- Email: [email protected]
Baclofen and alcohol use disorders: From miracle to mirage
European Neuropsychopharmacology (2017) 27, 691–692
www.elsevier.com/locate/euroneuro
LETTER TO THE EDITOR
Baclofen and alcohol use disorders: From miracle to mirage “A great deal of intelligence can be invested in ignorance when the need for illusion is deep.” Saul Bellow. Beraha et al. (2016) must be commended for their randomized trial that did not found any evidence of usefulness for baclofen in alcohol dependence. Their findings will be reinforced by the full publication of the French trial NCT01738282 (partially reported at the Berlin meeting last September, http://isbra-esbra-2016.org/, by the company marketing baclofen) which is awaited (final data collection for primary outcome measure in 2014). The 30% drop-out rate and the questionable analysis of a second trial, NCT01604330 (data bought by this company) did not preclude claiming for success. On the contrary, the signal observed on mortality in this study (7/162 deaths with baclofen vs 3/158 with placebo) as well as the known severity of baclofen poisoning (Pommier et al., 2014) should have added major warnings on the safety of this drug. Therefore, Beraha et al.'s conclusion “Prescribing baclofen widely as it currently happens in France might be premature and should be reconsidered” seems a too shy understatement: First, off-label drug use hinders the development of evidence-based medicine and exposes patients to the unnecessary risk of many adverse events, including mortality, for an all too often uncertain benefit (Braillon and Lexchin, 2016). Second, in 2014 the French drug agency (ANSM) created for baclofen a regulatory framework for controlling off-label drug prescribing, the “Temporary Recommendations for Use” which requires patient monitoring with data collection to ensure safety under the strict supervision while waiting application for a marketing authorization. Only 6000 patients out of an estimated 100,000 receiving the drug off label are registered. Third, in practice, baclofen off-label prescription is too frequently a first line, without previous use of other drugs (eg. acamprosate and naltrexone) and without psychotherapies, the cornerstone of any treatment. Fourth, patients included in clinical trials are not representative of the real life setting, being more compliant and without co-
http://dx.doi.org/10.1016/j.euroneuro.2017.05.003 0924-977X/& 2017 Elsevier B.V. and ECNP. All rights reserved.
morbidities. It is not surprising that the flow of serious adverse effects is sky rocking in the real life setting (Olivier et al., 2016). ANSM must update its Temporary Recommendations for Use but it may not be enough as the whole story seems a severe dissociative disorder. The French Society of Alcohology fails to raise sufficient concerns about the safety issue but rightly questioned the use of high doses (https://www. sfalcoologie.asso.fr/download/SFA-Communique Presse-2016_09_19.pdf). The Fédération Addiction (the cluster of French charities against addiction) is claiming “Baclofen, neither a universal panacea, nor a placebo but a drug useful in the treatment of alcohol addiction” (http:// www.federationaddiction.fr/app/uploads/2016/09/ article-baclofe%CC%80ne-addictions.pdf). Such societies should simply preclude the use of baclofen.
Funding No Funding.
Conflict of interest AB was a late co-investigator for NCT01738282 and did not include patients. He is an expert of several taskforce groups at Agence nationale de sécurité du médicament(ANSM). FN had relationships (travel/accommodations expenses covered/reimbursed) with Servier, BMS, Lundbeck and Janssen. He was invited by Lundbeck as a speaker at a symposium on the neurobiology of alcohol dependence and refused to be paid for. FN is funded by Laura and John Arnold Foundation, Fondation Pierre Deniker and Rennes University Hospital (CORECT: COmité de la Recherche Clinique et Translationnelle) which had no role in the manuscript.
References Beraha, E.M., Salemink, E., Goudriaan, A.E., Bakker, A., de Jong, D., Smits, N., Zwart, J.W., Geest, D.V., Bodewits, P., Schiphof, T., Defourny, H., van Tricht, M., van den Brink, W., Wiers, R.W., 2016. Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: a multicentre, randomised,
692 double-blind controlled trial. Eur. Neuropsychopharmacol. 26, 1950–1959. Braillon, A., Lexchin, J., 2016. Off-label drug use and temporary recommendations for use: rearranging the deckchairs on the Titanic? Health Policy 120, 890–891. Olivier, P.Y., Joyeux-Faure, M., Gentina, T., Launois, S.H., d'Ortho, M.P., Pépin, J.L., Gagnadoux, F., 2016. Severe central sleep apnea associated with chronic baclofen therapy: a case series. Chest 149, e127–e131. Pommier, P., Debaty, G., Bartoli, M., Viglino, D., Carpentier, F., Danel, V., Maxime, M., 2014. Severity of deliberate acute baclofen poisoning: a nonconcurrent cohort study. Basic Clin. Pharmacol. Toxicol. 114, 360–364.
