Alcoholism Treatments Exert Extended Effect

Psychiatric TimesPsychiatric Times Vol 25 No 6
Volume 25
Issue 6

Maintaining abstinence from alcohol "one day at a time" may be easier with appropriate treatment, but even with the best treatment it can become more difficult as the days add up.

Maintaining abstinence from alcohol "one day at a time" may be easier with appropriate treatment, but even with the best treatment it can become more difficult as the days add up. A recently published analysis of long-term outcomes in the COMBINE study (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) found that patients benefit for up to a year after completing treatment with naltrexone (Depade, ReVia) and/or a behavioral intervention but not after treatment with acamprosate (Campral); and the effects of all treatments did diminish over time.1

Dennis Donovan, PhD, director of the Alcohol and Drug Abuse Institute at the University of Washington in Seattle, and lead author of the report from the COMBINE Study Research Group, described the study to Psychiatric Times as having a "bifocal approach" to evaluating the pharmacological and behavioral therapies by assessing both short-term response, anticipated to occur with medication, and long-term outcomes, expected to be principally influenced by the behavioral therapy.

"There is a belief that in many cases behavioral therapies need an opportunity to be acquired and practiced over time and that while this may occur during the active treatment phase, it often occurs afterward as well," Donovan explained. "It is as if the active phase is a form of 'incubation' and the posttreatment phase is often a point at which newly acquired and better incorporated and practiced skills can actually begin to have an impact on behavior."

The double-blind, placebo-controlled design evaluated the medications singly and in combination, along with brief medical management with or without a combined-modality behavioral intervention (CBI) to foster skills for relapse prevention. The main treatment phase was conducted over 16 weeks, and follow-up assessments were obtained at weeks 26, 52, and 68 weeks (1 year after completing active treatment). The study population comprised 1383 patients (428 women) who met diagnostic criteria for alcohol dependence; the patients were found to consume an average of more than 12 drinks a day on 75% of the days in the 3-month prebaseline screening period. One drink was considered to be equal to Z\x oz of absolute alcohol: 10 oz of beer, 4 oz of wine, or 1 oz of 100-proof distilled spirits.

Naltrexone was administered at 100 mg/d and acamprosate at 3 g/d. The tolerability of the naltrexone/ acamprosate combination was assessed, along with treatment retention and changes in drinking and craving during a 3-month preliminary phase. Medication management, provided to all patients receiving either medication or placebo, consisted of up to 9 sessions of about 20 minutes, aimed at enhancing medication adherence and encouraging participation in a 12-step program. The more intensive CBI, involving up to 20 individual 50-minute sessions, was described by the investigators as "a state-of-the-art psychotherapy for alcohol dependence as might be delivered in a specialty alcoholism-treatment clinic."1

The principal outcome measures were the percentage of days of abstinence (PDA) and time to relapse of heavy drinking, which was defined as 1 or more days with 5 or more drinks for men and 4 or more drinks for women. Medication response in the active treatment period was predictive of status over the extended follow-up period. Those receiving naltrexone had significantly lower relapse rates during active treatment than those receiving placebo. Results with acamprosate treatment did not differ from those with placebo, and its addition to naltrexone did not improve outcome.2 At the 1-year follow-up, those who had received naltrexone continued to have a higher PDA and a lower rate of relapse to heavy drinking compared with those who had received placebo and those who had received acamprosate, although the measured advantage declined with time.1

Despite the fact that use of CBI had no apparent advantage over medication management in the 16-week acute treatment, those who received CBI were slower to return to drinking during follow-up and more likely (approximately a 20% advantage) to meet criteria for good clinical response than those who received only medication management.

"As has been found with other behavioral therapies," Donovan commented, "this appears to have been an emergent 'sleeper effect.'" There was a decrement in therapeutic effect of CBI over time as well, with less advantage over medication management at year-end. The investigators point out, however, that all study groups demonstrated greater reduction in alcohol consumption over the posttreatment year than has been historically found in no-treatment, wait-list, and placebo conditions in alcoholism-treatment research.1

The prolonged therapeutic effect of naltrexone treatment was a welcome finding but it was not as surprising to the investigators as the absence of a similar effect with acamprosate, which has demonstrated efficacy in other studies. Donovan suggested that differences in study design and cohort may have contributed to the different findings.

"One of these is the degree of alcohol dependence," he indicated. "It has been suggested that our sample may have been less severely dependent than others. Another difference is that most of the studies of acamprosate in Europe had recruited and randomized individuals into the treatments from inpatient or residential treatment settings."

Donovan explained that the inpatient treatment may be consistent with a higher level of dependency. "It also suggests that there may have been differences across samples in the length of abstinence before participants began taking the medication," he noted.

Maintaining recovery
The pattern of favorable and then diminished response to the naltrexone and CBI treatments, with periods of relapse, is consistent with the course of other chronic medical conditions, the investigators pointed out. Because of this, alcoholism and drug dependence should be viewed and managed as a chronic and relapsing condition, they said. Donovan and colleagues1 proposed that "alcohol-dependent individuals should be monitored across time, and... treatment should be introduced or reintroduced as needed by changes in clinical status."

Donovan told Psychiatric Times that there should be more emphasis on methods to maintain and sustain the positive gains made in active treatment. "This is consistent with the growing view that addictive behaviors such as alcohol dependence be conceptualized, treated, and managed as a chronic health condition for which an acute care treatment model is inappropriate," Donovan said.

"As much, if not more, emphasis needs to be given to keeping individuals abstinent as it has been on getting them there," Donovan declared.

In the published report, the investigators speculate that there might be greater long-term benefit by extending naltrexone treatment or by reintroducing the medication as a "booster" treatment in the course of maintaining recovery. Similarly, they speculate that the response to the initial course of CBI might be enhanced and better sustained if followed by "maintenance" counseling and ongoing medication management.1

Next, the research group will focus on determining predictors of response to either naltrexone or acamprosate, Donovan indicated. "If we are able to identify differential predictors, it would provide health care providers with important information about the likelihood of a positive response to either of the 2 medications," Donovan said.




Donovan DM, Anton RF, Miller WR, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence (The COMBINE study): examination of posttreatment drinking outcomes. J Stud Alcohol Drugs. 2008;69:5-13.


Anton RF, O'Malley SS, Ciraulo DA, et al; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295:2003-2017.

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