Articles www.thelancet.com Vol 370 December 8, 2007 1915 Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study Giovanni Addolorato, Lorenzo Leggio, Anna Ferrulli, Silvia Cardone, Luisa Vonghia, Antonio Mirijello, Ludovico Abenavoli, Cristina D’Angelo, Fabio Caputo, Antonella Zambon, Paul S Haber, Giovanni Gasbarrini Summary Background Intervention to achieve alcohol abstinence represents the most effective treatment for alcohol-dependent patients with liver cirrhosis; however, anticraving drugs might worsen liver disease. We aimed to investigate the effectiveness and safety of baclofen in achieving and maintaining alcohol abstinence in patients with liver cirrhosis. Methods Between October, 2003, and November, 2006, 148 alcohol-dependent patients with liver cirrhosis were referred to the Institute of Internal Medicine, Rome, Italy. 84 were randomly allocated either oral baclofen or placebo for 12 weeks. Primary outcome was proportion of patients achieving and maintaining alcohol abstinence. Measures of this outcome were total alcohol abstinence and cumulative abstinence duration, which were assessed at outpatient visits. Relapse was defined as alcohol intake of more than four drinks per day or overall consumption of 14 or more drinks per week over a period of at least 4 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00525252. Findings Of 42 patients allocated baclofen, 30 (71%) achieved and maintained abstinence compared with 12 (29%) of 42 assigned placebo (odds ratio 6·3 [95% CI 2·4–16·1]; p=0·0001). The number of dropouts (termination of treatment) did not differ between the baclofen (6/42 [14%]) and placebo (13/42 [31%]) groups (p=0·12). Cumulative abstinence duration was about twofold higher in patients allocated baclofen than in those assigned placebo (mean 62·8 [SE 5·4] vs 30·8 [5·5] days; p=0·001). No hepatic side-effects were recorded. Interpretation Baclofen is effective at promoting alcohol abstinence in alcohol-dependent patients with liver cirrhosis. The drug is well tolerated and could have an important role in treatment of these individuals. Introduction Alcohol remains the most frequent cause of liver cirrhosis in developed countries. 1 Persistent alcohol intake in people with alcoholic cirrhosis is associated with high mortality. 2 The most effective management strategy for these individuals is to achieve total alcohol abstinence, since medical and surgical treatments for alcoholic liver disease have limited success when drinking continues. 1 In the past few decades, several drugs have been assessed for their ability to reduce alcohol craving and, consequently, to increase abstinence and prevent alcohol relapse. 3 However, at present, no formal pharmacological trials are in progress that aim to reduce alcohol intake in people with alcoholic cirrhosis. 1 In trials of anticraving drugs, individuals with high amounts of aminotransfer- ases, advanced liver disease, or both are typically excluded 4,5 because these agents undergo extensive liver metabolism and drug-related liver damage is possible. In particular, naltrexone is contraindicated in people with liver disease owing to its hepatic metabolism and reports of drug- related hepatic injury. 6 Findings of a preliminary study 7 suggested that acamprosate administered for 1 day was well tolerated in patients with Child-Pugh class A and B cirrhosis. However, as far as we are aware, no trials of pro- longed treatment with this drug in people with cirrhosis have been undertaken. Topiramate is a promising agent. However, to our knowledge, no trials of this drug have been done in individuals with cirrhosis. Topiramate might induce hyperammonaemia, 8 and important changes in hepatic function tests have been noted. 9 Baclofen, a γ aminobutyric acid (GABA) B-receptor agonist, represents a promising drug for treatment of craving in alcohol-dependent patients. 10 In accordance with data from preclinical experiments, 11 preliminary findings showed that the drug reduced alcohol craving and intake and enhanced abstinence in alcohol-dependent patients. 12,13 Baclofen has low liver metabolism (about 15%) and is mainly eliminated unmodified by the kidney. 14 No hepatic side-effects of the drug have been reported either in patients dependent on alcohol 12,13,15 or those with neuro- logical disorders. 14 As a result, baclofen could represent a useful drug to augment alcohol abstinence in individuals affected by alcoholic liver cirrhosis. The aim of our study was to assess the effectiveness and safety of baclofen ad- ministration in achieving and maintaining alcohol absti- nence in alcohol-dependent patients with liver cirrhosis. Methods Patients Between October, 2003, and November, 2006, all alcohol- dependent patients affected by liver cirrhosis consecu- tively referred to the Institute of Internal Medicine of the Lancet 2007; 370: 1915–22 See Comment page 1884 Institute of Internal Medicine, Catholic University of Rome, Rome, Italy (G Addolorato MD, L Leggio MD, A Ferrulli MD, S Cardone MD, L Vonghia MD, A Mirijello MD, L Abenavoli MD, C D’Angelo MD, Prof G Gasbarrini MD); “G Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Internal Medicine, Cardioangiology, and Hepatology, University of Bologna, Bologna, Italy (F Caputo MD); Unit of Biostatistics and Epidemiology, Department of Statistics, University of Milan-Bicocca, Milan, Italy (A Zambon PhD); and Drug Health Services, Royal Prince Alfred Hospital, Camperdown, and University of Sydney, Sydney, NSW, Australia (Prof P S Haber MD) Correspondence to: Dr Giovanni Addolorato, Institute of Internal Medicine, Catholic University of Rome, Largo A Gemelli 8, I-00168 Rome, Italy g.addolorato@rm.unicatt.it Downloaded from ClinicalKey.com.au at South Metropolitan Health Service May 04, 2016. 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