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# Should the French approval of baclofen for alcohol dependence be extended to abstinence maintenance?

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## L'autorisation française du baclofène dans la dépendance à l'alcool doit-elle être étendue au maintien de l'abstinence ?

Benjamin Rolland<sup>a,f,*</sup>, Laurent Karila<sup>b,g</sup>, Nicolas Franchitto<sup>c,h</sup>, Camille Barrault<sup>d</sup>, Mickael Naassila<sup>e</sup>, French Alcohol Society

## ARTICLE INFO

**Article history:**

Received 13 October 2023

Accepted 17 May 2024

Available online 6 September 2024

**Keywords:**

Baclofen

Alcohol dependence

Approval

France

## ABSTRACT

Ever since 2018 France has been the only country to approve the gamma aminobutyric acid type B (GABA-B) receptor agonist baclofen for alcohol dependence. This authorization follows a ten-year period of intensive off-label use during which baclofen was used in doses of up to 300 and even 400 mg per day to support the gradual reduction of alcohol consumption in patients suffering from alcohol dependence. However, in international clinical trials, baclofen has mainly been studied to support the maintenance of abstinence. The French use of baclofen was therefore somewhat atypical as it paved the way for drug-supported approaches to reducing alcohol consumption, even before nalmefene was marketed. In line with this specific use of baclofen, approval was granted only for alcohol reduction support. However, a recent Cochrane systematic review and meta-analysis by Agabio et al. found significant efficacy only for abstinence maintenance, while no significant effect was found on alcohol reduction outcomes and no dose-response relationship was identified in the analyses. The safety of baclofen was judged to be good. Based on these substantial new results, the Société française d'alcoologie (SFA) now considers that baclofen should also be approved for the maintenance of abstinence. The extension of approval should not lead to the removal of the initial indication or the possibility of using high doses, as some patients have found this therapeutic regimen particularly useful for them. France, which has been a open skies national laboratory on the use of baclofen in alcohol dependence for over ten years, should let this original therapeutic option available to patients. However, it should update the regulatory framework defining the main conditions of access to treatment for patients based on the latest and highest scientific evidence.

© 2024 L'Encéphale, Paris. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Depuis 2018, et jusqu'à présent, la France est le seul pays à avoir accordé une autorisation de mise sur le marché au baclofène, agoniste des récepteurs de l'acide gamma aminobutyrique de type B (GABA-B), dans la dépendance à l'alcool. Cette autorisation fait suite à une période de dix ans d'usage hors AMM intensif du baclofène, au cours de laquelle les prescriptions pouvaient atteindre des doses de 300, voire 400 mg par jour, pour accompagner la réduction progressive de la consommation d'alcool chez les patients. Par

**Mots clés :**

Baclofène

Dépendance à l'alcool

Approbation

France

<footnote><sup>a</sup> Service universitaire d'addictologie de Lyon (SUAL), hospices civils de Lyon, CH Le Vinatier, 95, boulevard Pinel, 69500 Lyon, France</footnote>

<footnote><sup>b</sup> Centre d'enseignement, de recherche et de traitement des addictions, hôpital universitaire Paul-Brousse (AP-HP), 94800 Villejuif, France</footnote>

<footnote><sup>c</sup> Service universitaire d'addictologie, CHU de Purpan, Toulouse, France</footnote>

<footnote><sup>d</sup> Service d'hépatologie, hôpital Beaujon, Clichy, France</footnote>

<footnote><sup>e</sup> Unité Inserm UMRS 1247, université de Picardie Jules-Verne, Amiens, France</footnote>

<footnote><sup>f</sup> UPSYR2, CRNL, U1028, CNRS, UMR5292, Inserm, UCBL1, Lyon, France</footnote>

<footnote><sup>g</sup> UR PSYCOMADD, université Paris Saclay, 94270 Le-Kremlin-Bicêtre, France</footnote>

<footnote><sup>h</sup> EQUITY Research Team, CERPOP, UMR 1295, University Toulouse III, Paul Sabatier, Toulouse, France</footnote>

