R(+)-Baclofen, but Not S(−)-Baclofen, Alters Alcohol Self-Administration in Alcohol-Preferring Rats

The gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, has recently been shown to reduce alcohol intake in alcohol-preferring rats and alcohol consumption and craving for alcohol in an open study in humans. The present study was aimed at providing a first evaluation of the efficacy of baclofen in inducing and maintaining abstinence and reducing craving for alcohol in alcohol-dependent patients in a double-blind placebo-controlled design. A total of 39 alcohol-dependent patients were consecutively enrolled in the study. After 12-24 h of abstinence from alcohol, patients were randomly divided into two groups. Twenty patients were treated with baclofen and 19 with placebo. Drug and placebo were orally administered for 30 consecutive days. Baclofen was administered at the dose of 15 mg/day for the first 3 days and 30 mg/day for the subsequent 27 days, divided into three daily doses. Patients were monitored as out-patients on a weekly basis. At each visit alcohol intake, abstinence from alcohol, alcohol craving and changes in affective disorders were evaluated. A higher percentage of subjects totally abstinent from alcohol and a higher number of cumulative abstinence days throughout the study period were found in the baclofen, compared to the placebo, group. A decrease in the obsessive and compulsive components of craving was found in the baclofen compared to the placebo group; likewise, alcohol intake was reduced in the baclofen group. A decrease in state anxiety was found in the baclofen compared to the placebo group. No significant difference was found between the two groups in terms of current depressive symptoms. Baclofen proved to be easily manageable and no patient discontinued treatment due to the presence of side-effects. No patient was affected by craving for the drug and/or drug abuse. Baclofen proved to be effective in inducing abstinence from alcohol and reducing alcohol craving and consumption in alcoholics. With the limits posed by the small number of subjects involved, the results of this preliminary double-blind study suggest that baclofen may represent a potentially useful drug in the treatment of alcohol-dependent patients and thus merits further investigations.

Gamma-aminobutyric acid-B (GABA(B)) receptor agonists have been shown to suppress operant self-administration of ethanol in nondependent rats. However, little work has focused on the effects of GABA(B) receptor agonists on self-administration of ethanol in dependent animals. In the present experiment, the GABA(B) receptor agonist baclofen was tested for the ability to modulate both fixed- (FR) and progressive-ratio (PR) responding for ethanol in rats while nondependent and subsequently after ethanol dependence induction. Following the acquisition and stabilization of baseline operant ethanol self-administration and after dependence induction, baclofen [0.0, 0.5, 1, 2, and 4 mg/kg, intraperitoneal (IP)] was tested on FR-1 responding for ethanol. The ability of baclofen (2.0 mg/kg) to affect responding under a PR schedule of reinforcement was also evaluated. Dependence was induced in the animals by subjecting them to a 1-month intermittent vapor-exposure period in which animals were exposed to ethanol vapor for 14 h/d. Following the 1-month period, the vapor-exposed animals resumed FR-1 and PR baclofen drug testing (doses as described above) in the operant chambers at a time point corresponding to the animals being 6 hours into withdrawal (i.e., 6 hours after the ethanol vapor had been discontinued for that day). Baclofen (0.0, 0.5, 1, 2, and 4 mg/kg, IP) dose-dependently decreased ethanol self-administration in both nondependent and dependent rats on a FR schedule of reinforcement. However, the dose of baclofen that significantly reduced responding for ethanol was shifted to the left in the ethanol vapor-exposed animals, indicating an increased sensitivity to baclofen in animals that were chronically exposed to ethanol. When tested using a PR schedule of reinforcement, there was a significant increase in the breakpoint for the vapor-exposed animals (i.e., the animals were willing to work more in a dependent state). Baclofen (2.0 mg/kg, IP) suppressed intake for both nondependent and dependent animals. Ethanol dependence produced increased self-administration of ethanol as reflected in increased ethanol intake and increased responding on a PR schedule of reinforcement. As baclofen suppressed ethanol self-administration and showed evidence of increased potency in dependent animals, the present experiment suggests that the GABA(B) receptor could be a potential pharmacotherapeutic target for the treatment of chronic alcoholism.

Both preclinical and clinical research studies have shown the GABA(B) receptor agonist baclofen represents a promising treatment for alcohol dependence. Preliminary clinical studies indicate that baclofen is able to suppress withdrawal symptoms in alcohol-dependent patients affected by the alcohol withdrawal syndrome. Moreover, baclofen has shown efficacy and safety in promoting alcohol abstinence in alcohol dependent patients in two placebo-controlled trials including one in alcohol-dependent patients with liver cirrhosis. These trials also demonstrated that baclofen was associated with reductions in withdrawal-related anxiety and alcohol craving. However, more work is needed to clearly demonstrate the efficacy of baclofen and to ascertain whether efficacy is limited to certain subtypes of alcoholic patients. For example, a recent US trial failed to demonstrate a robust effect of baclofen in treating alcohol-dependent patients though the relative moderate severity of alcohol-dependence in that trial has been suggested as one factor that may have contributed to the finding. In the present review, the authors will summarize the published clinical studies on the role of baclofen in alcohol dependence and will also present some unpublished secondary analyses. Finally, the authors will discuss possible future directions to further investigate the role of baclofen in alcohol dependence (e.g., baclofen's biobehavioral mechanisms, different baclofen doses, differences in severity and in alcoholic subtypes, different formulations of baclofen, possible combination of baclofen with other medications).