Alcohol use disorder is a leading cause of morbidity and mortality.1–2 Alcohol consumption is related to approximately 4% of the global burden of disease.1 In clinical settings and compared with the general population, the relative risk of mortality has been estimated to be 3·38 for male patients and 4·57 for female patients with alcohol use disorder.2 Patients who reduce their alcohol consumption can halve this increased risk of mortality compared with patients with alcohol use disorder who do not.3 However, the approved pharmacotherapies that could help patients with alcohol use disorder to achieve abstinence or reduce alcohol consumption are limited in number and efficacy.4,5 Therefore, there is an urgent need to develop more effective treatments in this area.
Preclinical and human studies suggest that baclofen, a γ-aminobutyric-acid (GABA)B receptor agonist, might be a novel treatment for patients with moderate-to-severe alcohol use disorder.6 Clinical studies done in Australia, Europe, Israel, and the USA that evaluated baclofen efficacy in alcohol use disorder have yielded conflicting results, with some but not all randomised clinical trials (RCTs) showing an effect.6 Notably, a few years after initial RCTs were done, the potential use of this medication for alcohol use disorder substantially increased in its popularity because of a French case report describing the use of very high doses of baclofen to treat alcohol craving and drinking.7 This intriguing yet purely anecdotal case report led to substantial scientific and mass-media attention, and in France to the use of baclofen (off-label) in the treatment of alcohol use disorder, such that the French drug regulatory agency became involved in evaluating the use of baclofen for this disorder.
Three meta-analyses do not draw definitive conclusions on the efficacy of baclofen in the treatment of alcohol use disorder.8–10 One meta-analysis8 found no superiority of baclofen over placebo on the primary outcomes of each study, whereas the other two meta-analyses found that baclofen treatment increased the number of abstinent patients9,10 and time to first drink9 compared with placebo. Furthermore, one meta-analysis found better results of baclofen among heavy drinkers than in people with less severe alcohol use disorder, and in studies that used lower doses of the drug (30–60 mg per day) than in those that used higher doses (>60 mg per day).9 For example, the effect of baclofen on time to first drink was moderate and significant for studies using lower doses of the drug, and effects were very small and not significant for studies using higher doses.9 The other study found no significant efficacy of baclofen in reducing the severity of craving for alcohol, anxiety, and depression.10 Additionally, these two meta-analyses reported no efficacy of baclofen on other important outcomes, such as number of abstinence days9,10 or heavy drinking days.10 Chiefly, all three meta-analyses found overall a small effect size and substantial heterogeneity among studies.8–10 Since the publication of these meta-analyses,8–10 a further RCT has been completed, and data analysis is underway (Garbutt JC, unpublished; NCT01980706).
Despite the absence of consistent evidence of efficacy, baclofen is frequently used off-label to treat alcohol use disorder, especially in Australia and some European countries. The use of baclofen for clinical research and in medical practice varies substantially, because of differences in treatment provision for alcohol use disorder, clinical experience, and country-specific regulations and culture.
A consensus statement on the use of baclofen for alcohol use disorder, based on evidence from clinical practice and research of baclofen in patients with moderate-to-severe alcohol use disorder, was developed by an international group (panel). Most members of the consensus group had a meeting on May 25, 2018, in Cagliari, Italy, at the GABAB Receptor Conference, in a post-conference closed session. To develop the consensus statement, we used a modified Delphi method (appendix).12 The 26 members of the Cagliari Expert Consensus Group were from seven countries and included 21 physicians, two psychologists, two researchers, and one consultant nurse. The members’ backgrounds included addiction medicine, addiction psychiatry, biomedical research, clinical neuropsychopharmacology, emergency medicine, epidemiology, gastroenterology, hepatology, internal medicine, pharmacology, pharmacoepidemiology, primary care, psychiatry, public health, and toxicology.
Panel: Consensus statement of the Cagliari Expert Consensus Group on the use of baclofen to treat patients with moderate-to-severe alcohol use disorder.
General statements on the treatment of patients with alcohol use disorder
-
1
Each country differs regarding medication regulations, laws, models of care, and reimbursement systems that need to be considered in the prescribing of medications and the provision of treatment.
-
2
Pharmacotherapy is only one component of the treatment of moderate-to-severe alcohol use disorder. Patient-centred individualised treatment plans should be used. These plans should also include psychotherapy, in-person or web-based treatments, and community and peer support groups.
