To the Editor: In the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study, Dr Anton and colleagues1 evaluated the effects of combining medications with behavioral interventions in treatment of alcohol dependence. While all 9 study groups showed marked reductions in drinking from baseline to end of study, treatment with acamprosate, naltrexone, or both when added to the background of medical management did not substantially improve percent days abstinent or time to first heavy drinking day (the 2 coprimary outcomes) compared with placebo and medical management, regardless of whether a combined behavioral intervention (CBI) was added.
In this multifactorial design, naltrexone statistically separated from nonnaltrexone groups on time to severe relapse but demonstrated a significant interaction with CBI for percent days abstinent. The direction of interaction indicatedthat the medication effect was weaker when CBI was added, an unexpected finding. Furthermore, the magnitude of additional benefits of naltrexone over placebo with medical management and over acamprosate (6 and 3 additional days of abstinence, respectively, over a 4-month period) is of questionable clinical relevance despite statistical significance.
These results are inconsistent with the previous data for both acamprosate and naltrexone. Clinical trials have consistently demonstrated the efficacy of acamprosate in maintaining abstinence2 and reducing alcohol consumption.3 In that context, important differences between the COMBINE Study and other trials should be considered. A key feature of COMBINE that sets it apart from other alcohol dependence trials is a rigorous retention strategy that included options for taxi reimbursement, babysitting arrangements, and weekend/holiday appointments. These resulted in retention rates as high as 94%, vs 46% to 63% in acamprosate trials2 ,4 and 47% in a naltrexone/acamprosate combination trial.5 Other unique features of COMBINE that may limit the generalizability to clinical practice include the intensity of the background medical management (45-minute initial session, followed by 20-minute biweekly sessions) and a highly selected cohort of patients (representing only 28% of all screened participants). These design features are likely responsible for the high placebo response rate observed in the study. With a minimal difference between the 2 pharmacological therapies, COMBINE provides little evidence to support preferential use of either.
One message of the COMBINE Study is that combinations of behavioral and pharmacological interventions may help a population that is significantly undertreated and that adjunctive medications improve treatment outcome. More clinical data are needed to validate the preferential use of specific combination therapies for alcohol dependence.
Financial Disclosures: Dr Jonas is executive vice president and chief medical officer for Forest Research Institute and reports ownership of the company stock. Dr Chabac is a vice president for Merck Santé and reports ownership of the company stock.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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