<footnote>* Corresponding author. Service universitaire d'addictologie de Lyon (SUAL), hospices civils de Lyon, CH Le Vinatier, 95, boulevard Pinel, 69500 Lyon, France. E-mail address: benjrolland@gmail.com (B. Rolland).</footnote>
contraste, dans les essais cliniques internationaux, le baclofène avait essentiellement été étudié dans le maintien de l'abstinence. L'utilisation française du baclofène a donc été quelque peu atypique, puisqu'elle a ouvert la voie à des approches de réduction de la consommation d'alcool soutenues par des médicaments, avant même la mise sur le marché du nalméfène. Conformément à cette utilisation particulière du baclofène dans le pays, l'AMM n'a été accordée que pour l'aide à la réduction de la consommation d'alcool. Cependant, une récente revue systématique et méta-analyse Cochrane réalisée par Agabio et al., a retrouvé une efficacité significative uniquement pour le maintien de l'abstinence, alors qu'aucun effet n'a été conстатé sur les paramètres de réduction de la consommation d'alcool, et qu'aucune relation dose–effet n'a été mise en évidence. La sécurité du baclofène a été jugée bonne. Sur la base de ces nouveaux résultats importants, la Société française d'alcoologie (SFA) estime que l'AMM du baclofène devrait être étendue à l'indication de maintien de l'abstinence. Cette révision d'AMM ne devrait pas mener à la suppression de l'indication initiale et de la possibilité d'utiliser des doses élevées, car certains patients ont pu trouver ce schéma thérapeutique particulièrement utile pour eux. La France, qui constitue depuis plus de dix ans un laboratoire national « à ciel ouvert » sur l'utilisation du baclofène dans l'alcoolodépendance, devrait laisser cette option thérapeutique originale à la disposition des patients, mais devrait aussi mettre à jour le cadre réglementaire définissant les principales conditions d'accès au traitement pour les patients, sur la base des preuves scientifiques les plus récentes et les plus élevées.

© 2024 L'Encéphale, Paris. Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

In October 2018, the gamma aminobutyric acid type B (GABA-B) receptor agonist baclofen has been granted an approval by the French drug agency for alcohol dependence [1], as a second-line medication, and in addition to psychosocial support. To this date, and still so far, France has been the only country to label this medication for alcohol dependence. The 2018 approval followed from a ten-year period of intensive off-label use, during which baclofen was used in doses of up to 300 or even 400 mg per day, to support progressive drinking reduction among patients. This prescribing practice was inspired by the personal experience of Olivier Ameisen, a French cardiologist who suffered from alcohol dependence, and self-medicated using very high doses of baclofen, before publishing a best-seller book entitled "Le Dernier Verre" [2]. Until then, in international clinical trials, baclofen had mainly been studied to support abstinence maintenance [3]. The French use of baclofen was therefore somewhat atypical, as it paved the way for drug-supported approaches to reducing alcohol consumption, even before nalmefene was marketed.

Based on the French way of using baclofen in alcohol dependence, national approval was granted for drinking reduction exclusively, as a second-line treatment after nalmefene [1]. The question of which dose range should be used has been the subject of considerable debate in France, as baclofen can have dose-dependent sedative effects [4], and a national study carried out using near-complete data from the French health insurance database found a significant association between baclofen dose range, on the one hand, and risks of hospitalization and mortality, on the other [5]. However, this study was criticized because the data analyzed did not involve the concurrent daily doses of alcohol, which could also explain hospitalizations and mortality. Initially, the maximum dose of baclofen was limited to 80 mg per day, but after lengthy legal proceedings between the French drug agency and patient associations, this maximum dose limit was removed by a judge's decision, and now the current version of the baclofen marketing authorization no longer specifies any dose limitation.

At the same time, a recent Cochrane systematic review and meta-analysis found significant efficacy only in maintaining abstinence, with baclofen reducing the ongoing risk of relapse by an average of 13% compared with placebo [6]. By contrast, there was no significant effect on outcomes relating to the reduction of alcohol consumption, such as the reduction in the number of heavy

drinking days or the total number of drinks per day of alcohol consumption. Similarly, baclofen showed no difference in reducing levels of craving for alcohol compared with placebo. The safety of baclofen was judged to be good. The significant efficacy of baclofen in supporting the maintenance of abstinence, but not in reducing alcohol consumption, raises questions about the underlying mechanisms of action, and it seems that the hypothesis of a substitution effect of baclofen, which could pharmacologically "replace" alcohol [7,8] should give way to other explanatory mechanisms.

In July 2013, Olivier Ameisen died suddenly, a year before the French drug agency finally agreed to recognize and regulate what was, at the time, an off-label prescription practice. More than ten years later, the national controversy and impassioned positions seem to have subsided, and it now seems possible to address the issues surrounding baclofen with a purely scientific and pragmatic approach. In the light of the results of the meta-analysis by Agabio et al. [6], the French approval of baclofen should probably be reconsidered. The introduction of baclofen, after a period of supervised detoxification, appears to be becoming, if not the only indication, at least an additional option to official authorization, since it has been established as the most evidence-based practice to date, for the use of baclofen in alcohol dependence.

