Flore-Anne Mayne – Sciences pharmaceutiques. 2014. – dumas-01674555

HAL Id: dumas-01674555 https://dumas.ccsd.cnrs.fr/dumas-01674555

THÈSE PRESENTÉE POUR L’OBTENTION DU TITRE DE DOCTEUR EN PHARMACIE Le18 Décembre 2014

RÉSUMÉ

Introduction : L’obésité et les compulsions alimentaires semblent partager des mécanismes neurobiologiques communs avec les addictions pour lesquelles l’utilisation du baclofène depuis quelques années montre des résultats prometteurs.

Objectifs: Evaluer l’efficacité du baclofène dans les compulsions alimentaires (CA) chez des patients en impasse thérapeutique. Dans un second temps, identifier des critères cliniques et psychopathologiques prédictifs d’une réponse thérapeutique, évaluer la tolérance et caractériser les modalités de prescription du baclofène.

Méthode: Il s’agit d’une étude compassionnelle, prospective, non contrôlée, de l’efficacité d’un traitement par baclofène chez 27patients présentant des CA qui évoluent depuis plus de 5 ans. Une évaluation de l’évolution de différents paramètres a été réalisée: le poids, l’intensité et la fréquence des CA, le craving, certaines caractéristiques psychopathologiques et la tolérance biologique.

Résultats: Sur les 6 mois de traitement, 56% des patients ont perdu du poids sans consigne restrictive. Par ailleurs quelle que soit la variation pondérale, tous les types de compulsions alimentaires ont diminué parallèlement à la diminution du craving. Une prédominance d’hyperphagie nocturne ne semble pas constituer une indication privilégiée pour un traitement par baclofène. Malgré une dose journalière moyenne de 150mg de baclofène, les effets indésirables sont principalement bénins et transitoires.

Conclusion: Cette étude a montré que le baclofène semble agir sur les capacités de contrôle des patients face à leurs troubles. Elle a permis de préciser la nécessité d’une prescription personnalisée.

Mots clés: obésité, compulsions alimentaires, baclofène, addiction, psychoéducation, tolérance

Le document complet : Thèse Flore-Anne Mayne

Renaud de Beaurepaire^1*, Mathis Heydtmann² and Roberta Agabio³

• ¹Groupe Hospitalier Paul-Guiraud, Villejuif, France
• ²Department of Gastroenterology, Royal Alexandra Hospital Paisley, Paisley, United Kingdom
• ³Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

Editorial on the Research Topic
Baclofen in the Treatment of Alcohol Use Disorder

Alcohol use disorder (AUD) is a severe illness for which available treatments are of limited efficacy. Over the last 20 years, baclofen has progressively emerged as a potentially useful treatment for AUD, but our knowledge on the best way to prescribe it, on potential influencing factors on its effects, and on its mechanism of action in AUD is still limited. Knowledge on its efficacy is also debated. As all three of us—RB, MH, and RA—have a long practice of baclofen use in the treatment of AUD, we thought of writing a special issue on this topic, and were delighted when Frontiers in Psychiatry accepted to give us this opportunity [two of us, RB and MH, have previously participated in the writing of a book on the same topic (1, 2)]. The realization of this new special issue has proved to be a kind of adventure we did not expect at the start.

We aimed at joining our competencies to provide a shared description of the methods to obtain an optimal therapeutic effect of baclofen in the treatment of AUD. We were aware that to obtain its therapeutic effect, the required dose of baclofen may largely vary among patients, certain patients requiring low doses and other high or very high doses. In other words, our experience showed that patients require “personalized doses” of baclofen that allow them to say “well, at this dose I have no more craving for alcohol, I do not experience craving when I see bottles or people who drink,” meaning that, following Olivier Ameisen’s words, the patient has reached a state of “indifference towards alcohol” (3).

Our special issue had three goals. The first was to give a general view of baclofen use for AUD treatment in different countries. The second was to provide joined information on the methods to prescribe baclofen in the treatment of AUD. The third was to obtain recent data from different research teams involved in various aspects of baclofen use in the treatment of AUD. To achieve these goals, we solicited the participation of a large number of baclofen prescribers worldwide.

For our first goal, Garbutt describes the use of baclofen in the US. According to this contribution, there is a limited use of baclofen to treat AUD in the US. However, Garbutt points out that there is, in general, a very low rate of medication use for the treatment of AUD in the US, largely due to a lack of knowledge of physicians and patients about the potential value of medications. Regarding baclofen, the results of meta-analyses showing that its efficacy is equivocal, the concerns of tolerability, and the fact that its prescription remains off label are all elements that may deter clinicians and patients. Garbutt nevertheless mentions that there are no accurate data on the use of baclofen in AUD in the US, making it difficult to know if clinicians prescribe it. These remarks probably apply to most other countries, except France, which is the only country where baclofen has an official approval from Health Authorities in the treatment of AUD, and where baclofen is more widely prescribed.

For our second goal, we convened a large group of international experts, representative of researchers and physicians who contributed to the recent studies on baclofen and AUD. This group of experts achieved a consensus on the use of baclofen to treat AUD—“the Cagliari Statement”—published by Lancet Psychiatry in 2018 (4). After this concise and rigorous document, the group decided to provide a more detailed description of the different methods used to administer baclofen in the treatment of AUD (de Beaurepaire et al.). In detail, we describe how, especially in experimental studies, baclofen is usually administered in fixed doses to evaluate the efficacy and safety of each specific dose whereas, in clinical practice, baclofen is usually administered in flexible doses. In other words, the dose is gradually increased until the patient achieves the desired effects or side effects that prevent a further increase in dose. In this article, other than this description of the methods adopted for baclofen administration, there is also an unprecedented exhaustive review of published studies, approved by 26 authors coming from seven different countries (Australia, France, Germany, Great Britain, Italy, The Netherlands, and the US).

