Treatments

Evidence-Based Treatments for Alcohol Dependence:
New Results and New Questions*

Henry R. Kranzler, MD

An estimated 8 million adults in the United States have alcohol dependence.1 Of this number, only a minority ever receive treatment for the disorder, even when treatment is defined broadly to include participation in Alcoholics Anonymous. Of the alcohol-dependent individuals who receive treatment, only a small fraction ever receive a medication specifically approved by the US Food and Drug Administration (FDA) to treat the disorder.

In 1994, the FDA approved naltrexone for the treatment of alcohol dependence.2-3 This followed by nearly 50 years the approval of disulfiram, which was approved prior to the modern era of efficacy review. Meta-analytic studies of naltrexone have shown that the drug reduces the risk of relapse to heavy drinking and, to a lesser extent, the frequency of drinking.4-5 In 2004, following use of acamprosate in Europe for more than a decade, the FDA approved this drug for treatment of alcohol dependence. Meta-analysis of the European acamprosate studies indicated that the drug helped alcohol-dependent individuals maintain abstinence once they had stopped drinking. In contrast to disulfiram, which produces an aversive reaction when combined with alcohol, both naltrexone and acamprosate appear to exert their efforts directly on the individual's motivation to drink alcohol.

In this issue of JAMA, the report by Anton and colleagues of the results of the COMBINE Study provides evidence that an FDA-Approved medication can be of benefit when used to treat alcohol dependence in routine medical practice. These authors describe the results of a randomized, placebo-controlled trial of naltrexone, acamprosate, and the 2 drugs combined, conducted at 11 sites in the United States.

To accomplish the aims of the study, a complex study design was required. In additions to study medication, 8 of the 9 study groups received low-intensity medical management and 4 of these groups also received combined behavioral intervention, a high-intensity psychosocial treatment. In a design feature unique among trials of medications to treat alcohol dependence, the study also included a group that received only the behavioral intervention with no active or placebo medication, making it possible to analyze the comparative effect of a placebo on drinking outcomes.

This study of nearly 1400 abstinent participants was well designed and well executed. Nearly complete data on participant drinking behavior during the 4-month treatment period lends confidence to the findings. Overall, alcohol consumption decreased by 80% during the treatment period, and all treatments were well tolerated. Compared with placebo, naltrexone significantly decreased the likelihood of heavy drinking and increased the number of abstinent days, even in the absence of intensive behavioral treatment. Surprisingly, however, acamprosate, either alone or in combination with naltrexone, showed no advantage over placebo on any of the drinking outcome measures. When combined with placebo, the high-intensity behavioral treatment also increased the number of abstinent days. Participants who received the combined behavioral intervention, but neither an active nor a placebo medication, showed significantly less improvement than those who were treated with placebo, underscoring the substantial placebo response among these alcohol-dependent individuals. At 1-year posttreatment follow-up, although treatment effects were diminished, and between-group differences no longer statistically significant, the direction of the findings was the same. This suggests that treatment may be required for longer than 4 months to produce sustained benefits.

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While this important study provides evidence of the efficacy of some treatments for alcohol dependence, it also raises a number of questions. In view of studies from Europe providing consistent evidence that acamprosate helps to maintain abstinence, the lack of efficacy of this medication in the COMBINE Study is perplexing. Although population differences must be considered, differences in study design may have contributed to the lack of replication of the European acamprosate studies. The modest effects of the specific treatment and a lack of additive or synergistic benefits if combining treatments suggest that other compounds and therapeutic approaches should be explored to yield further improvements in the treatment of alcohol dependence.

The findings from the COMBINE Study should be of great interest to primary care physicians treating patients with alcohol dependence. Patients who decline an offer of pharmacological treatment to reduce their drinking can be referred for intensive behavioral treatment. Notably, however, the beneficial effects of naltrexone were seen in the context of medical management similar to what is routinely available in primary care practice. This offers the prospect that an efficacious treatment for alcohol dependency can be made as widely available as are current treatments for smoking cessation and major depression.

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*Taken from JAMA, May 3, 2006-Vol 295, No.17, page 2075