Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial.

Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1 -blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1 -blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty-one AD individuals were randomized, 30 (doxazosin = 15) completed the treatment phase and 28 (doxazosin = 14) also completed the follow-up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA × medication interactions for both DPW (pcorrected = 0.001, d = 1.18) and HDD (pcorrected = 0.00009, d = 1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high FHDA and by contrast increased drinking in those with low FHDA. Doxazosin may be effective selectively in AD patients with high FHDA. This study provides preliminary evidence for personalized medicine using α1 -blockade to treat AD. However, confirmatory studies are required.

A preliminary double-blind, placebo-controlled randomized study of baclofen effects in alcoholic smokers.

RATIONALE: There is presently no approved single treatment for dual alcohol and nicotine dependencies. OBJECTIVE: This pilot study investigated baclofen effects in alcoholic smokers. METHODS: This was a preliminary double-blind placebo-controlled randomized clinical study with 30 alcoholic smokers randomized to baclofen at 80 mg/day or placebo. A subgroup (n=18) participated in an alcohol cue-reactivity experiment. RESULTS: Baclofen, compared with placebo, significantly decreased the percent days of abstinence from alcohol-tobacco co-use (p=0.004). Alcohol dependence severity moderated baclofen effects, with the higher severity group having the greater baclofen response (p<0.001). Although the percent days of alcohol-tobacco co-use declined in both groups, this decline was greater after placebo than baclofen (p<0.001). Secondary analyses on alcohol or tobacco use alone suggested that the increase in percent days of co-abstinence was driven by the medication differences on heavy drinking days and on percent days smoking. In the cue-reactivity substudy, baclofen slightly decreased alcohol urge (p=0.058) and significantly reduced salivation (p=0.001), but these effects were not related to cue type. CONCLUSIONS: This study provides preliminary evidence suggesting a possible role of baclofen in the treatment of alcoholic smokers. However, the mixed results and the small sample require larger confirmatory studies.

Intravenous ghrelin administration increases alcohol craving in alcohol-dependent heavy drinkers: a preliminary investigation.

BACKGROUND: There is a need to identify novel pharmacologic targets to treat alcoholism. Animal and human studies suggest a role for ghrelin in the neurobiology of alcohol dependence and craving. Here, we were the first to test the hypothesis that intravenous administration of exogenous ghrelin acutely increases alcohol craving. METHODS: This was a double-blind, placebo-controlled human laboratory proof-of-concept study. Nontreatment-seeking, alcohol-dependent, heavy-drinking individuals were randomized to receive intravenous ghrelin 1 mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol cues. The primary outcome variable was the increase in alcohol craving (also called urge) for alcohol, assessed by the Alcohol Visual Analogue Scale. RESULTS: Out of 103 screenings, 45 individuals received the study drug. Repeated measures of analysis of covariance revealed a group effect across ghrelin doses in increasing alcohol craving (p < .05). A dose-specific examination revealed a significant effect of ghrelin 3 mcg/kg versus placebo in increasing alcohol craving (p < .05) with a large effect size (d = .94). By contrast, no significant ghrelin effect was found in increasing either urge to drink juice or food craving (p = ns). No significant differences in side effects were found (p = ns). CONCLUSIONS: Intravenous administration of exogenous ghrelin increased alcohol craving in alcohol-dependent heavy-drinking individuals. Although the small sample requires confirmatory studies, these findings provide preliminary evidence that ghrelin may play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacologic target for treatment.