For our third goal, several innovative reports dealing with baclofen prescription and use, pharmacokinetics, preclinical research, and clinical investigations aiming to understand its potential mechanisms of action in AUD are published in the special issue. Reports on baclofen prescription and use include a long-term retrospective study (Pinot et al.); a research report on the response to baclofen in patients receiving antidepressants (Heng et al.); reviews on the effects of baclofen in alcohol withdrawal syndrome (AWS) (Cooney et al.), on the adverse effects of baclofen (Rolland et al.), and on the management of self-poisoning with baclofen (Franchitto et al.); and reviews focused on comorbidities—with liver cirrhosis (Mosoni et al.) and other mental disorders (Agabio and Leggio). In a 3-year retrospective study, Pinot et al. have followed 144 patients with AUD receiving tailored doses of baclofen (50 to 520 mg/day; average dose, 211 mg/day), and the treatment was successful in 63.3% of the patients (according to the WHO classification criteria) (Pinot et al.), a percentage of success grossly similar to that reported in other previously published observational studies. Depression and antidepressant treatment are common features in patients with AUD, and it was important to search for a potential interaction between baclofen and antidepressants. Heng et al. show that in patients on long-term treatment with antidepressants prior to starting baclofen, a beneficial effect on drinking outcomes can be shown like in patients who are not using antidepressants. However, there was a trend to an interaction between the two that needs further investigations (baseline tobacco use or alcohol liver disease may interfere with the interaction) (Heng et al.). The effectiveness of baclofen in the treatment of AWS is controversial, and Cooney et al., in their review, confirm that the evidence does not support the use of baclofen as a first-line treatment of AWS. Adverse effects too often limit or circumvent baclofen treatment, and this issue must be seriously considered. Rolland et al. propose a thoughtful review on baclofen adverse effects, separating the common and benign ones (sedation, insomnia, dizziness, and tinnitus) from the rare but potentially dangerous ones (seizures, mania, and sleep apnea), and point that concurrent consumption of alcohol, benzodiazepines, and other sedatives may worsen many adverse effects. These considerations have consequences on baclofen treatment management in terms of prevention of adverse effects and obtaining an optimal response (Rolland et al.). Cases of intentional or non-intentional baclofen self-poisoning have increased in parallel with the increasing use of baclofen in AUD. These cases present with particular clinical features that clinicians must be aware of. Franchitto et al. review the literature on that subject and address the management of this condition. AUD is often associated with liver cirrhosis and/or mental illnesses. AUD is difficult to treat in patients with liver cirrhosis because approved AUD medications may impair liver function. Baclofen is attractive because it has no liver toxicity, and Mosoni et al. review the clinical trials investigating the effect of baclofen in patients with AUD associated with liver disease. The results show a very favorable effect of baclofen in these patients, although the most appropriate dose of the drug remains to be determined (Mosoni et al.). Mental illness may alter the outcome in baclofen-treated patients. Agabio and Leggio address this issue by using a narrative analysis of all clinical and human laboratory studies of baclofen treatment in patients with AUD with or without mental illness. The most frequent psychiatric comorbidities are anxiety and depression. Further work is needed to determine if these comorbidities interfere with baclofen treatment outcome (Agabio and Leggio).

Reports on baclofen pharmacokinetics include two studies by Simon et al. In their first article, Simon et al. investigate the pharmacokinetics of baclofen in 60 patients with AUD treated with various doses of baclofen (up to 300 mg/day). The results show that baclofen has a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor (Simon et al.). In their second article, Simon et al. review the literature investigating the baclofen dose in relation to the pharmacokinetics of the drug. Indeed, the dose–response variability in baclofen-treated patients may be related to variability in pharmacokinetics. In particular, the effects of intestinal absorption, blood–brain barrier transport, and renal elimination are highlighted (Simon et al.).

Preclinical research is reviewed by Colombo and Gessa. Baclofen suppresses many alcohol-related behaviors in laboratory animals, including locomotor activity, alcohol drinking and self-administration, binge-like drinking, relapse drinking, alcohol seeking, and AWS symptoms. These effects of baclofen in animals provide interesting elements for the understanding of its mechanism of action in AUD (Colombo and Gessa). Two clinical studies also bring new data that could help the understanding of the mechanism of action of baclofen. Morley et al., using magnetic resonance spectroscopy, show that baclofen increases the concentrations of the antioxidants glutathione and N-acetyl aspartate in the brain of patients with AUD, and that higher glutathione levels predict favorable outcomes at follow-up. This supports the idea that the beneficial effects of baclofen in the treatment of AUD could be, at least in part, related to neuroprotective mechanisms (Morley et al.). Durant et al. show that the effects of an acute administration of baclofen are very different in patients with AUD compared with healthy controls. The measured effects were growth hormone release and subjective experience (for instance, feeling “drunk”, “dizzy”, or “stimulated”). All these responses were blunted in patients with AUD while they were very marked in healthy controls. According to the authors, these results indicate a lower sensitivity to baclofen and, by extension, a general lower GABA-B receptor sensitivity in patients with AUD (Durant et al.). Finally, the potential mechanisms of baclofen in AUD are reviewed in an article that concludes that baclofen may produce an indifference to alcohol by suppressing the Pavlovian association between alcohol cues and rewards through an action in a critical part of the dopaminergic network (the amygdala). This action of baclofen is made possible by the fact that baclofen and alcohol act on similar brain systems (in particular GABA-B systems) (de Beaurepaire).

We really hope that this special issue will contribute to improve our knowledge and enhance debates and research on the use of baclofen in the treatment of AUD, a devastating illness that is dramatically undertreated.

Author Contributions

All authors equally contributed to this work.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The reviewer GA declared a past co-authorship with one of the authors RA to the handling Editor.

References

1. Heydtmann M. Introduction. In: Baclofen: a new tool in the fight against alcoholism. Sunrise River Press (2017). p. vii–xi.
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2. de Beaurepaire R. Individual adjustment of baclofen dosage to treat alcohol dependence. In: Baclofen: a new tool in the fight against alcoholism. Sunrise River Press (2017). p. 9–24.

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3. Ameisen O. The end of my addiction. New-York: Sarah Crichton Books (2009).
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4. Agabio R, Sinclair JMA, Addolorato G, Aubin HJ, Beraha EM, Caputo F, et al. Baclofen for the treatment of alcohol use disorder: the Cagliari Statement. Lancet Psychiatry (2018) 5(12):957–60. doi: 10.1016/S2215-0366(18)30303-1
PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: alcohol use disorder, baclofen, prescription, safety, mode of action

Citation: de Beaurepaire R, Heydtmann M and Agabio R (2019) Editorial: Baclofen in the Treatment of Alcohol Use Disorder. Front. Psychiatry 10:338. doi: 10.3389/fpsyt.2019.00338
Received: 14 February 2019; Accepted: 30 April 2019;
Published: 15 May 2019.