In line with its previous recommendations [9–11], the French Alcohol Society (Société française d'alcoologie [SFA]) is not advocating for the removal of the indication of drinking reduction and of the possible use of high doses, depending on situations and individual needs of patients. However, using high dose baclofen should require intensive supervision of patients, and very regular reappraisal of the risk–benefit ratio of the treatment. France, which has been a national laboratory for the use of baclofen in alcohol dependence for over ten years, should keep this pharmacological option alive for patients. However, the official indication should be updated, in the light of the latest and best evidence in the field, which suggests that baclofen's most demonstrated effect is to help people suffering from alcohol dependence to maintain sustained abstinence.

## Disclosure of interest

Benjamin Rolland declares that he has received honoraria for presentations at congresses or scientific expertise assignments
for Ethypharm, Zentiva, PolPharma, Abbvie, Gilead, HAC Pharma, Biocodex, InfectoPharm, Janssen, PiLeJe, Indivior, Accord Health-care, Grünenthal, Camurus and Recordati.

Nicolas Franchitto declares financing as a speaker for Ethypharm France, Indivior and Abbvie France, and participation in scientific congresses and events (with travel and accommodation expenses paid) by Ethypharm and Indivior.

Mickael Nassila declares invitations as a speaker for Indivior France, clinical trials as co-investigator, non-principal investigator, study collaborator for Bioprojet Biotech, occasional interventions: consulting activities for Lilly France.

Laurent Karila declares that he has received fees for webinars and face-to-face interventions in addictology for the Ethypharm laboratory, fees for an educational project on alcohol and cocaine addiction for the Zentiva laboratory, and fees for a Social Network Reel (Facebook, Instagram) on hepatitis C and addictions for the Abbvie laboratory.

Camille Barrault has received honoraria as principal investigator, coordinator or principal investigator for Zentiva, as speaker for Abbvie, Ethypharm, Gilead and Viatris, as auditor for Abbvie, Ethypharm, Gilead and Sandoz, and as expert for Abbvie, B3TSI and Edimark.

## References

[1] Agence nationale de sécurité des médicaments et des produits de santé (ANSM). L'ANSM octroie une autorisation de mise sur le marché pour une utilisation du baclofène dans l'alcoolodépendance – communiqué. Published on Oct. 23, 2018; updated on Jan. 15, 2021. Available online: https://ansm.sante.fr/actualites/lansm-octroie-une-autorisation-de-mise-sur-le-marche-pour-une-utilisation-du-baclofene-dans-lalcoolodépendance-communique [consulted on Oct. 10, 2023].

[2] Ameisen O. Le dernier verre. Paris: Denoël; 2008, 298 p.

[3] Agabio R, Sinclair JM, Addolorato G, et al. Baclofen for the treatment of alcohol use disorder: the Cagliari Statement. Lancet Psychiatry 2018;5(12):957-60.

[4] Rolland B, Labreuche J, Duhamel A, et al. Baclofen for alcohol dependence: relationships between baclofen and alcohol dosing and the occurrence of major sedation. Eur Neuropsychopharmacol 2015;25(10):1631-6.

[5] Chaignot C, Zureik M, Rey G, et al. Risk of hospitalisation and death related to baclofen for alcohol use disorders: comparison with nalmefene, acamprosate, and naltrexone in a cohort study of 165,334 patients between 2009 and 2015 in France. Pharmacoepidemiol Drug Saf 2018;27(11):1239-48.

[6] Agabio R, Saulle R, Rösner S, et al. Baclofen for alcohol use disorder. Cochrane Database Syst Rev 2023;1(1). CD012557.

[7] Chick J, Nutt DJ. Substitution therapy for alcoholism: time for a reappraisal? J Psychopharmacol 2012;26(2):205-12.

[8] Rolland B, Bordet R, Deheul S, et al. Baclofen for alcohol-dependence: anticraving or partial substitution? J Clin Psychopharmacol 2013;33(2):280-1.

[9] Société française d'alcoologie. Recommandations de bonne pratique. Mésusage de l'alcool : dépistage, diagnostic et traitement. Version révisée du 5 juin 2023. Available online: https://sfalcoologie.fr/wp-content/uploads/RECOS-SFA-Version-2023-2-2.pdf [consulted on Oct. 10, 2023].

[10] Louvet A, Trabut JB, Moreno C, et al. Management of alcohol-related liver disease: the French Association for the Study of the Liver and the French Alcohol Society clinical guidelines. Liver Int 2022;42(6):1330-43.

[11] Rolland B, Paille F, Gillet C, et al. Pharmacotherapy for Alcohol Dependence: the 2015 Recommendations of the French Alcohol Society, issued in partnership with the European Federation of Addiction Societies. CNS Neurosci Ther 2016;22(1):25-37.