Dépendance à l’alcool : Evolution des stratégies thérapeutiques Henri-Jean Aubin Hôpital Paul Brousse Université Paris-Sud 11 1

Le syndrome de dépendance Perte de contrôle Tolérance Désir persistant Syndrome de sevrage Temps passé à boire Poursuite malgré les problèmes Abandon des activités DSM IV

Les troubles liés à l’alcool : un continuum None Heavy Consumption None Severe Consequences Alcohol dependence Alcohol abuse Problem drinking Risky use Low-risk use Abstinence Unhealthy use Alcohol use disorder Gastfriend et al. J Subst Abuse Treat 2007;33(1):71–80

Risk levels of alcohol consumption (WHO) Total consumption (g/day) Men Women Low risk 1 to 40 1 to 20 Medium risk >40 to 60 >20 to 40 High risk >60 to 100 Very high risk >100 >60 Table adapted from World Health Organization (WHO). International guide for monitoring alcohol consumption and related harm. 2000 WHO=World Health Organization

Traitement de l’alcoolodépendance Les questions à se poser Objectif de consommation ? Réduction Abstinence Syndrome de sevrage ? Risque d’accident de sevrage Traitement pharmacologique Le patient est en danger ? Urgences Programme résidentiel Quelle prévention de la rechute ? Pharmacologique Psychothérapie individuelle Psychothérapie de groupe Groupe d’entraide

Traitement de l’alcoolodépendance Les questions à se poser Objectif de consommation ? Réduction Abstinence Syndrome de sevrage ? Risque d’accident de sevrage Traitement pharmacologique Le patient est en danger ? Urgences Programme résidentiel Quelle prévention de la rechute ? Pharmacologique Psychothérapie individuelle Psychothérapie de groupe Groupe d’entraide

Treatment goal preference among patients UK survey of patients with alcohol problems (n=742)1 Canadian study of patients with chronic alcoholism (n=106)2 Approximately 50% of patients would choose reduction as a treatment goal 1. Heather et al. Alcohol Alcohol 2010;45(2):128–135; 2. Hodgins et al. Addict Behav 1997;22(2):247–255

Treatment programmes for problem drinkers Clinic from: http://cloud.globalgiving.org/pfil/8444/clinic_3D_view_Grid7.jpg Ambrogne. J Subst Abuse Treat 2002;22(1):45–53; Miller & Rollnick. Motivational interviewing: Preparing people for change. Guilford Press, 2002

Treatment programmes for problem drinkers No alcohol from: http://www.lifeworkscommunity.com/components/com_wordpress/wp/wp-content/uploads/2011/04/alcohol-rehab-clinic.jpg Ambrogne. J Subst Abuse Treat 2002;22(1):45–53; Miller & Rollnick. Motivational interviewing: Preparing people for change. Guilford Press, 2002

Treatment programmes for problem drinkers Man gripping bottle: http://www.drugrehabs.info/wp-content/uploads/2011/04/alcohol-abuse-treatment-center-at-work.jpg Ambrogne. J Subst Abuse Treat 2002;22(1):45–53; Miller & Rollnick. Motivational interviewing: Preparing people for change. Guilford Press, 2002

Treatment gap in alcohol dependence Alcohol abuse and dependence have the widest treatment gap among all mental disorders Less than 10% of patients with alcohol abuse and dependence are treated *Treatment gap=difference between number of people needing treatment for mental illness and number of people receiving treatment Kohn et al. Bull World Health Organ 2004;82:858–866

Reasons given for not receiving alcohol treatment in the past year by persons aged 12 who needed treatment and who perceived a need for it: 2004 to 2007 Not ready to stop using Cost/insurance barriers Social stigma Access Did not think needed treatment/ thought could handle without treatment Did not know where to go for treatment Did not have time Treatment would not help Other barriers Percent SAMHSA 2007, National Survey on Drug Use and Health (NSDUH)

Treatment programmes for problem drinkers Ambrogne. J Subst Abuse Treat 2002;22(1):45–53; Miller & Rollnick. Motivational interviewing: Preparing people for change. Guilford Press, 2002

Treatment programmes for problem drinkers Ambrogne. J Subst Abuse Treat 2002;22(1):45–53; Miller & Rollnick. Motivational interviewing: Preparing people for change. Guilford Press, 2002

Treatment goal stability in severe chronic alcoholics 49% 11% Hodgins et al. Addict Behav 1997;22(2):247–255

