Baclofen improves abstinence in alcoholic cirrhosis: Still better to come?
Authors: Pascal Gache, Antoine Hadengue
Journal: Journal of Hepatology (2008)

Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G.BackgroundIntervention 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.MethodsBetween 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.FindingsOf 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.InterpretationBaclofen 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.[Abstract reproduced by permission of Lancet 2007;370:1915–1922] Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G. 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. 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. 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. 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. [Abstract reproduced by permission of Lancet 2007;370:1915–1922] Craving for alcohol and loss of control of alcohol intake define alcoholism as an addiction. With about two million deaths in 2002, harmful use of alcohol is the third leading contributor to the burden of disease in developed countries [[1]WHO Global Status Report on Alcohol 2004. Available from: <http://www.who.int/substance_abuse/publications/global_status_report_2004_overview.pdf/>.Google Scholar]. Although abstinence from alcohol is the mainstay of therapy in alcohol-induced diseases, as few as 30% of patients with alcohol dependence eventually achieve sustainable abstinence. This has been the case in recent years despite many efforts, including the development of pharmacological agents aimed at improving abstinence rates [[2]Soyka M. Roesner S. New pharmacological approaches for the treatment of alcoholism.Expert Opin Pharmacother. 2006; 7: 2341-2353Crossref PubMed Scopus (31) Google Scholar]. Most hepatologists do not consider the use of these agents, partly because of the limited benefit obtained in alcoholics in general, and partly because these drugs have not been tested in patients with liver disease in particular. γ-Aminobutyric acid (GABA), is the primary inhibitory transmitter substance in the mammalian central nervous system. Alcohol, among other effects, increases the release of presynaptic GABA. GABA may in turn activate ligand-gated GABAA channels and G-protein coupled GABAB receptors. Stimulation of GABAA chloride channels, on the one hand, results in neuronal inhibition due to membrane hyperpolarization. Some genetic studies in alcoholics have linked some clusters of GABAA receptors subtypes to alcohol addiction [[3]Lobo I.A. Harris R.A. GABA(A) receptors and alcohol.Pharmacol Biochem Behav. 2008; 90: 90-94Crossref Scopus (120) Google Scholar]. In keeping with a possible involvement of GABAA receptors in alcohol dependence acamprosate, a GABAA agonist (as well as NMDA-R antagonist), showed some capacity to reduce craving for alcohol in animals [[4]Mason B.J. Acamprosate in the treatment of alcohol dependence.Expert Opin Pharmacother. 2005; 6: 2103-2115Crossref Scopus (35) Google Scholar]. Human studies, however, showed limited efficacy and acamprosate has not been tested in patients with liver disease [[4]Mason B.J. Acamprosate in the treatment of alcohol dependence.Expert Opin Pharmacother. 2005; 6: 2103-2115Crossref Scopus (35) Google Scholar]. GABAB G protein-coupled receptors, on the other hand, inhibit intracellular cyclic AMP/Protein kinase A and C (cAMP/PKA/PKC) pathways in mammalian presynaptic nerve terminals and activate Kir3 channels at the postsynaptic membrane. When exposed to alcohol, primary cortical neurons in culture modulate PKA signalling through GABAB receptors [[5]Lee H.Y. Naha N. Li S.P. Jo M.J. Naseer M.L. Park M.S. et al.In vivo and in vitro ethanol exposure in prenatal rat brain: GABA(B) receptor modulation on dopamine D(1) receptor and protein kinase A.Synapse. 2008; 62: 534-543Crossref Scopus (16) Google Scholar]. Furthermore, some degree of interaction between GABAB and dopaminergic/glutamatergic signals is likely, which may be of relevance since the mesolimbic dopamine system seems to be an early target of addictive drugs of abuse, including alcohol [5Lee H.Y. Naha N. Li S.P. Jo M.J. Naseer M.L. Park M.S. et al.In vivo and in vitro ethanol exposure in prenatal rat brain: GABA(B) receptor modulation on dopamine D(1) receptor and protein kinase A.Synapse. 2008; 62: 534-543Crossref Scopus (16) Google Scholar, 6Cousins M.S. Roberts D.C. de Wit H. GABAB receptor agonists for the treatment of drug addiction: a review of recent findings.Drug Alcohol Depend. 2002; 65: 209-220Abstract Full Text Full Text PDF Scopus (222) Google Scholar]. Baclofen is a potent GABAB receptor agonist and has been used for about 40 years in spastic patients. Doses as high as 200 mg/day of baclofen have been used to reduce spasticity without severe side-effects except drowsiness. Drowsiness, which is a problem when beginning therapy, seems to decrease with time and be manageable with stepwise dose increases [[7]Davidoff R.A. Antispasticity drugs: mechanisms of action.Ann Neurol. 