The Declining Efficacy of Naltrexone Pharmacotherapy for Alcohol Use Disorders Over Time: A Multivariate Meta‐Analysis

Oral naltrexone, an opioid antagonist medication, is currently one of only four FDA-approved medications for treating alcohol use disorders (Harris et al., 2010). Although numerous studies and meta-analyses have supported its efficacy, a meta-analysis by Feinn and Kranzler (2005) found that, compared to earlier studies, more recent trials had smaller effects for relapse to heavy drinking and percent drinking days, although the trend for the latter outcome was not quite significant. In addition, multi-center trials (compared to single-site studies) had smaller medication effects on relapse to heavy drinking. Previous reviews of pharmacotherapy trials for depression and schizophrenia have come to similar conclusions (Kemp et al., 2010; Rief et al., 2009). That is, effect sizes in those trials both attenuated over time and were smaller in multi-center studies. Several factors have been pointed to that may account for these findings. The attenuation of effects in more recent pharmacotherapy trials may be attributed to (a) regression to the mean as a function of publication bias for earlier studies (Finney, 2008), (b) confounding of more recent studies with multi-center designs (Feinn and Kranzler, 2005), and (c) increasing placebo group improvement over time (Del Re et al., in submission). Multi-center studies are thought to have smaller effects due to variability in (a) study execution (e.g., varying fidelity to treatment protocol, recruitment procedures) among centers (Feinn and Kranzler, 2005) and (b) other contextual factors across sites (e.g., variation in participant and provider characteristics) which then attenuate the aggregated effect size (ES). The current review extends Feinn and Kranzler’s (2005) meta-analysis by using multivariate meta-analytic methods to examine the efficacy of naltrexone (vs. placebo) in a larger sample of single-site and multi-center studies over a longer time period. The additional studies provide more statistical power to detect the effects of potential moderators, such as time and multi- versus single-center trials. Utilizing multivariate procedures allows for simultaneous modeling of both percent days abstinent (the inverse of percent drinking days) and relapse to heavy drinking outcomes, and thus provides independent estimates for each outcome. This procedure is advantageous as it considers the correlation between the modeled outcome variables, instead of assuming independence as two separate univariate procedures do, thereby reducing the likelihood of Type I error (i.e., erroneously rejecting the null hypothesis). We hypothesize that naltrexone effect sizes continue to decrease after 2003 (the last year examined by Feinn and Kranzler), but eventually plateau (we expect that at no point in time will effect sizes average zero or less) and that multi-center trials continue to yield smaller effect sizes than single-site trials. Further extending the work of Feinn and Kranzler, we planned to examine whether placebo group improvement has been increasing over time, thus accounting for smaller medication effects over time. We also test whether the presence of a placebo run-in period moderates naltrexone effect sizes. Placebo run-in periods eliminate non-compliant participants or participants who exhibit a strong initial placebo response. Thus, studies with a placebo run-in period are expected to have stronger medication effects. Lastly, we examine the interaction between publication year and multi-center (vs. single site), to determine if there are differential effect sizes in multi-center sites versus single site studies on average (grand mean centered intercept) and over time (slope coefficient).