Medication effects on cue-induced craving in the human laboratory are associated with return to heavy drinking in randomized clinical trials for alcohol use disorder: A follow-up meta-analysis.

Abstract

The alcohol cue-reactivity paradigm is widely used to test the initial efficacy of potential medications for alcohol use disorder (AUD); however, there is limited quantitative evidence demonstrating that medication effects on cue-induced craving are associated with efficacy in clinical trials. This meta-analysis examined whether medication effects on cue-induced alcohol craving are associated with medication effects in randomized clinical trials (RCTs). Follow-up meta-analysis of RCTs. Participants included people who engaged in heavy drinking or have AUD. Medications were compared with a placebo control. We computed medication effect sizes (Cohen's d) for cue-induced craving (k_{# of studies} = 36 studies; 15 medications) and for the following individual RCT endpoints (k_{# of studies} = 139 studies; 19 medications): percent days abstinent, percent heavy drinking days, the percentage of participants who returned to any drinking, the percentage of participants who returned to heavy drinking, drinks per day and drinks per drinking day. We applied Williamson-York regression models to test the relationship between medication effects on cue-induced craving and the six individual RCT endpoints. One-sided P values were used to test directional hypotheses and two-sided P values were also reported to allow for exploratory interpretation. Medication effect sizes on cue-induced craving were positively associated with medication effect sizes on percent participants who returned to heavy drinking [ <math xmlns="http://www.w3.org/1998/Math/MathML"><mover><mi>β</mi> <mo>̂</mo></mover> </math> = 1.06, standard error (SE) = 0.63, one-sided P = 0.04, two-sided P = 0.09; k _{# of effect size} = 74; 7 medications] in RCTs but no other RCT endpoints tested. Specifically, medications that reduced cue-induced craving in the human laboratory also decreased the percentage of participants who returned to heavy drinking in RCTs. Medications that produce greater reductions in cue-induced alcohol craving appear to be associated with lower rates of return to heavy drinking, but not consistently with other drinking outcomes. This pattern indicates that the cue-reactivity paradigm has limited and outcome-specific translational validity rather than functioning as a universal indicator of clinical efficacy.