Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial

Abstract

Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06–0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04–0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (−0.09–0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (−0.12–0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16–1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07–0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

Sex as a Potential Moderator for Baclofen Response in the Treatment of Alcohol Dependence

“…These findings are consistent with a recently completed trial by Garbutt et al ( 22 ), which indicated the potential of an enhanced treatment effect for women compared to men. These authors found that women demonstrated a greater reduction in heavy drinking days and abstinence from alcohol ( 22 ).…”

“…Baclofen, a selective g-aminobutyric acid type B (GABAB) receptor agonist, provides a potential treatment for alcohol dependence, with several clinical trials ( 19 – 22 ), and meta-analyses ( 23 , 24 ) demonstrating efficacy. We have previously reported that baclofen delays time to lapse and relapse relative to placebo ( 25 ) in addition to attenuating alcohol cue-elicited brain activation ( 26 ), cardiovascular response ( 27 ), and emotional regulation during high threat stimuli ( 28 ).…”

“…The response to baclofen has previously been found to be predicted by baseline anxiety levels ( 19 ) and the level of alcohol consumption ( 23 , 31 ). Interestingly, one recently completed trial by Garbutt et al ( 22 ) supports a therapeutic effect of baclofen but also indicates the potential of an enhanced treatment effect for women at low doses and reduced tolerability at higher doses compared to men. In this study, women treated with baclofen demonstrated a greater reduction in heavy drinking days and abstinence from alcohol ( 22 ).…”

“…The current study thus aimed to examine the moderating role of sex on baclofen treatment response ( 22 ). We conducted a secondary analysis of Baclofen in the treatment of Alcohol Liver Disease (BacALD) randomized controlled trial results ( 25 ) stratified by sex.…”

Treating Alcohol Use Disorder in Patients with Alcohol-Associated Liver Disease: Controversies in Pharmacological Therapy

“…The last RCT tested 10 mg tid and 30 mg tid of baclofen with respect to placebo. Gender and level of pre-randomization drinking on response to baclofen were evaluated as moderators for efficacy or tolerability (107). A significant effect of baclofen in reducing heavy drinking days and increasing abstinent days was found.…”