severity and impact of the disease, and the need for careful evaluation of new therapeutic modalities for its treatment. Alcoholism is a prevalent disease that will affect on the order of 10 percent of the adult population of the United States. An estimated 100,000 Americans die each year from alcohol-related disease or injury. The serious financial and nonfinancial impact of this disease extends to family members and society in general, and its annual dollar cost to the country has been estimated (as of 1995) to exceed $166 billion.

The treatment of alcohol dependence requires a two-step approach that includes withdrawal and detoxification followed by further interventions to maintain abstinence. There is considerable uncertainty about the best treatment strategies for patients in the post-detoxification stage. Some advocate a "drug-free" 12-step approach developed by Alcoholics Anonymous (AA), while others assert that the 12-step approach or other psychosocial approaches combined with appropriate nonaddictive pharmacotherapies may improve treatment outcomes.

Reporting the Evidence

The evidence report from which this summary is drawn focuses on the pharmacotherapies used for the treatment of alcohol dependence. The report is organized around a series of major clinical questions. These involve pharmaceutical agents that have been historically or are presently used in the treatment of alcoholism: disulfiram, the opiate antagonists naltrexone and nalmefene, serotonergic agents such as ondansetron, buspirone, and the selective serotonin reuptake inhibitors (SSRIs, such as citalopram, fluoxetine, paroxetine, sertraline, etc.), and lithium. Disulfiram and naltrexone, in particular, are mainstream agents in use in the United States today. However, it is important to recognize that the field of pharmacotherapy for alcohol dependence has evolved substantially over the past 5 years, especially with the emergence of data on the opiate antagonists.

Concomitantly, there is one promising pharmaceutical agent currently in use in Europe - acamprosate (calcium acetyl homotaurinate) - for preventing alcohol relapse. An investigational new drug (IND) application is on file for this drug at the United States Food and Drug Administration (FDA), and it is in Phase III trials in this country.

Much of the literature examined for the evidence report was designed to establish efficacy: Does the medication reduce alcohol intake in a well-controlled study setting? Examination of potential harms associated with treatment is equally important. The evidence on treatment harms was sometimes found within randomized controlled trials (RCTs) but was also identified through prospective cohort studies or secondary data sources, although the latter sources were not systematically searched.

Key Clinical Questions

Five questions were addressed relevant to the core symptoms of alcohol dependence and related factors such as craving, loss of control (relapse), abstinence, and total drinking or nondrinking days. The first three questions relate to three agents used primarily for the treatment of alcohol dependence: disulfiram, the opiate antagonists naltrexone and nalmefene, and acamprosate. These agents have been in use for different periods of time, and the amount of evidence available for each agent differs substantially.

Disulfiram inhibits aldehyde dehydrogenase and leads to increased levels of acetaldehyde when alcohol is consumed, with subsequent adverse physical effects such as nausea, headache, and weakness. Disulfiram has been in use for approximately 50 years. The opiate antagonists (naltrexone and nalmefene), which block opioid receptors leading to a hypothesized reduction in the rewarding properties of alcohol, have been in use in the United States for only a few years. Acamprosate, whose mechanism of action has not been clearly established as yet, is not available in the United States but has been used in Europe for a few years. The first three questions are:

1.

What is the efficacy of disulfiram relative to placebo in treating alcohol dependence?

2.

What is the efficacy of naltrexone relative to placebo in treating alcohol dependence?

3.

What is the efficacy of acamprosate relative to placebo in treating alcohol dependence?

The fourth and fifth questions relate to drugs that have been approved by the FDA for conditions other than alcohol dependence such as depression and bipolar disease:

4.

What is the efficacy of serotonergic agents relative to placebo in the treatment of alcohol dependence?

5.

What is the efficacy of lithium relative to placebo in the treatment of alcohol dependence?

Animal studies indicate that alcohol intake can be reduced by SSRIs and other serotonergic agents such as buspirone and ondansetron. A moderate literature has examined the efficacy of these agents in maintaining remission in humans.

Finally, lithium has been used to treat alcoholism. Lithium has been a mainstay of treatment for bipolar affective disorder, although the literature in the area of alcohol dependence is limited. Nonetheless, clinical issues remain.

The efficacy of each of these agents was determined by an assessment of the following factors: reduction in the number of standard drinks of alcohol, reduction in the number of drinking days (or increase in the number of nondrinking days), reduction in relapse rates defined as time to first drink or development of an a priori defined relapse, overall resumption of drinking over the course of the study, number of episodes of heavy drinking, severity of side effects, and compliance with drug therapy.

Multiple other agents have been used to assist in the maintenance of remission from active drinking. These include agents that directly affect brain dopaminergic systems (bromocriptine) or gamma-amino butyric acid (GABA) systems (gamma-hydroxy butyrate). Evaluating the role of all agents that have been tried in the treatment of alcohol dependence would be of interest to the alcohol treatment professional but is outside the scope of the evidence report.

Methodology

The research methodology used in developing the evidence report is summarized here, including the inclusion and exclusion criteria for the literature search, the Medical Subject Headings (MeSH) used, the databases searched, and the data abstraction process. Procedures used for assessing quality and grading the evidence and development of evidence tables and supplemental analyses are also briefly discussed.

Findings

Findings are presented in bullet format for the five major drugs or drug classes reviewed.

Future Research

Although the quality of the research on pharmacotherapies for alcohol dependence has improved substantially since the 1960s, numerous difficulties were encountered in developing the evidence report. These difficulties involved both reviewing the available literature and developing concrete conclusions or drawing appropriate inferences about the efficacy of these drugs in treating the different patient populations suffering from alcoholism. To address some of these drawbacks and deficiencies in the empirical knowledge base, several significant areas have been identified for attention in future research. The topics and/or methodologic issues deserving high priority include:

• Pharmacotherapies shown to have efficacy in the treatment of alcoholism should be studied over longer time periods to establish their efficacy as maintenance treatments. These trials should probably last several years. Extending the length of followup once active treatment has ended, perhaps as long as 5 to 10 years, would also provide information on whether efficacy is still evident beyond active treatment. Lack of efficacy beyond active treatment would then raise the question of the value of long-term maintenance.
• Combination therapies, i.e., therapeutic regimens that involve two or more medications given simultaneously, should be examined for efficacy.
• Psychosocial co-interventions used within pharmacotherapy trials require more standardization, better compliance assessment, and better reporting in future publications. These include psychosocial interventions provided outside specialized treatment programs and in primary care settings.
• Effectiveness studies are needed to establish the benefit of these treatments in various settings (i.e., outside the specialized centers typically used in RCTs to date and, by implication, in patient populations encountered in all types of settings) once efficacy for alcohol dependence has been established.
• Common outcome measures need to be determined by standardizing the definition of outcomes and how they are assessed and using broader sets of endpoints that include clinical and health-related quality-of-life indicators.
• High dropout rates warrant attention, including identifying reasons for (differential) dropout, improving the reporting of baseline characteristics of different groups, and designing innovative ways to overcome significant dropout, especially for long-term studies.
• Research on the pharmacokinetics of these medications includes evaluating the relationship of drug blood levels and of drug metabolites to therapeutic or toxic outcome.
• All RCTs should include pharmacotherapy compliance assessment and enhancement for all treatment groups.
• The relationship of pharmacotherapy to patient heterogeneity needs to be better understood, including effects related to the patient's sex, severity of dependence, coexisting mental disorders, and the interactions among these factors.