-
3
The goal of a pharmacological treatment for patients with alcohol use disorder can be both abstinence and reducing alcohol consumption, ideally below harmful amounts. However, in certain subgroups of patients, the goal should be complete abstinence.4,5
Effectiveness of baclofen in the treatment of patients with alcohol use disorder
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4
Baclofen is not licensed as an approved treatment of alcohol use disorder, and its use is therefore off-label.
-
5
Clinical research evidence is not clear about the most effective setting for baclofen treatment, but patients with alcohol use disorder may be treated in a range of treatment settings by clinicians with appropriate experience and training.
-
6
The majority of clinical trials started baclofen after detoxification and obtaining abstinence. In clinical practice, some physicians prescribe off-label baclofen while the patient is still drinking. These patients should be warned of the risks of side-effects (eg, excessive sedation) due to the pharmacological interaction of baclofen and alcohol.
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7
Baclofen should be considered a second-line pharmacotherapy in patients who have not responded to approved pharmacological treatments for alcohol use disorder. However, the off-label use of baclofen may be considered among first-line pharmacological treatments in patients with contraindication to approved medications (eg, patients with advanced liver disease for whom the use of disulfiram or naltrexone may be contraindicated).
-
8
The daily baclofen dose should be based on safety, tolerability, and patient’s response.
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9
The daily dose of baclofen required to achieve abstinence, a substantial reduction in alcohol consumption, or a substantial decrease in craving for alcohol can vary widely between patients, over a ten-fold range.
-
10
Baclofen should be started at a low dose (5 mg three times per day) and slowly titrated upwards (eg, 5–10 mg per day, every three days) to minimise possible side-effects, including sedation and overdose.
-
11
There is no evidence on the use of baclofen in combination with other medications for alcohol use disorder (eg, disulfiram, naltrexone, acamprosate, or nalmefene).
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12
Baclofen should not be used instead of benzodiazepines in the treatment of alcohol withdrawal syndrome, as there is no evidence of its efficacy in preventing the development of potentially life-threatening complications of alcohol withdrawal syndrome, such as seizures and delirium tremens.
Safety of baclofen in the treatment of patients with alcohol use disorder
-
13
History of renal impairment needs to be considered before starting baclofen, because the drug is mainly excreted by the kidneys. If prescribed, the management of baclofen in patients with renal impairment requires close supervision because of the higher risk of baclofen toxicity.
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14
The most frequent side-effects observed among patients with alcohol use disorder include: sedation, fatigue, drowsiness, tiredness, somnolence, sleep disorders or insomnia, dizziness, headache, dry mouth, paresthesia, fasciculations, nausea, myalgia, and arthralgia. Most side-effects occur at the beginning of baclofen treatment, or if the dose is increased too rapidly.
-
15
Many side-effects tend to be dose-related, although the contribution of other factors to the onset or severity of side-effects cannot be ruled out.
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16
Particular caution is needed for the combination of baclofen with other sedative medications (including alcohol) since there are additive side-effects (eg, sedation, drowsiness, and somnolence).
-
17
Particular caution is needed among patients with alcohol use disorder and other comorbidities, such as patients with a history of epilepsy, because baclofen can lower the seizure threshold, patients with mood disorders, because baclofen can increase the risk of hypomanic and manic episodes, and patients with suicidal ideation or a history of suicide attempts, because of the risk of intentional overdose.
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18
Treatment with baclofen should not be abruptly interrupted to avoid the risk of withdrawal symptoms. The daily dose should be slowly reduced (eg, 5–10 mg per week).
