What are the major findings of the COMBINE study?

Answer: The COMBINE study was a large scale study in 2001 to test the effectiveness of pharmacotherapy in conjunction with psychological therapy for alcohol cessation. They found that naltrexone, combined behavioral intervention, or both improved outcomes for patients, while acamprosate did not improve alcohol cessation outcomes substantially.

COMBINE study naltrexone acamprosate alcohol abuse

Alcohol use disorder is a recurring brain disease that has severe negative health outcomes for patients. It is estimated that some 16 million Americans (about 6% of the population) experience an alcohol use disorder. Despite the high prevalence of alcohol use disorder, less than 10% of patients ever seek help.

There were two major approaches to treating alcohol dependence. A pharmacological approach, such as treatment with naltrexone, relies on a patient taking a medication. These therapies affect the way that the patient experiences alcohol craving. On the other hand, psychological therapies in the form of Combined Behavioral Intervention (CBI) use cognitive behavioral therapy, face-to-face interviews with clinical psychologists, and integrating the patient with a 12-step program.

The COMBINE study was initiated in 2001 and ran for three years. It was the first large scale, multi-site study to assess the effectiveness of CBI with pharmacological intervention to decrease alcohol use disorders.


The COMBINE study had a large sample size of 1383 recently abstinent volunteers. The study took place across a total of 11 site across the US.

The study recruited subjects who were considered to have alcohol dependence under the criteria put forth in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).

The two major outcome measures that they reported in the COMBINE study were the percentage of days abstinent since the initiation of treatment, and the number of days until their first heavy drinking day.


Two different drugs were tested in the COMBINE study.

Oral naltrexone was given at a dose of 100 mg daily. Naltrexone is an opioid receptor antagonist.

Oral acamprosate was given at a dosage of 3 mg daily. Acamprosate modifies glutamate rich signaling.

In addition to the medicine they were given, all patients were provided with medical management. This medical management was essentially a consultation with the physician, sessions generally lasting 20 to 45 minutes. In these sessions, patients were given information about their disease and ways to manage their alcohol intake. They were also given the opportunity to ask about any side effects they might be experiencing. During medical management, physicians would provide important advice about best strategies for staying adherent to the medications.


The patients were divided into one of nine groups. They were either given naltrexone, acamprosate, both drugs, or a placebo. Among each group, half were assigned to receive combined behavioral intervention.

As a final control, the ninth group did not receive any medication. Instead, this group of patients received only the behavioral intervention.

The treatment regime was four months long. A follow up interview was conducted one year later to assess the success of the therapy.


They found that naltrexone or both naltrexone and the combined behavioral intervention were effective at decreasing the signs of relapse.

One of the surprising results of the COMBINE study was that acamprosate was ineffective at decreasing alcohol dependence. In a metanalysis of 17 randomized clinical trials of 4087 alcohol dependent patients (The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: results of a meta-analysis), previous studies have found that acamprosate was effective at decreasing dependence on alcohol after abstinence.

The findings from the study were published in 2006 in the Journal of the American Medical Association (Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial.)