Edited by:

Yasser Khazaal, Centre Hospitalier Universitaire Vaudois, Switzerland

Reviewed by:

Teresa R. Franklin, University of Pennsylvania, United States
Giovanni Addolorato, The Catholic University of America, Rome Campus, Italy

*Correspondence: Renaud de Beaurepaire, debeaurepaire@wanadoo.fr

Renaud de Beaurepaire¹, Julia M. A. Sinclair², Mathis Heydtmann³, Giovanni Addolorato^4,5, Henri-Jean Aubin^6,7,8,9, Esther M. Beraha¹⁰, Fabio Caputo¹¹, Jonathan D. Chick^12,13, Patrick de La Selle¹⁴, Nicolas Franchitto¹⁵, James C. Garbutt¹⁶, Paul S. Haber^17,18, Philippe Jaury¹⁹, Anne R. Lingford-Hughes²⁰, Kirsten C. Morley²¹, Christian A. Müller²², Lynn Owens²³, Adam Pastor^24,25, Louise M. Paterson²⁰, Fanny Pélissier²⁶, Benjamin Rolland^27,28, Amanda Stafford²⁹, Andrew Thompson²³, Wim van den Brink³⁰, Lorenzo Leggio^31,32,33 and Roberta Agabio^34*

¹Groupe Hospitalier Paul-Guiraud, Villejuif, France – ²Faculty of Medicine, University of Southampton, Southampton, United Kingdom – ³Department of Gastroenterology, Royal Alexandra Hospital Paisley, Paisley, United Kingdom – ⁴AUD 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 – ⁵Department of Internal Medicine and Gastroenterology, Università Cattolica del Sacro Cuore, Rome, Italy – ⁶Faculté de Médecine, Centre de Recherche en Epidémiologie et Santé des Populations, Université Paris-Sud, Paris, France – sup>7Faculté de Médecine, Université de Versailles Saint-Quentin-en-Yvelines, Paris, France – ⁸Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Paris, France – ⁹Hôpitaux Universitaires Paris-Sud, Paris, France – ¹⁰Department of Psychology, University of Amsterdam, Amsterdam, Netherlands – ¹¹Department of Internal Medicine, SS. Annunziata Hospital, Cento, Italy – ¹²Castle Craig Hospital, Blyth Bridge, United Kingdom – ¹³School of Health and Social Care, Edinburgh Napier University, Edinburgh, United Kingdom – ¹⁴Private Practice, Montpellier, France – ¹⁵Department of Addiction Medicine, Poisons and Substance Abuse Treatment Centre, Toulouse-Purpan University Hospital, Toulouse, France – ¹⁶Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States – ¹⁷National 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 – ¹⁸Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia – ¹⁹Département de Médecine Générale, Faculté de Médecine, Université Paris Descartes, Paris, France – ²⁰Neuropsychopharmacology Unit, Division of Brain Sciences, Centre for Psychiatry, Imperial College London, London, United Kingdom – ²¹Discipline of Addiction Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia – ²²Department of Psychiatry, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany – ²³Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, United Kingdom – ²⁴Department Addiction Medicine, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia – ²⁵Department of Medicine, University of Melbourne, Melbourne, VIC, Australia – ²⁶Poison Control Center, Toulouse-Purpan University Hospital, Toulouse, France – ²⁷Service Universitaire d’Addictologie de Lyon, Lyon, France – ²⁸University of Lyon, Lyon, France – ²⁹Royal Perth Hospital, Perth, WA, Australia – ³⁰Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam University, Amsterdam, Netherlands – ³¹Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Division of Intramural Clinical and Basic Research, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, MD, United States – ³²Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, United States –³³Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, RI, United States – ³⁴Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

Introduction

After promising preclinical evidence [for review see Colombo and Gessa (1)], clinical studies started to investigate whether baclofen may be useful in the treatment of alcohol use disorder (AUD). However, to date, clinical studies have yielded conflicting results. Despite the lack of consistent evidence, baclofen is often used off-label in clinical practice to treat AUD, especially in some European countries and Australia (2). In this manuscript, a large group of researchers and clinicians combine their expertise in this area to provide (a) a review of the current research evidence and clinical experience of using baclofen in the treatment of AUD, (b) a description of the two different approaches used to administer baclofen in clinical practice settings (“fixed doses” or “flexible doses”) to treat AUD, and (c) a brief overview of the clinical use of baclofen to treat AUD.

Review Of The Current Research Evidence And Clinical Experience

Alcohol Use Disorder and the Need for Additional Medications

AUD is a major public health problem associated with high rates of mortality and morbidity worldwide (3–7). The previous editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) described two disorders related to a pattern of maladaptive alcohol consumption, alcohol abuse and alcohol dependence [e.g., DSM-IV; 8]. The diagnosis of dependence required the fulfillment of three (or more) criteria out of a set of seven, whereas the diagnosis of abuse required at least one out of four different criteria. These two disorders have been combined into a single disorder (AUD), where one set of criteria is now used (DSM-5; 3). In DSM-5, the AUD diagnosis requires the fulfillment of two (or more) criteria out of a set of 11, including “craving,” or a strong desire or urge to use alcohol (3), instead of legal problems (included among DSM-IV alcohol abuse criteria, but excluded by DSM-5 AUD criteria). Accordingly, the previous diagnosis (DSM-IV) of alcohol dependence corresponds approximately to moderate/severe DSM-5 AUD (9).

AUD is characterized by periods of excessive alcohol consumption and a chronic relapsing, remitting course (3). According to the different AUD phases, the goal of medical treatment may be to achieve and maintain abstinence, if patients are currently drinking—or just maintain abstinence.

Even if abstinence is the best goal for AUD medical treatment, some patients prefer to reduce their alcohol consumption to low-risk drinking, instead of total abstinence. According to the US National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking corresponds to an alcohol consumption ≤ 14 (men) or 7 (women) drinks per week and ≤ 5 (men) or 4 (women) drinks on a single day (1 drink = 14 g alcohol) (10). This consumption pattern is associated with lower risks than moderate/high risk drinking, even if the safest level of drinking is none (5).

Accordingly, the recent guidelines of the American Psychiatric Association for the pharmacological treatment of AUD recommend the use of naltrexone, acamprosate, or disulfiram, based on the treatment objective (reducing alcohol consumption or achieving and maintaining abstinence), patient preference, and presence of comorbidities that may contraindicate a specific drug (11). In Europe, nalmefene has also been approved for the treatment of alcohol dependence (12). Nevertheless, only a minority of people with AUD seek and receive medical treatment (4, 13, 14) and current approved medications for AUD are of limited effectiveness (15). Therefore, identification of other medications may contribute toward increasing the number of AUD patients who benefit from pharmacological treatments with a different mechanism of action.

Baclofen and Alcohol Use Disorder

Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD (16). It has been marketed since the early 1970s for the treatment of muscle spasticity, secondary to neurological conditions. The wide use of baclofen as a myorelaxant has provided detailed information on its safety and side effects in these patients (17). From the 1970s, research, largely in animal addiction models, suggested that baclofen may also be effective in the treatment of AUD (1).

Evidence For the Effect of Baclofen on Alcohol Use

Preclinical Studies

Animal studies showed that baclofen induced a dose-related reduction in (a) the behavioral effects caused by alcohol (18), (b) acquisition and maintenance of alcohol consumption (19–21), including binge-like drinking (22), (c) relapse-like drinking (23), (d) severity of alcohol withdrawal signs (20), (e) cue-induced reinstatement of previously extinguished alcohol seeking behavior (24), and (f) reinforcing and motivational properties of alcohol (25–30) in different validated rodent models of AUD [for a recent review, see Colombo and Gessa (1)].