2005; 17: 107-116Crossref Scopus (265) Google Scholar]. In alcohol-preferring rats, baclofen reduces voluntary alcohol use in a dose-dependent manner [8Colombo G. Vacca G. Serra S. Brunetti G. Carai M.A. Gessa G.L. Baclofen suppresses motivation to consume alcohol in rats.Psychopharmacology (Berl). 2003; 167: 221-224PubMed Google Scholar, 9Colombo G. Agabio R. Carai M.A. Lobina C. Pani M. Reali R. et al.Ability of baclofen in reducing alcohol intake and withdrawal severity: I–Preclinical evidence.Alcohol Clin Exp Res. 2000; 24: 58-66PubMed Google Scholar, 10Walker B.M. Koob G.F. The gamma-aminobutyric acid-B receptor agonist baclofen attenuates responding for ethanol in ethanol-dependent rats.Alcohol Clin Exp Res. 2007; 31: 11-18Crossref PubMed Scopus (160) Google Scholar]. By contrast with other “anticraving agents” such as naltrexone, acamprosate, topiramate or rimonabant which reduce but do not suppress craving in these animals, baclofen is the only agent to completely suppress craving at doses ⩾ 3 mg/kg [8Colombo G. Vacca G. Serra S. Brunetti G. Carai M.A. Gessa G.L. Baclofen suppresses motivation to consume alcohol in rats.Psychopharmacology (Berl). 2003; 167: 221-224PubMed Google Scholar, 9Colombo G. Agabio R. Carai M.A. Lobina C. Pani M. Reali R. et al.Ability of baclofen in reducing alcohol intake and withdrawal severity: I–Preclinical evidence.Alcohol Clin Exp Res. 2000; 24: 58-66PubMed Google Scholar]. Similar effects of baclofen have been described in animals preferring cocaine, nicotine, heroin, and alcohol [[11]Johnson B.A. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings.Biochem Pharmacol. 2008; 75: 34-56Crossref PubMed Scopus (215) Google Scholar]. Krupitsky et al. first used baclofen in alcoholic patients in 1993, concluding with the superiority of baclofen over placebo for the treatment of anxiety and depression in these patients [[12]Krupitsky E.M. Burakov A.M. Ivanov V.B. Krandashova G.F. Lapin I.P. Grinenko A.J. et al.Baclofen administration for the treatment of affective disorders in alcoholic patients.Drug Alcohol Depend. 1993; 33: 157-163Abstract Full Text PDF PubMed Scopus (77) Google Scholar]. In 2000, Addolorato et al. reported the use of baclofen, 30 mg/day for 4 weeks in 10 patients with alcohol dependence. The results of this first open trial showed a significant reduction of the Alcohol Craving Scale throughout the one month treatment period [[13]Addolorato G. Caputo F. Capristo E. Colombo G. Gessa G.L. Gasbarrini G. Ability of baclofen in reducing alcohol craving and intake: II a preliminary clinical evidence.Alcohol Clin Exp Res. 2000; 24: 67-71PubMed Google Scholar]. Two years later, the same group randomised 39 patients with alcohol dependence to receive baclofen, 30 mg/day or placebo [[14]Addolorato G. Caputo F. Capristo E. Domenicali M. Bernardi M. Janiri L. et al.Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study.Alcohol Alcohol. 2002; 37: 504-508Crossref PubMed Scopus (409) Google Scholar]. Seventy percent of patients allocated to baclofen achieved abstinence versus 21% of those allocated to placebo. In a small open trial Flannery et al. also suggested the ability of baclofen to reduce drinking, anxiety and craving in patients with alcohol dependence [[15]Flannery B.A. Garbutt J.C. Cody M.W. Renn W. Grace K. Osborne M. et al.Baclofen for alcohol dependence: a primary open label study.Alcohol Clin Exp Res. 2004; 28: 1517-1523Crossref PubMed Scopus (135) Google Scholar]. Among patients with alcohol dependence and cirrhosis, however, the effect of baclofen, or any other “anticraving agent”, had not been tested. Addolorato et al. published the first randomized controlled trial with baclofen in 84 patients with alcoholic liver disease [[16]Addolorato G. Leggio L. Ferrulli A. Cardone S. Vonghia L. Mirijello A. et al.Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.Lancet. 2007; 370: 1915-1922Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar]. All had cirrhosis and fulfilled alcohol dependence criteria according to the DSM IV classification. Forty-two patients received 30 mg baclofen per day during three months, compared to placebo. Patient drop-out was similar in both groups and there was no difference between baclofen and placebo groups for side-effects. More specifically, no case of encephalopathy or hyperammonemia was noted in relation to the sedative effect of the drug. Thirty patients (71%) achieved and maintained abstinence in the baclofen group compared to 12 (29%) in the placebo group, a conclusion very similar to what was achieved in patients without liver disease [[13]Addolorato G. Caputo F. Capristo E. Colombo G. Gessa G.L. Gasbarrini G. Ability