Patient involvement in treatment goals 12-month follow-up status by actual treatment received The overall level of success achieved during one year was virtually identical, at around 50%, for goals of abstinence and controlled drinking This supports the view that controlled drinking oriented treatment is an acceptable and effective alternative to abstinence-oreinted treatment particularly when it is compatible with the individual’s beliefs and preferences) Allowing patients to set their own treatment goals is more likely to result in a successful outcome Orford & Keddie. Br J Addict 1986;81(4):495–504 16

Qui est au centre ? Thérapeute Centre de soins Théorie Programme Règlement Patient

Traitement de l’alcoolodépendance Les questions à se poser Objectif de consommation ? Réduction Abstinence Syndrome de sevrage ? Risque d’accident de sevrage Traitement pharmacologique Le patient est en danger ? Urgences Programme résidentiel Quelle prévention de la rechute ? Pharmacologique Psychothérapie individuelle Psychothérapie de groupe Groupe d’entraide

Benzodiazépines Quelle benzodiazépine ? Durée ? Voie ? Risques ? Alternatives ?

Vitamine B1 Dose ? Durée ?

Traitement de l’alcoolodépendance Les questions à se poser Objectif de consommation ? Réduction Abstinence Syndrome de sevrage ? Risque d’accident de sevrage Traitement pharmacologique Le patient est en danger ? Urgences Programme résidentiel Quelle prévention de la rechute ? Pharmacologique Psychothérapie individuelle Psychothérapie de groupe Groupe d’entraide

Traitement résidentiel Antécédent d’accident de sevrage Crise grand mal Delirium tremens Détérioration cognitive Environnement social toxique

Traitement de l’alcoolodépendance Les questions à se poser Objectif de consommation ? Réduction Abstinence Syndrome de sevrage ? Risque d’accident de sevrage Traitement pharmacologique Le patient est en danger ? Urgences Programme résidentiel Quelle prévention de la rechute ? Pharmacologique Psychothérapie individuelle Psychothérapie de groupe Groupe d’entraide

Traitement pharmacologique Disulfirame Dissuasion Risque de réaction éthanol-disulfirame Abstinence continue d’un patient sevré Acamprosate Excellente tolérance naltrexone Antagoniste opiacés Prévention du dérapage après la prise d’un premier verre

Campral Maintien de l’abstinence Johnson. Biochemical pharmacology 2008

Naltrexone Prévention de la rechute Nestler Nature Neuroscience 2005

Naltrexone Prévention de la rechute Nestler Nature Neuroscience 2005

Rosner et al. Opioid antagonists for alcohol dependence Rosner et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2010:CD001867. Rosner et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev 2010:CD004332

Rosner et al J Psychopharmacol 2008

Acamprosate Premier verre Rosner et al J Psychopharmacol 2008

Acamprosate Premier verre - 16% Rosner et al J Psychopharmacol 2008

Naltrexone Premier verre Rosner et al J Psychopharmacol 2008

Naltrexone Premier verre - 7% Rosner et al J Psychopharmacol 2008

Acamprosate Rechute après le premier verre Rosner et al J Psychopharmacol 2008

Acamprosate Rechute après le premier verre - 2% Rosner et al J Psychopharmacol 2008

Naltrexone Rechute après le premier verre Rosner et al J Psychopharmacol 2008

Naltrexone Rechute après le premier verre - 12% Rosner et al J Psychopharmacol 2008

Acamprosate Prescription Effets secondaires Contre-indication Aotal 6 cp / j (4 cp/j si < 60 kg) Durée : 1 an Effets secondaires Diarrhée Contre-indication Insuffisance rénale

Naltrexone Prescription Effets secondaires Contre-indications ReVia 1 cp / j le matin (1/2 à 2 cp / j) Durée : 3 mois Effets secondaires Nausées / vomissements, céphalées, insomnie, anxiété, nervosité, douleurs abdominales, douleurs articulaires / musculaires Contre-indications Insuffisance hépatique sévère, prise d’opiacés

Espéral Dissuasion de la reprise d’un verre 40

Gaval-Cruz & Weinshenker Mol Interv 2009

Gaval-Cruz & Weinshenker Mol Interv 2009

Réaction Ethanol-disulfirame Bouffées congestives du visage Nausées / vomissements Sensation de malaise Tachycardie Hypotension Exceptionnellement : Collapsus, mort subite, TDR, angor, IDM, dépression respiratoire, accidents neurologiques

disulfirame Efficacité Problèmes méthodologiques +++ Etudes anciennes = pauvreté méthodologique Résultats équivoques Supériorité de la supervision dans le cadre d’une prise en charge globale

difficultés méthodologiques disulfirame placebo randomisé double aveugle Effet thérapeutique = menace de la réaction aversive Avant premier verre : menace identique dans les deux groupes Après premier verre : rupture de l’aveugle

Meta-analysis of Hedges' g effect-size of all RCTs comparing the efficacy of disulfiram and controls Aubin et al.