Clinical Studies

Studies Using baclofen 30 mg/Day

Addolorato and colleagues were the first to investigate the efficacy of baclofen in reducing alcohol consumption in AUD patients (31). In this first study, 10 male AUD patients received 30 mg/day baclofen (starting from 5 mg, three times a day, and then 10 mg, three times a day) for four consecutive weeks. Patients reported their last alcohol intake in the preceding 24 h. Seven patients achieved and maintained abstinence, and another two significantly reduced their alcohol consumption. Flannery and colleagues replicated these findings in 12 AUD patients, including three women, that were active drinkers (three days abstinent before the beginning of the trial), using the same dose of baclofen for 12 weeks (32). However, conclusions that can be drawn from these results are limited by the open-label design and the absence of a (placebo) control group.

In 2002, Addolorato and colleagues conducted the first randomized controlled trial (RCT) (see Table 1). In this RCT, 39 AUD male participants received 30 mg/day baclofen or placebo, for 4 weeks. Participants were active drinkers (last intake in the preceding 24 h), did not suffer from any other mental disorder, were treated as outpatients, and received psychological support every week. Their mean baseline alcohol consumption was 17.6 drinks per day (1 drink = 12 g of alcohol) in the baclofen group. Compared to placebo, baclofen increased the percentage of patients who achieved and maintained abstinence (abstinent patients), as well as the number of abstinent days, and decreased the number of drinks per drinking day and anxiety levels (33).

However, a similar RCT found different results [(34); see Table 1]. In this RCT, 80 AUD patients, active drinkers (three days abstinent before beginning the trial), received either 30 mg/day baclofen or placebo for 12 weeks, in an outpatient setting, together with eight sessions of a comprehensive psychological intervention named BRENDA. In this study, there was no difference between baclofen and placebo in the percentage of heavy drinking days, abstinent days, time to first drink (time to lapse), or time to heavy drinking day (time to relapse).

This RCT differed from the Addolorato et al. (33) in several aspects: (a) the high number of women recruited (45% females); (b) the number of individuals who suffered from other mental disorders (e.g., 29% on antidepressants); (c) the low amount of alcohol consumed at baseline (7.3 drinks per day with 1 drink = 14 g of alcohol in baclofen group); (d) the low baseline levels of alcohol withdrawal; (f) the high placebo response; (g) the different aims of the treatment (including abstinence, occasional use, and regular but reduced use); and (h) financial compensation for attending each visit (46).

More recently, three RCTs (each with three arms) compared the efficacy of 30 mg/day (10 mg, three times a day) to another dose of baclofen and placebo in the treatment of AUD, for 12 weeks (39–41).

Regarding participants treated with 30 mg/day baclofen compared to placebo, the first RCT found that baclofen significantly reduced the number of drinks per drinking day (39), whereas the second RCT found no difference in time to relapse nor time to lapse (40). The third RCT found that baclofen treatment (both dose group composite), compared to placebo, increased (a) time to first lapse, (b) time to first relapse, and (c) percentage of days abstinent. The characteristics of these RCTs are described in detail below. Recently, another 3-arm RCT (30 mg/day, 90 mg/day and placebo) was completed, and data analysis is underway (Garbutt JC, unpublished; https://clinicaltrials.gov/, identifier NCT01980706).

Two additional RCTs tested baclofen 30 mg/day in AUD patients with liver disease. In 2007, Addolorato et al. investigated the efficacy of baclofen in AUD patients with liver cirrhosis (Table 1). The rationale for selecting this specific sample was that, in these patients, certain AUD pharmacological agents (e.g., disulfiram and naltrexone) are contraindicated because of their liver metabolism, whereas baclofen has lower liver metabolism and primarily renal excretion. In this RCT, 42 outpatients received 30 mg/day baclofen and 42 received placebo for 12 weeks (35). Participants were active drinkers [at least two heavy drinking days per week and an average consumption of 21/14 drinks (men/women) per week, or more, during the 4 weeks before enrollment], included 23 women (27.4% of the entire sample), did not suffer from other severe mental disorders, and were seen every week for the first month, and then every 2 weeks. At each visit, patients received an individual session of counseling support lasting 30 min. At the end of the 12-weeks study, a higher rate of participants allocated baclofen achieved and maintained abstinence and had a longer cumulative abstinence duration compared with placebo.

More recently, Hauser et al. (36) conducted a similar RCT among AUD patients with chronic hepatitis C (HCV), enrolled at four US Veteran Affairs Medical Centers (Table 1), and found that 30 mg/day baclofen did not increase abstinence or reduce alcohol use, craving for alcohol, or anxiety compared to placebo. In this RCT, 40 participants received 30 mg/baclofen and 40 participants placebo for 12 weeks. These patients were active drinkers (at least one heavy drinking day per week or more than 7 drinks per week, for each of the preceding 2 weeks), did not suffer from other mental disorders, and were seen every week for the first month, and then every 2 weeks. However, unlike the RCT by Addolorato et al. (35), the Hauser et al. study (36) included only three women (3.7% of the entire sample), had low baseline levels of alcohol consumption (7.1 drinks per drinking days with 1 drink = 14 g of alcohol in baclofen group), and participants received manual-guided counseling lasting 15 min at each visit.

Anecdotal and Open-Label Observations With Doses of baclofen >30 mg/Day

Some case reports (47–49) suggested the potential utility of increasing the doses of baclofen to treat patients with AUD. The first of these case reports was published in 2005 by Olivier Ameisen, a physician suffering from severe AUD, who reported that he achieved abstinence from alcohol with 270 mg/day of baclofen (47). Similar observational studies started being published from 2010 (50–62). These case-series (without control groups) suggested that doses of baclofen ranging from 30 to more than 300 mg/day may be effective, with some patients achieving up to a maximum daily dose of 400 mg (55, 63). The effectiveness of baclofen was also reported in AUD patients affected by liver disease (55, 64, 65).

RCTs Using Doses of Baclofen >30 mg/day and <100 mg/Day

Subsequently, a series of RCTs investigated the efficacy of higher doses of baclofen in the treatment of AUD compared to those administered in early studies (Table 1), as detailed below.

Two RCTs investigated the efficacy of 50 mg/day baclofen administered in two, instead of three, times a day [37, 38, Table 1]. In both studies, participants did not suffer from other severe mental disorders, were seen every week, as outpatients, for 12 weeks, and received an individual psychosocial intervention. In one RCT, 64 AUD participants included 16 women (25% of total sample), consumed 7.4 drinks per drinking day (patients allocated to baclofen treatment; 1 drink = 12 g of alcohol), and, other than the weekly individual intervention, also received group counseling sessions, every 2 weeks (37). Participants were active drinkers (at least two heavy drinking days per week and average overall consumption >21/14 drinks per week (men/women) during the month preceding recruitment, and no more than six abstinent days per month). This study did not find differences in the percentages of heavy drinking and abstinent days between the baclofen and the placebo group. However, a high placebo effect was observed (e.g., percentage of abstinent days was 47.5% for placebo and 46.1% for baclofen).