of baclofen in reducing alcohol craving and intake: II a preliminary clinical evidence.Alcohol Clin Exp Res. 2000; 24: 67-71PubMed Google Scholar]. Among secondary end-points, cumulative abstinence duration was about twofold higher in patients treated by baclofen, which was associated with reduced craving scores. This first RCT with an anticraving agent in patients with alcoholic cirrhosis, a population usually excluded from such trials, is certainly a landmark and opens the way for more studies. The questions of (a) treatment duration; (b) tolerance; and (c) dose, should probably be addressed before the use of baclofen in non-abstinent patients with alcoholic liver disease can be recommended. Three months of therapy represent a relatively short period considering alcoholism as a chronic disease with a high long-term relapse rate. However, this study and many others in the field chose 3 months as a realistic time point, probably accounting for the relatively low drop-out rates. Looking at changes in the Obsessive Compulsive Drinking Scale (OCDS) over time in this study, it may be observed that craving significantly decreases during baclofen therapy but is not completely suppressed. Thus, craving, a likely cause of relapse, might recur promptly after treatment cessation. While acknowledging these limitations, we feel that longstanding clinical experience with the tolerance and efficacy of long-term baclofen administration in spasticity suggests that prolonged baclofen administration should be tested in alcohol-dependent patients. This would certainly require validation in long-term studies. Given the high mortality associated with persistent drinking in patients with alcoholic cirrhosis, survival might well be considered as an end-point in such studies. Second, drowsiness or fatigue, reportedly the main side-effects of baclofen, seem to be overcome in many cases by progressive dose escalation, up to >80 mg/day as used by neurologists in charge of spastic patients [[17]Smith C.R. LaRocca N.G. Giesser B.S. Scheinberg L.C. High-dose oral baclofen: experience in patients with multiple sclerosis.Neurology. 1991; 41: 1829-1831Crossref PubMed Google Scholar]. Using a two-step increase in dose, Addolarato et al. did not notice excess sedation in this population. Importantly, patients with clinical encephalopathy were excluded from this study, leaving some uncertainty as to whether sedative effects of baclofen might precipitate encephalopathy. Despite this potential limitation, and considering the high level of safety of baclofen, including when high doses are used in patients without liver disease, the safety and efficacy of higher doses of baclofen could probably be safely explored in patients with alcoholic cirrhosis. With regard to dose, three recently published case-reports with high-doses of baclofen up to 3 mg/kg describe complete suppression of craving and a greater facility to achieve abstinence or controlled drinking [18Ameisen O. Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician.Alcohol Alcohol. 2005; 40: 147-150Crossref PubMed Scopus (189) Google Scholar, 19Bucknam W. Suppression of symptoms of alcohol dependence and craving using high-dose baclofen.Alcohol Alcohol. 2007; 42: 158-160Crossref PubMed Scopus (94) Google Scholar, 20Agabio R. Marras P. Addolorato G. Carpiniello B. Gessa G.L. Baclofen suppresses alcohol intake and craving for alcohol in a schizophrenic alcohol-dependent patient: a case report.J Clin Psychopharmacol. 2007; 27: 319-320Crossref PubMed Scopus (53) Google Scholar]. One is a self case report [[18]Ameisen O. Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician.Alcohol Alcohol. 2005; 40: 147-150Crossref PubMed Scopus (189) Google Scholar], where the use of high doses of baclofen for prolonged periods was perfectly tolerated and achieved complete suppression of craving, in keeping with experimental data. Adjusting baclofen dose to the OCDS score and doing so for prolonged periods of time is probably an option that would deserve further studies. The goal of these studies might be to suppress, not only reduce craving, and avoid craving-fighting, a condition associated with a high relapse rate. In conclusion, the study by Addolorato et al.is the first randomised trial to show the efficacy of any pharmacological agent to increase abstinence rate in patients with alcoholic cirrhosis. Of note, concerning a very cheap drug belonging to the public domain, this trial was funded by the Italian Ministry for University, Scientific and Technological Research (MURST), and by the European Research Advisory Board. Because of the excellent safety profile of baclofen in patients without encephalopathy, its potential for long-term use as well as dose increase, we believe that baclofen might soon become an important tool for hepatologists treating patients with alcoholic dependence.