In conclusion, we believe baclofen remains a promising pharmacotherapy for alcohol use disorder, however, baclofen’s superiority versus placebo has not been established. The strength of the evidence for baclofen efficacy is lower than that of approved medications for alcohol use disorder.4,5 Research is needed to understand baclofen dose-response relationships, its use in specific subgroups (eg, patients with alcohol use disorder and liver disease), the potential risks associated with the use of baclofen, especially at higher doses, as well as characterisation of responders versus non-responders. Future studies on the GABAB receptor as a target using other pharmacological approaches such as positive allosteric modulators are desirable to extend understanding of the potential mechanism of action of this receptor in alcohol use disorder.6
Supplementary Material
Acknowledgments
RA served as the Chair of the Cagliari Expert Consensus Group and oversaw all stages of the process to ensure consistency across the stages of development of the Consensus. RA, LL, and JMAS served as the coordinating workgroup of the Cagliari Expert Consensus Group and led all stages of the development of the manuscript. RA, RdB, PdLS, PSH, MH, and PJ drafted the initial document before the expert meeting. RA, EMB, PJ, and AS revised the initial document based on the outcomes of the expert meeting. RA, LL, and JMAS drafted the full text manuscript. RA, LL, and JMAS led and coordinated revisions before and after each round up until completion of the manuscript and submission. All authors contributed to the manuscript and approved its final version. H-JA reports personal fees from Ethypharm, grants, personal fees, and non-financial support from Lundbeck, personal fees and non-financial support from D&A Pharma, and other types of support from Pfizer, Lilly, Indivior, AbbVie, Arbor Pharmaceuticals, Alkermes, and Amygdala Neurosciences, outside the submitted work. PJ reports personal fees from Polpharma, outside the submitted work. ARL-H reports grants and personal fees from Lundbeck, personal fees from Silence Therapeutics, Janssen-Cilag, Pfizer, and Sanofi-Aventis, other types of support from Opiant, Lightlake, and Britannia, and grants from GSK, during the conduct of the study. CAM reports personal fees from Silence Therapeutics, outside the submitted work. BR reports personal fees from Ethypharm, outside the submitted work. WvdB reports personal fees from Lundbeck, Eli Lilly, Indivior, Mundipharma, Bioproject, D&A Pharma, Novartis, and Opiant Pharmaceuticals, outside the submitted work. RA, JMAS, GA, EMB, FC, JDC, PdLS, NF, JCG, PSH, MH, KCM, LO, AP, LMP, FP, AS, AT, RdB, and LL declare no competing interests. RA is supported by the University of Cagliari intramural funding FIR 2017. GA has received funding from the European Foundation for Alcohol Research (ERAB). AT has received funding from the Medical Research Council, UK. KCM is supported by a NSW Health Translational Research Fellowship and receives funding from the National Health and Medical Research Council of Australia. LL is supported by the National Institutes of Health intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology), jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism and the Intramural Research Program of the National Institute on Drug Abuse. The content of this Comment is solely our responsibility and does not necessarily represent the official views of the funders, which had no role in the development of this article.
Contributor Information
Roberta Agabio, Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria, I-09042 Monserrato, Italy.
Julia MA Sinclair, Faculty of Medicine, University of Southampton, Southampton, UK.
Giovanni Addolorato, AUD and Alcohol Related Diseases Unit, Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy; Department of Internal Medicine and Gastroenterology, Università Cattolica del Sacro Cuore, Rome, Italy.
Henri-Jean Aubin, Centre de Recherche en Epidémiologie et Santé des Populations, Faculté de Médecine, Université Paris-Sud, Paris, France; Faculté de Médecine, Université de Versailles Saint-Quentin-en-Yvelines, Paris, France; Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Paris, France; Hôpitaux Universitaires Paris-Sud, Paris, France.
Esther M Beraha, Department of Psychology, University of Amsterdam, Amsterdam, Netherlands.
Fabio Caputo, SS Annunziata Hospital, Department of Internal Medicine, Cento, Italy.
Jonathan D Chick, Castle Craig Hospital, Blyth Bridge, UK; School of Health and Social Care, Edinburgh Napier University, Edinburgh, UK.
Patrick de La Selle, Montpellier 34000, France.
Nicolas Franchitto, Department of Addiction Médicine, Poisons and Substance Abuse Treatment Centre, Toulouse-Purpan University Hospital, Toulouse, France.
James C Garbutt, Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Paul S Haber, National Health Medical Research Council, Centre of Research Excellence in Mental Health and Substance Use, Central Clinical School, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
Mathis Heydtmann, Department of Gastroenterology, Royal Alexandra Hospital Paisley, Paisley, UK.
Philippe Jaury, Département de Médecine Générale, Faculté de Médecine, Université Paris Descartes, Paris, France.
Anne R Lingford-Hughes, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, London, UK.
Kirsten C Morley, Discipline of Addiction Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
Christian A Müller, Department of Psychiatry, Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Berlin, Germany.
Lynn Owens, Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK.
Adam Pastor, Department of Addiction Medicine, St Vincent’s Hospital Melbourne, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
Louise M Paterson, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, London, UK.
Fanny Pélissier, Poison Control Centre, Toulouse-Purpan University Hospital, Toulouse, France.
Benjamin Rolland, Service Universitaire d’Addictologie de Lyon, Lyon, France; University of Lyon, Lyon, France.
Amanda Stafford, Royal Perth Hospital, Perth, WA, Australia.
Andrew Thompson, Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK.
Wim van den Brink, Department of Psychiatry, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam University, Amsterdam, Netherlands.
Renaud de Beaurepaire, Groupe Hospitalier Paul-Guiraud, Paris, France.
Lorenzo Leggio, Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Basic Research and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, MD, USA; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, RI, USA.
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