In the second RCT, 32 AUD participants were abstinent from alcohol consumption for at least 7 days and consumed 8.5 g of pure ethanol per week at baseline (for patients allocated to baclofen treatment, equal to ~0.1 drink per drinking day if patients drink every day, 1 drink = 12 g of alcohol) and the number of women recruited was not provided (38). The study found no differences between baclofen and placebo in alcohol consumption and time to relapse.

Two RCTs (each with three arms) compared the efficacy of 60 mg/day (20 mg three times a day) to 30 mg/day baclofen and placebo in the treatment of AUD, for 12 weeks (39, 40). The first RCT found that, compared with patients allocated to placebo, participants treated with baclofen significantly reduced the number of drinks per drinking day and this effect was greater among participants treated with 60 mg/day baclofen than those with 30 mg/day (39). Participants included 32 men (76%) and 10 women (24%) and did not suffer from other severe mental disorders. They were active drinkers (at least two heavy drinking days per week and an average overall consumption of >21/14 drinks (men/women) per week during the 4 weeks before enrollment, and ability to refrain from drinking at least 3 days before randomization day) and consumed a mean of ~12 drinks per drinking day at baseline, with 1 drink = 12 g of alcohol). Each participant was seen as an outpatient, every week for the first month, and then every 2 weeks. At each visit, patients received an individual session of counseling support lasting 30 min.

In contrast, the second RCT found no difference between baclofen 60 mg, baclofen 30 mg, and placebo on time to relapse, nor time to lapse (40). Participants included 19 men (45%) and 23 women (55%), were active drinkers (abstinent from alcohol at least 3 days prior to randomization) and consumed high levels of alcohol at baseline [more than 15 drinks per drinking day (1 drink = 10 g of alcohol) in baclofen groups], were seen as outpatients every week for the first month, then every 2 weeks, and, at each visit, received 30-min psychosocial therapy. In addition, 41% of participants suffered with current anxiety disorders. A post-hoc analysis showed a beneficial effect of baclofen, compared to placebo, only among AUD patients with comorbid anxiety disorders. Namely, AUD patients with anxiety disorder treated with baclofen had the first lapse and relapse after a significantly longer period of time, compared to AUD patients with anxiety treated with placebo. However, no difference was found between 60 and 30 mg/day baclofen.

One RCT compared the efficacy of 75 mg/day (25 mg three times a day) to 30 mg/day baclofen and placebo in the treatment of 104 AUD patients (including 30 (29%) women), for 12 weeks [(41); Table 1]. In this study, participants were seen as outpatients every 2 weeks, and, at each visit, received adherence therapy lasting 20–60 min. People with active major mental disorders were excluded, but 55% of participants were prescribed antidepressants and 56% suffered from liver disease (with or without cirrhosis). Participants were abstinent from alcohol consumption for between three and 21 days and their baseline level of alcohol consumption was equal to 15 drinks per drinking day with 1 drink = 10 g of alcohol). The aims of treatment included both abstinence and reduction of alcohol consumption. The study found that baclofen treatment (both dose groups combined), compared to placebo, increased: (a) time to first lapse, (b) time to first relapse, and (c) percentage of days abstinent. However, there were no differences between the effects of the 75 mg/day and the 30 mg/day groups. When the results were analyzed according to the presence of liver disease, baclofen (both dose group composite) was shown to be effective in increasing the time to lapse and relapse among participants affected by liver disease, but not among those without liver disease.

One RCT investigated the efficacy of 80 mg/day (20 mg at 4 times/day) baclofen in the treatment of 30 patients affected by AUD and nicotine use disorder [(42); Table 1]. In this 12-weeks study, consistent with FDA recommendations, the daily dose of baclofen 80 mg/day was divided into four administrations (20 mg, four times a day). Participants included 12 females (40%), did not suffer from other severe mental disorders, were seen as outpatients every week for the first month, then every 2 weeks, and, at each visit, received an individual session of medical management. They were active smokers and drinkers at the beginning of the trial and their consumption of alcohol at baseline was high but expressed as percent of heavy drinking days (78% for patients allocated to baclofen). Participants were looking for treatment for both AUD and smoking, but with different treatment goals (i.e., reducing or quitting both substances or quitting one and reducing the other). Regarding alcohol consumption, 48% of overall participants wanted to quit drinking. The results of the study showed that the rate of abstinent days from co-use of alcohol and tobacco was higher among participants treated with baclofen compared to those treated with placebo (42).

RCTs Using Doses of Baclofen >100 mg/Day

A recent RCT compared the efficacy of an intended maximum dose of 150 mg/day baclofen (in three daily administrations) to 30 mg/day baclofen and placebo in 151 AUD patients [(43); Table 1]. The trial did not find any difference between the three groups in any outcome evaluated (time to first relapse, total alcohol consumption, and proportion of abstinent patients). However, the results showed a very high placebo effect (e.g., 66% of participants allocated to placebo remained abstinent for the full study period). This study also included patients (31% females) with comorbid depression, anxiety, and bipolar disorder. Participants were abstinent for a mean of ~12 days (range: 4–21 days) and their baseline levels of alcohol consumption were equal to 141.8 g per day (equal to ~12 drinks per drinking day when 1 drink = 12 g of alcohol). The RCT comprised two phases. In the first phase (lasting 6 weeks), participants gradually increased the daily dose of baclofen up to 150 mg depending on tolerance (titration phase; 10 mg every other day, up to 30 mg/week). In the second phase (lasting 10 weeks), participants received the maximum dose achieved during the previous phase. Participants in both baclofen groups started with 30 mg/day (in three daily administrations) from the first day of treatment. Participants allocated to baclofen 30 mg/day received the same dose for the whole study period (16 weeks). In this multicenter trial, the setting varied between the centers. The majority of participants were treated as inpatients for the first 4–6 weeks (79%) followed by 10–12 weeks outpatient treatment. In all centers, participants received weekly group or individual psychotherapy sessions. The results of the trial showed that among participants allocated to baclofen, up to 150 mg/day, only 16% achieved the highest dose. Overall, these patients received a mean of 93.6 mg/day baclofen.

