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Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence

Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence

There are some important questions that clinicians and third-party payers always ask: Do medications to treat alcoholism really work—and if they do, can they be used alone or with behavioral therapies or other interventions? Do medications work any better than behavioral interventions? These are very practical questions . . . ones that experienced clinical researchers tried to address a few years ago in the NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA)-sponsored multicenter clinical trail, the COMBINE (Combining Medications and Behavioral Interventions for Alcoholism) study.1

Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity), another NIAAA-sponsored trial, showed that several different types of psychosocial interventions, such as cognitive-behavioral therapy (CBT), motivational enhancement therapy (MET), and a 12-step facilitation approach, appeared to be equally effective in promoting abstinence and reducing relapse when delivered by qualified and trained counselors.2 In addition to interventions used in Project MATCH, several medications have been shown to be effective in the treatment of alcohol dependence and were approved by regulatory authorities in the United States and Europe.

Naltrexone, an opiate antagonist, had shown efficacy in a number of studies when combined with psychosocial interventions that included CBT, and there was some evidence that the drug worked best in this context.3 In addition, findings from European trials suggest that acamprosate, a brain glutamate stabilizer, helps maintain abstinence post-detoxification across a range of ancillary treatments that had not been well defined.4 In the United States, a multicenter trial did not show acamprosate to be more efficacious than placebo in the context of a medical model supportive/educational approach.5

Given this background, the COMBINE study was designed to address several important questions:

• Do naltrexone and acamprosate produce effects that are different from those of placebo in a well-defined outpatient group of treatment-seeking alcohol-dependent individuals?

• Since naltrexone and acamprosate have different, and perhaps complementary, modes of action, do they work better when combined or when either one is used alone?

• Is the combination of moderately intensive behavioral intervention/counseling and either naltrexone or acamprosate more efficacious than using these agents with a medical management approach (discussed in greater detail below)?

• How do the outcomes of a group that receives behavioral intervention alone compare with those of a group that receives either active drug or placebo?

What is already known about treatment for alcoholism?

? We have known that heavy drinking and alcohol dependence are very common in the United States and that many people with alcohol problems present to primary physicians and other health care providers (including mental health professionals) with problems related to their drinking. These health care providers often do not know how to screen for heavy drinking and if they do, they do not know how to treat it or what options are available, short of referral to Alcoholics Anonymous or an addiction clinic.

What new information does the COMBINE study add?

? The COMBINE (Combining Medications and Behavioral Interventions for Alcoholism) study was able to show that using a medication such as naltrexone combined with some focused medical management could be an option to treat moderate to severe alcoholism in various health care settings. It is likely that inpatient or rehabilitation centers are not necessary for most heavy drinkers with alcohol-related problems. More convenient and affordable treatment options exist that do not remove individuals from their communities, jobs, and family. This opens up access for many more individuals. In addition, it was shown that even up to 3 years after treatment, the various societal costs were lowered by application of the effective treatments used in the COMBINE study. Finally, some ancillary data generated in the study indicate that a more personalized approach to treatment using genetic-based testing might be useful in the future. This should improve effectiveness and reduce costs in the long run.


The COMBINE study recruited 1383 persons with alcohol dependence, mostly derived from community volunteers not currently in treatment, across 11 academic centers. The initial assessment lasted 4 to 6 hours over several days, and the volunteers were required to remain abstinent for a minimum of 4 days. This was required because previous studies done with both naltrexone and acamprosate were initiated after a period of abstinence. From a clinical point of view, patients may not tolerate these medications while drinking; withdrawal symptoms may also complicate their use. The volunteers were randomized to receive naltrexone (up to 100 mg daily), acamprosate (3 g daily), a combination of the two drugs, or placebo for 16 weeks. All participants also received medical management with or without combined behavioral intervention (CBI).


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