Medical management was developed to provide an approach that could be used in an addiction treatment setting or primary care setting and could be delivered by various health care providers (nurses, physicians, physician assistants, etc). Medical management—similar to that provided in the treatment of diabetes, hypertension, etc—involved up to 9 sessions of medical education, advice, compliance enhancement, feedback on laboratory results, and adverse—effect review, as well as Alcohol(Drug information on alcohol)ics Anonymous attendance encouragement.6,7
CBI consisted of a patient-centered approach in which aspects of MET, CBT, and 12-step facilitation were delivered by trained and supervised counselors and that was based on individual needs but drawn from a limited procedure manual.8 To evaluate whether drinking outcomes were better for the groups receiving the active drugs or placebo and/or medical management, one group was randomized to CBI only, without any drugs and with limited medical management.
The results were in some ways unexpected but important. The main positive finding was that individuals treated with naltrexone(Drug information on naltrexone) did significantly better than the placebo group on various drinking measures—but only when they received medical management alone. When they received CBI in addition to medical management, the difference between the placebo and naltrexone groups was no longer evident.
These results are best illustrated by a good composite outcome measure, defined as abstinence or moderate drinking without alcohol-related problems during the last 8 weeks of the trial (Figure 1). The number of individuals with alcohol dependence that need to be treated (number needed to treat [NNT]) to get 1 response that was more favorable with naltrexone than with placebo was 6. This compares favorably with the NNT in studies of chronic depression, Crohn disease, type 2 diabetes mellitus, and Alzheimer disease.
Important negative findings indicated that:
• Acamprosate(Drug information on acamprosate) was no better than placebo—with or without CBI
• Acamprosate added to naltrexone was not significantly better than naltrexone alone
• CBI was less effective when given without active drug or placebo or medical management.
After 1 year of follow-up, the effects observed during the treatment period were still observable but for the most part were no longer significant. This suggests that at least some individuals relapsed to heavier drinking once treatment had stopped.
A cost-effectiveness analysis showed that the best combination of costs and effectiveness was observed in the naltrexone-treated group, which also received medical management.9 Three years later, the treatment provided during the study remained effective in reducing social costs (health care utilization, arrests, and motor vehicle accidents) in these alcohol-dependent individuals.10
The COMBINE study investigators had planned to evaluate the effects of genes on treatment response and collected DNA samples from willing participants. During the trial, it had been reported by researchers not involved in the study that a single nucleotide polymorphism (SNP) in the µ-opioid receptor (OPRM1) gene might be associated with better naltrexone response.11 In a post hoc analysis of the COMBINE study, this asparagine to aspartate (Asn40Asp) OPRM1 SNP, found in 22% of the white participants, was associated with the best response to naltrexone.12 Using the Clinical Global Outcome measure, one can see this effect in Figure 2.
The COMBINE study was important for what it discovered and for the questions it raised. First of all, it was surprising that the study did not find acamprosate efficacious, considering the many positive European studies.4 The lack of effect, however, was consistent with another multicenter study performed in the United States.5 It is possible that alcohol-dependent individuals who for the most part had not experienced alcohol withdrawal symptoms or who were not sufficiently abstinent during acamprosate induction might not have been the best candidates for this medication. Also, the fact that naltrexone did not add anything to CBI therapy (as long as participants were receiving either active drug or placebo and seeing a health care provider) was a bit puzzling, given that naltrexone has been used to augment CBT.3
CBI may have been more effective than routine CBT and therefore may have provided maximal treatment effectiveness so that naltrexone did not add additional effectiveness. The fact that CBI was not as effective when individuals were not seeing a health care provider and taking either active drug or placebo is worth noting but must be interpreted in light of the fact that participants, on balance, expected to receive “pills” when they volunteered. Whether this effect was a negative expectancy effect or whether seeing a health care provider in addition to a therapist is important for maximal treatment effectiveness cannot be elucidated more clearly from the study design.13