Another multicenter RCT compared the efficacy of baclofen, up to 180 mg/day (in three daily administrations), to placebo in 310 AUD patients for 26 weeks [(44); Table 1]. This RCT found no difference between baclofen and placebo in the percentage of abstinent patients and in the reduction of alcohol consumption. Compared to the study of Beraha et al. (43), this RCT recruited a similar percentage of women (27%), participants were abstinent for a similar period of time prior to the start of the study medication (3–14 days) and consumed a slightly lower amount of alcohol at baseline (95.5 g of alcohol per day for patients allocated to baclofen group, equal to 7.9 drinks per drinking day when 1 drink = 12 g of alcohol). However, the two RCTs differed in the duration, mean actual baclofen dose, presence of comorbid mental disorders, setting, and frequency of psychosocial treatment. The duration of the Reynaud et al. (44) RCT was longer than in the Beraha et al. (43) study (26 vs. 16 weeks). In this RCT, a higher percentage of participants reached the maximum dose of baclofen (66 vs. 16%) and participants received a higher mean daily dose of baclofen (153.5 vs. 93.6 mg). Both RCTs excluded participants with current severe mental disorders. However, participants with bipolar disorder were excluded in Reynaud et al. (44) and included by Beraha et al. (43). In the Reynaud et al. (44) RCT, all patients were seen as outpatients, whereas in the Beraha et al. (43) study 79% of participants were treated as in patients for the first 4–6 weeks. Participants also received psychotherapy sessions less frequently (every 2 weeks vs. weekly in the other RCT) and the placebo effect was lower (e.g., 11 vs. 66%).

Only one RCT using doses of baclofen up to 270 mg/day has been published [(45); Table 1]. The results of a second RCT (using up to 300 mg/day) have been presented at scientific meetings but have not yet been published in full (66). Unlike the other two similar RCTs presented above (43, 44), this study found that baclofen substantially increased the percentage of abstinent patients and cumulative abstinence duration compared to placebo [(45); see Table 1].

In this RCT (45), patients allocated to baclofen received a mean dose of 180 mg/day (in three daily administrations) (compared to 153.5 and 93.6 mg/day in the other 2 RCTs), and 36% of these patients achieved the maximum dose (vs. 66 and 16% in the other two RCTs with doses >100 mg/day). This RCT was conducted at a single outpatient unit and recruited 56 AUD participants with high baseline levels of alcohol consumption (206.2 g per day, equal to about 17 drinks per drinking day with 1 drink = 12 g of alcohol vs. 12 and 8 drinks per drinking day in the other 2 RCTs with doses >100 mg/day). The 3 RCTs did not differ in other characteristics. This RCT included 17 women (30%) and participants did not suffer from current severe mental disorders. The study lasted 24 weeks, participants were abstinent for a mean of ~12 days at the beginning of the trial and received supportive therapy (Medical Management).

Meta-Analyses

To date, there have been four meta-analyses of baclofen for the treatment of AUD, based on the studies described above [(67–70); see Table 2]. These meta-analyses vary in the number of RCTs evaluated between five (68) and 14 (67), as well as in the outcomes investigated. The most inclusive study (67) evaluated the efficacy of baclofen pooling the outcomes chosen by each single study as the primary outcome, and in two subgroups of outcomes, one related to abstinence and one to alcohol consumption. According to the results of this meta-analysis, baclofen did not differ significantly from placebo in any of the outcomes investigated.

Front. Psychiatry, 08 October 2018 | https://doi.org/10.3389/fpsyt.2018.00486
Juliette Pinot^1*, Laurent Rigal², Bernard Granger³, Stéphanie Sidorkiewicz¹ and Philippe Jaury¹

• ¹Département de Médecine Générale, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
• ²Département de Médecine Générale, Université Paris Sud, Paris Saclay, Faculté de Médecine, Paris, France
• ³Faculté de Médecine, Service de Psychiatrie et d’Addictologie Hôpital Tarnier, Hôpitaux Universitaire Paris Centre, Assistance publique—Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Background: More information is needed about the efficacy and safety of long-term baclofen in the treatment of alcohol use disorders. The objective of this study was to assess the effect of treatment with tailored-dose baclofen on alcohol consumption in patients with alcohol use disorders followed for 3 years after first initiating baclofen treatment.

Methods: This retrospective descriptive cohort included outpatients followed in a French general practice clinic for 3 years and treated with tailored-dose baclofen to reduce or eliminate alcohol consumption. At 3 years, treatment was considered successful if alcohol consumption was at or below levels defined as low-risk by the WHO (≤ 40 g/d in men and ≤ 20 g/d in women).

Results: The study population included 144 patients (88 men and 56 women). The participants’ mean age was 46 ± 11 years and mean daily alcohol intake before treatment was 167 ± 77 grams. At the end of the study, treatment was successful for 91 (63.2%) patients. Participants’ mean dose of baclofen at the end of study period was 100 ± 101 mg/d. We identified 75 (52.1%) patients for whom treatment was successful at each annual follow-up appointment: at 1, 2, and 3 years. The mean maximum dose of baclofen over follow-up of the 144 patients was 211 ± 99 mg/d (dose range: 40 mg/d to 520 mg/d).

Conclusion: In this study, tailored-dose baclofen appears to be an effective treatment in patients with alcohol use disorders, with sustainable effect over time (3 years). There are many adverse effects but they are consistent with those already described in the literature.

Introduction

Baclofen, a gamma-aminobutyric acid B-receptor agonist, has been prescribed for more than 40 years for treating spasticity caused by diseases of the central nervous system, at recommended doses between 30 and 80 mg/day. It appears to be a promising candidate for treating patients with alcohol use disorders (1), by reducing or even suppressing their craving.

The first randomized placebo-controlled double-blind trial to assess the benefits of baclofen at 30 mg/day to treat alcohol dependence was published in 2002 (2). Subsequent randomized placebo-controlled studies of doses up to 60 mg/day reported contradictory results (2–8). Four of these 7 studies reported positive findings for the primary outcome.

At the same time, several case reports (9–12) and retrospective observational studies (13–15) indicated that high-dose baclofen (up to 400 mg/d) could be effective for treating alcohol dependence. One randomized placebo-controlled double-blinded trial (Baclad) assessing high-dose baclofen (up to 270 mg/day) over 6 months for treating alcohol dependence reported a significantly higher proportion of abstinence with baclofen vs. placebo (42.9% vs. 14.3%, P = 0.037) (16). Another randomized placebo-controlled double-blind trial of doses up to 150 mg/day over 4 months in alcohol-withdrawn patients did not find a difference in the groups from the first initiating treatment to the first relapse (17). Two randomized placebo-controlled double-blind trials of high-dose baclofen were conducted in France (18, 19). The Alpadir study did not demonstrate the efficacy of baclofen at the target dose of 180 mg/day in maintaining abstinence over 6 months (19). The Bacloville study reported a significantly higher proportion of patients with a low risk alcohol consumption (WHO) or abstinent in baclofen group (doses up to 300 mg/day) vs. placebo group after 1 year (18).

