Baclofen Aids in Alcohol Abstinence in Cirrhosis Patients

Susan Jeffrey

December 07, 2007

December 7, 2007 -- Results of a randomized trial show alcohol-dependent patients with liver cirrhosis were able to attain alcohol abstinence at a higher rate with baclofen, an anticraving agent with a low liver metabolism, than with placebo.

"In conclusion, our results suggest that baclofen, because of its anticraving action and safety, could have an important role for treatment of alcohol-dependent patients with advanced liver disease," the researchers, with first author Giovanni Addolorato, MD, from the Institute of Internal Medicine, Catholic University of Rome, in Italy, write. "We have shown that a pharmacological agent can promote alcohol abstinence and prevent alcohol relapse in individuals with alcoholic liver disease."

Further studies are needed to define the optimal duration of treatment, assess possible tolerance to the drug in a more prolonged regimen, and define the role for baclofen in clinical practice, they added.

Their results appear in the December 8 issue of the Lancet.

Abstinence Most Effective

Intervention aimed at achieving alcohol abstinence represents the most effective treatment for patients with liver cirrhosis, the authors write. However, some anticraving agents are metabolized by the liver and can worsen liver disease. Naltrexone, for example, is contraindicated in patients with liver disease. Other drugs, such as acamprosate and topiramate, have shown promise but have not, to their knowledge, been studied in patients with cirrhosis.

Baclofen is a gamma aminobutyric acid (GABA) B-receptor agonist that has low liver metabolism (about 15%) and is mainly eliminated unmodified by the kidney. It has been shown in preliminary studies to reduce alcohol craving and intake and enhance abstinence in alcohol-dependent patients, and no hepatic adverse effects have been reported, either in patients dependent on alcohol or in those with neurologic disorders. "As a result, baclofen could represent a useful drug to augment alcohol abstinence in individuals affected by alcoholic liver cirrhosis," they write.

To find out, the researchers conducted a trial of 84 alcohol-dependent patients with liver cirrhosis who were referred to the Institute of Internal Medicine between October 2003 and November 2006. They were randomly assigned to receive either oral baclofen or placebo. For the first 3 days, baclofen was given 3 times per day at a dose of 5 mg; for the subsequent 12 weeks, baclofen was given 3 times per day at a dose of 10 mg.

Outcomes of interest were total alcohol abstinence and cumulative abstinence duration, assessed during outpatient visits. Relapse was defined as alcohol intake of more than 4 drinks per day or 14 or more drinks per week over a period of at least 4 weeks.

Significantly more patients allocated to baclofen achieved and maintained abstinence than patients on placebo, the authors report.

Baclofen vs Placebo: Abstinence Achieved and Maintained in Alcohol-Dependent Patients with Cirrhosis

End Point Baclofen, n=42 Placebo, n=30 Odds ratio (95% CI) P
Achieved and maintained
abstinence at 12 weeks, n (%)
30 (71) 12 (29) 6.3 (2.4 -- 16.1) .0001



The number of patients who terminated treatment did not differ significantly between groups, with 14% of baclofen patients and 31% of placebo patients stopping treatment ( P = .12). No hepatic adverse effects were recorded, they noted.

Cumulative abstinence duration was about twice as high in patients receiving baclofen (mean, 62.8 days) as it was in those receiving placebo (mean, 30.8 days; P = .001).

"Our results show that oral administration of baclofen is significantly more effective than placebo at achieving and maintaining alcohol abstinence and at increasing cumulative abstinence duration in alcohol-dependent patients with liver cirrhosis," they concluded. "This reduction in self-reported alcohol use was associated with significant reductions in clinical markers of liver injury (alanine aminotransferase, gamma glutamyltransferase, bilirubin, and international normalized ratio), findings that confirm self-reported data and suggest that the reduction in alcohol consumption was sufficient to lessen liver injury."

"Surprisingly Robust" Findings

In a Commentary accompanying the paper, James C. Garbutt, MD, from the University of North Carolina at Chapel Hill, and Barbara Flannery, PhD, from the Transdisciplinary Behavioral Science Program, RTI International, in Baltimore, Maryland, called the findings by Dr. Addolorato and colleagues "surprisingly robust in favor of baclofen, with nearly three-quarters of patients on baclofen maintaining sobriety compared with about a quarter of placebo patients."

More patients assigned to placebo dropped out and, because dropouts were counted as failures in the sobriety survival analysis, these would have affected the primary outcome measure, the editorialists noted. "However, the higher retention rate in the baclofen group is of interest in its own right," they write.

At 12 weeks, the study was relatively brief, so longer and larger studies of populations with varying inclusion and exclusion criteria will be required to assess whether baclofen has true value in patients with cirrhosis who continue to drink, they noted. "Nevertheless, the findings are welcome because they could spur further efforts to identify drug treatments for alcoholism complicated by cirrhosis.

The study was supported by the Italian Ministry for University, Scientific and Technological Research, and by the European Research Advisory Board. Neither the authors nor the editorialists have disclosed any relevant financial relationships.

Lancet. 2007; 370:1915-1922,1884-1885.

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