A. Braillon and F. Naudet
Alain Braillon University Hospital, 80000 Amiens, France E-mail address: [email protected]
Florian Naudet METRICS (Meta-research Innovation Center at Stanford), 1070 Arastradero Road, Palo Alto, CA 94304, USA 5 January 2017; accepted 11 May 2017
www.elsevier.com/locate/euroneuro
LETTER TO THE EDITOR
Baclofen and alcohol use disorders: From miracle to mirage “A great deal of intelligence can be invested in ignorance when the need for illusion is deep.” Saul Bellow. Beraha et al. (2016) must be commended for their randomized trial that did not found any evidence of usefulness for baclofen in alcohol dependence. Their findings will be reinforced by the full publication of the French trial NCT01738282 (partially reported at the Berlin meeting last September, http://isbra-esbra-2016.org/, by the company marketing baclofen) which is awaited (final data collection for primary outcome measure in 2014). The 30% drop-out rate and the questionable analysis of a second trial, NCT01604330 (data bought by this company) did not preclude claiming for success. On the contrary, the signal observed on mortality in this study (7/162 deaths with baclofen vs 3/158 with placebo) as well as the known severity of baclofen poisoning (Pommier et al., 2014) should have added major warnings on the safety of this drug. Therefore, Beraha et al.'s conclusion “Prescribing baclofen widely as it currently happens in France might be premature and should be reconsidered” seems a too shy understatement: First, off-label drug use hinders the development of evidence-based medicine and exposes patients to the unnecessary risk of many adverse events, including mortality, for an all too often uncertain benefit (Braillon and Lexchin, 2016). Second, in 2014 the French drug agency (ANSM) created for baclofen a regulatory framework for controlling off-label drug prescribing, the “Temporary Recommendations for Use” which requires patient monitoring with data collection to ensure safety under the strict supervision while waiting application for a marketing authorization. Only 6000 patients out of an estimated 100,000 receiving the drug off label are registered. Third, in practice, baclofen off-label prescription is too frequently a first line, without previous use of other drugs (eg. acamprosate and naltrexone) and without psychotherapies, the cornerstone of any treatment. Fourth, patients included in clinical trials are not representative of the real life setting, being more compliant and without co-
http://dx.doi.org/10.1016/j.euroneuro.2017.05.003 0924-977X/& 2017 Elsevier B.V. and ECNP. All rights reserved.
morbidities. It is not surprising that the flow of serious adverse effects is sky rocking in the real life setting (Olivier et al., 2016). ANSM must update its Temporary Recommendations for Use but it may not be enough as the whole story seems a severe dissociative disorder. The French Society of Alcohology fails to raise sufficient concerns about the safety issue but rightly questioned the use of high doses (https://www. sfalcoologie.asso.fr/download/SFA-Communique Presse-2016_09_19.pdf). The Fédération Addiction (the cluster of French charities against addiction) is claiming “Baclofen, neither a universal panacea, nor a placebo but a drug useful in the treatment of alcohol addiction” (http:// www.federationaddiction.fr/app/uploads/2016/09/ article-baclofe%CC%80ne-addictions.pdf). Such societies should simply preclude the use of baclofen.
Funding No Funding.
Conflict of interest AB was a late co-investigator for NCT01738282 and did not include patients. He is an expert of several taskforce groups at Agence nationale de sécurité du médicament(ANSM). FN had relationships (travel/accommodations expenses covered/reimbursed) with Servier, BMS, Lundbeck and Janssen. He was invited by Lundbeck as a speaker at a symposium on the neurobiology of alcohol dependence and refused to be paid for. FN is funded by Laura and John Arnold Foundation, Fondation Pierre Deniker and Rennes University Hospital (CORECT: COmité de la Recherche Clinique et Translationnelle) which had no role in the manuscript.
References Beraha, E.M., Salemink, E., Goudriaan, A.E., Bakker, A., de Jong, D., Smits, N., Zwart, J.W., Geest, D.V., Bodewits, P., Schiphof, T., Defourny, H., van Tricht, M., van den Brink, W., Wiers, R.W., 2016. Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: a multicentre, randomised,
692 double-blind controlled trial. Eur. Neuropsychopharmacol. 26, 1950–1959. Braillon, A., Lexchin, J., 2016. Off-label drug use and temporary recommendations for use: rearranging the deckchairs on the Titanic? Health Policy 120, 890–891. Olivier, P.Y., Joyeux-Faure, M., Gentina, T., Launois, S.H., d'Ortho, M.P., Pépin, J.L., Gagnadoux, F., 2016. Severe central sleep apnea associated with chronic baclofen therapy: a case series. Chest 149, e127–e131. Pommier, P., Debaty, G., Bartoli, M., Viglino, D., Carpentier, F., Danel, V., Maxime, M., 2014. Severity of deliberate acute baclofen poisoning: a nonconcurrent cohort study. Basic Clin. Pharmacol. Toxicol. 114, 360–364.
A. Braillon and F. Naudet
Alain Braillon University Hospital, 80000 Amiens, France E-mail address: [email protected]
Florian Naudet METRICS (Meta-research Innovation Center at Stanford), 1070 Arastradero Road, Palo Alto, CA 94304, USA 5 January 2017; accepted 11 May 2017