The maximal duration of the follow-up in these randomized placebo-controlled double-blind trials was 1 year and the longest retrospective study was for 2 years. Hence, we need information on long-term baclofen treatment. Indeed, studies are needed on whether patients who became abstinent or managed to control their alcohol consumption with baclofen could stop or reduce the treatment while remaining abstinent or controlling their consumption.

Here we present the retrospective clinical experience of a general practitioner (PJ) who has prescribed tailored-dose baclofen since 2008 for patients at high risk for alcoholism as defined by the World Health Organization (WHO; >40 g/day for women and >60 g/day for men). The primary objective of this study was to assess effectiveness of tailored-dose baclofen for alcohol consumption in patients with alcohol use disorders who were followed over 3 years after first initiating baclofen. Secondary objectives were to analyse the dose of baclofen prescribed during the 3 years of follow-up and tolerance of the treatment and to explore patient characteristics associated with low-risk alcohol consumption.

Methods

Study Design

This was a retrospective study among patients of a French general practitioner (PJ) trained in addictology. Patients were eligible for the study if they (1) were at least 18 years old, (2) drank at a high-risk level according to the WHO (20), (3) first began taking baclofen before December 31, 2011, and (4) were willing to be followed up for more than 3 months to assure stability of patient care.

Eligible patients were identified from an exhaustive list of patients who received a baclofen prescription that the general practitioner (PJ) maintained. For each patient, data were collected retrospectively from their medical file by one independent investigator (JP). If necessary, data collection was completed by asking the patient questions during a consultation with the general practitioner or by telephone with the investigator.

General Practitioner Follow-Up and Prescription

Patients did not necessarily stop drinking alcohol before beginning baclofen treatment. They could drink alcohol with the treatment. Baclofen was prescribed at progressively increasing doses according to the standard of care at the time. This practice was later published in prescription guidelines (21) without any pre-set limit up to the dose that allowed patients to control their alcohol consumption or even become indifferent to it. The objective for this treatment was harm reduction (as proposed by European Medicines Agency, 2010, and confirmed by recommendations from the US Food and Drug Administration, 2015, and UK Chief Medical Officers’ Low Risk Drinking Guidelines, 2016) (22). Each patient received comprehensive care according to NICE guidelines (23), with or without the additional prescription of psychotropic drugs. Each patient received written and oral information about the treatment (modality of prescription, follow-up, main side effects, potential risks of combining higher doses of baclofen and high volumes of alcohol importance of stopping treatment progressively).

Data Collection

The following data were collected:

– social and demographic data: age, sex, marital status, work status

– history of treatment for management of alcoholism: episodes of detoxification, participation in discussion groups, drug treatment (e.g., acamprosate, naltrexone, or disulfiram)

– psychiatric disorders: depression, bipolar, anxiety, or borderline personality disorders

– history of use of other toxic substances: tobacco, cannabis, heroin, cocaine

– history of eating disorders

– history of insomnia

– at treatment initiation and at 1, 2, and 3 years follow-up visits: reported alcohol consumption (in grams per day), daily baclofen dose (in milligrams), consumption of other toxic substances (tobacco, cannabis, heroin, cocaine), a list and dose of psychotropic drugs (anxiolytics, hypnotics, antidepressants, antipsychotics, and mood stabilizers), a list and dose of psychotropic drugs used as substitutes for opiates

– maximum dose of baclofen taken during follow-up.

– tolerability of baclofen (reported by the patient at each consultation). We focused on the sides effects reported by patients during the first year of follow-up given that it corresponds to the phase of baclofen initiation and titration. After titration, we only reported serious adverse effects (hospitalizations and deaths).

Outcome

Treatment was considered successful if patients were either abstinent or drinking at a low-risk level as defined by the WHO (≤ 40 g/day for men and ≤ 20 g/day for women) at 3 years after beginning the treatment even if no longer taking baclofen.

Data Analyses

We analyzed data for patients who were eligible for the study and for whom data on alcohol consumption was provided during the 3 years follow-up. Descriptive analyses were used for alcohol consumption defined according to the WHO risk categories and baclofen dosage during follow-up. Pearson’s correlation analysis was used to determine correlation between the maximum baclofen dose used for efficacy and patient characteristics as well as daily alcohol intake before starting baclofen. We attempted to identify factors associated with treatment success (baseline characteristics of patients associated with successful treatment at 3 years in univariate with p < 0.20 were considered in multivariate logistic regression). We described any adverse effects and compared patients lost to follow-up before 3 years to those who completed follow-up. Chi-square or Fisher’s exact test was used as appropriate to analyze categorical variables and Student t-test for quantitative variables. Statistical analyses involved use of STATA v12.0 and R 3.2.5. P < 0.05 was considered statistically significant.

Ethical Aspects

All patients included were informed of the study objective and provided informed consent during a consultation with the general practitioner or by telephone with the investigator. This study was not reviewed by a research ethics committee because as a retrospective study, it was not at this time within the scope of the French statutes regulating biomedical research.

Results

Descriptive Characteristics

We identified 219 eligible patients who initiated baclofen treatment before December 31, 2011: 75 were lost to follow-up, including 6 who died, resulting in a final cohort of 144 (65.8%) for analysis.

The mean (SD) age at inclusion was 46 (11) years and 88 (61.1%) were men (Table 1). The mean (SD) quantity of alcohol consumed daily at baclofen initiation was 167 (77) g. Overall, 103 patients (71.5%) previously received treatment for alcohol use disorder (drugs or detoxication or discussion groups). At baclofen initiation, 120 patients (83.3%) had a psychiatric disorder [Diagnostic and Statistical Manual of Mental Disorders, 4th [DSM-IV] criteria]. Before beginning baclofen treatment, 69.4% were taking at least one psychotropic drug.

Publication  de la fameuse étude CNAM  First published: 25 September 2018 – Christophe Chaignot, Mahmoud Zureik, Grégoire Rey, Rosemary Dray‐Spira, Joël Coste, Alain Weill

https://onlinelibrary.wiley.com/doi/abs/10.1002/pds.4635
Malgré un article à charge contre le baclofène,  un  graphique montre que le baclofène est plus sûr que les autres traitements aux doses comprises entre 75 et 180mg/j !

Très intéressante analyse (entre autre) de cette étude : Sécurité du baclofène : l’étrange appréciation de l’Agence française du médicament par Renaud de Beaurepaire, Amine Benyamina, Bernard Granger, Catherine Hill, Philippe Jaury : https://www.cairn.info/revue-psn-2018-3-p-37.htm

Bull. Acad. Natle Méd. , 2017, 201, n° 7-8-9, 1349-1359, séance du 10 octobre 2017

Philippe JAURY *, Stéphanie SIDORKIEWICZ **, Jean-Roger LE GALL **

Philippe Jaury déclare des liens d’intérêt avec : Ethypharm, Lundbeck, Novartis,Polpharma, Bouchara, Indivior.

RÉSUMÉ
Le baclofène, agoniste des récepteurs GABA B, est prescrit depuis 40 ans pour le traitement de la spasticité à une posologie de 30 à 80 mg par jour. Depuis 2005 de hautes doses de baclofène sont utilisées en France dans l’alcoolodépendance, hors Autorisation de Mise sur le Marché (AMM). En 2014 une Recommandation Temporaire d’Utilisation (RTU) est promulguée par l’Âgence Nationale de Sécurité du Médicament (ANSM). Bacloville est une étude multicentrique (60 médecins généralistes), randomisée en double aveugle baclofène versus placebo chez des buveurs à haut risque (selon les recommandations de l’Organisation Mondiale de la Santé) (OMS) pendant un an. C’est une étude pragmatique basée sur la réduction des risques. Pour le critère principal (consommation à bas risque au 12ème mois) il y a 56,8 % de succès avec le baclofène et 35,8 % avec le placebo (p=0,003). Il y a plus d’effets indésirables dans le bras baclofène en comparaison avec le bras placebo, laplupart étant modérés et bien tolérés. Vu les méfaits de l’alcool le rapport bénéfice risque esten faveur du baclofène.

Lire la suite : Bacloville_Academie_Medecine

Journal of Addiction Medicine and Therapeutic Science

Received: 18 September, 2017; Accepted: 23 October, 2017; Published: 24 October, 2017

Abstract

Since the discovery by Olivier Ameisen that high-dose baclofen can produce a state of indifference towards alcohol in those with Alcohol Use Disorders (AUD), the prescription of baclofen in AUD patients has exponentially increased. There are currently hundreds of thousands of patients with AUD who benefit from this treatment in France. However, the prescription of baclofen is difficult in many ways. First, the treatment, which consists in a slow progressive increase of doses, must be individually adapted, some patients needing low doses to achieve a state of indifference, while others need high or very high doses. Second, baclofen produces many adverse effects that can be very uncomfortable for patients, and may sometimes be dangerous. The third is that the patients must be strongly engaged in the management of the treatment, as they are the ones who will have to find the best way to target the moments of cravings and determine the distribution of the doses over the day to limit the occurrence of adverse effects. The doctor: patient therapeutic alliance is therefore a crucial element in the management of baclofen treatment. The present article is a guide written by both doctors and cured patients (“expert patients”) for the prescription of baclofen in AUD.

A_prescription_guide_for_baclofen_in_Alcohol_Use_Disorder-For_use_by_physicians_and_patients

https://www.peertechz.com/Addiction-Medicine-Therapeutic-Science/JAMTS-3-124.php

Ce guide de prescription sera prochainement traduit en français

Traduction en français de l’article http://www.baclofene.org/wp-content/uploads/2017/10/Baclofen_Treatment_of_Bulimia_Nervosa_and_Binge_Eating_Disorder_An_Internet_Survey.pdf

Résumé   

Objectifs: La Boulimie Nerveuse (BN) et l’hyperphagie (BED) sont des pathologies difficiles à traiter et pour lesquelles il existe très peu de traitements approuvés. Des études cliniques ont montré l’efficacité du  baclofène dans l’hyperphagie, mais cette efficacité doit être confirmée.   

Méthodes: Cette étude est une enquête Internet ciblant l’utilisation de baclofène pour le traitement de la boulimie nerveuse et de l’hyperphagie. Les questions de l’enquête ont été publiées sur le site Internet « Baclofène ». Ces questions portaient sur l’efficacité du baclofène, les doses, l’augmentation du traitement, les effets indésirables et l’impact sur la qualité de vie.   

Résultats: Cent huit personnes ont satisfait aux critères diagnostics d’hyperphagie et de boulimie (61 BN, 47 BED). 41% des participants du groupe BN et 40% des participants du groupe BED déclarent une guérison totale, tandis que 29% du groupe BN et 34% du groupe BED déclarent une amélioration. Les participants du groupe BN étaient significativement plus jeunes que ceux du groupe BED.  Les doses efficaces individuelles étaient très variables (10-590 mg/j) et la moyenne de la dose maximale était de 174 mg/j. Il n’y avait pas de corrélation entre la dose maximale de baclofène et l’intensité des effets indésirables, la qualité de vie ou l’efficacité du traitement.   

Discussion: Les pourcentages élevés de réussite de cette étude sont probablement supérieurs à la réalité de l’efficacité du baclofène pour ces pathologies, parce que les patients améliorés par le baclofène étaient probablement plus enclins à répondre à l’enquête que ceux pour qui le traitement avait échoué. Néanmoins, les résultats confirment l’efficacité des doses de baclofène ajustées individuellement pour le traitement de nombreux patients souffrant d’hyperphagie et suggère son intérêt potentiel pour la boulimie nerveuse. Des études contrôlées utilisant des doses de baclofène ajustées individuellement sont nécessaires.   

Mots-clés: Troubles du comportement alimentaire; Titrage individuel; Effets indésirables; GABA-B; Qualité de vie

Traitement_par_le_baclofene_de_la_boulimie_nerveuse_et_de_lhyperphagie_une_enquete_Internet

Un article sur l’intérêt potentiel du baclofène sur l’hyperphagie et la boulimie nerveuse

Objective: Bulimia Nervosa (BN) and Binge Eating Disorder (BED) are conditions that are difficult to treat and for which there are very few approved treatments. Clinical studies have shown baclofen effectiveness in BED, but this
must be confirmed.

Methods: The present study is an Internet survey targeting the use of baclofen for the treatment of BN and BED. Survey questions were released on the “Baclofène” Internet site. Questions relate to baclofen effectiveness, doses, treatment increase, adverse effects, and impact on quality of life.

Results: One hundred and eight responders met diagnostic criteria for BED and BN (61 BN, 47 BED). Forty-one percent of BN and 40% of BED participants reported total recovery, while 29% of BN and 34% of BED reported some improvement. BN participants were significantly younger than BED participants. Individual effective doses were highly variable (10-590 mg/d) and the average maximal dose was 174mg/d. There were no correlations between the maximal baclofen dose and the intensity of adverse effects, quality of life, or recovery.

Discussion: The high percentages of success in this study probably overestimate the reality of the effectiveness of baclofen in BN and BED because patients who were improved by baclofen were likely more prone to respond
to the survey than those for whom the treatment had failed. Nevertheless, the results confirm the effectiveness of individually adjusted doses of baclofen in the treatment of many patients with BED and suggest its potential interest for BN. Controlled studies using individually adjusted doses of baclofen are needed.

Keywords: Eating disorder; Individual titration; Adverse effects; GABA-B; Quality of life

Baclofen_Treatment_of_Bulimia_Nervosa_and_Binge_Eating_Disorder_An_Internet_Survey