Meta-analysis of Hedges' g effect-size comparing the efficacy of disulfiram and controls in blinded versus open-label RCTs Aubin et al.

Meta-analysis of Hedges' g effect-size comparing the efficacy of disulfiram and controls in RCTs with supervision versus no supervision Aubin et al.

Meta-analysis of Hedges' g effect-size comparing the efficacy of disulfiram and controls in RCTs that included alcohol dependent cocaine subjects versus those that did not include cocaine subjects Aubin et al.

Subgroup analysis of Hedges' g effect-size comparing the efficacy of disulfiram and controls by control types Aubin et al.

Nalmefene (Selincro)

Nalmefene is an opioid system modulator with a distinct µ, δ, and k profile In vitro receptor profile Antagonist at µ opioid receptors Antagonist at δ opioid receptors Partial agonist at k opioid receptors Spatially normalized average [11C]carfentanil BP images of two individuals at the level of thalamus before and 50 h after administration of a single dose of 20 mg nalmefene HCl. Equal high potency on µ and k opioid receptors Lower potency on δ opioid receptors

HDD – change from baseline in the 6-month studies ESENSE 1 ESENSE 2 23 HDDs 23 HDDs In ESENSE 1 and ESENSE 2, nalmefene was superior to placebo in reducing the number of HDDs (p <0.05 in both studies) and TAC (p <0.05 in both studies) at Month 6 in the patients with a high or very high DRL at baseline and randomisation. In both studies, the effect of nalmefene was observed already at Month 1 and maintained throughout the treatment period.   The treatment effect was larger in the patients with a high or very high drinking risk level at baseline and randomisation than in the total population. At Month 6, the mean difference to placebo (MMRM) in the number of HDDs and TAC was -3.7 days/month and -18.3g/day, respectively, in ESENSE 1, and -2.7 HDDs/month and -10.3 g/day, respectively, in ESENSE 2. In the patients with a high or very high DRL at baseline and randomisation, in ESENSE 1 and ESENSE 2, the standardised effect sizes (based on MMRM analyses) were 0.37 and 0.27, respectively, for the number of HDDs and 0.46 and 0.25, respectively, for TAC. These effect sizes are at least of the same order of magnitude as those reported for drinking variables for medicinal products approved in the EU for a different indication (maintenance of abstinence) and within the range reported for approved medicinal products in other CNS indications. In ESENSE 1, the mean number of HDDs decreased from 23 to 11 days/month and the mean TAC decreased from 102 to 44g/day in the nalmefene group at Month 6, a reduction of approximately 57% (MMRM). In the placebo group, the mean number of HDDs decreased from 23 to 15 days/month and the mean TAC decreased from 99 to 59g/day at Month 6, a reduction of approximately 40% (MMRM). In ESENSE 2, the mean number of HDDs decreased from 23 to 10 days/month and the mean TAC decreased from 113 to 43g/day in the nalmefene group at Month 6, a reduction of approximately 62% (MMRM). In the placebo group, the mean number of HDDs decreased from 22 to 11 days/month and the mean TAC decreased from 108 to 48g/day at Month 6, a reduction of approximately 55% (MMRM). National Institute for Health and Clinical Excellence (NICE) [Internet]. Alcohol dependence and harmful alcohol use: Appendix 17d – pharmacological interventions forest plots. 2011. Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psych 2012; 200:97-106. 11 HDDs 10 HDDs R R van den Brink W, Aubin HJ, Bladstrom A, Torup L, Gual A, Mann K. Alcohol Alcohol. 2013

TAC – change from baseline in the 6-month studies ESENSE 1 ESENSE 2 102 g/day 113 g/day In ESENSE 1 and ESENSE 2, nalmefene was superior to placebo in reducing the number of HDDs (p <0.05 in both studies) and TAC (p <0.05 in both studies) at Month 6 in the patients with a high or very high DRL at baseline and randomisation. In both studies, the effect of nalmefene was observed already at Month 1 and maintained throughout the treatment period.   The treatment effect was larger in the patients with a high or very high drinking risk level at baseline and randomisation than in the total population. At Month 6, the mean difference to placebo (MMRM) in the number of HDDs and TAC was -3.7 days/month and -18.3g/day, respectively, in ESENSE 1, and -2.7 HDDs/month and -10.3 g/day, respectively, in ESENSE 2. In the patients with a high or very high DRL at baseline and randomisation, in ESENSE 1 and ESENSE 2, the standardised effect sizes (based on MMRM analyses) were 0.37 and 0.27, respectively, for the number of HDDs and 0.46 and 0.25, respectively, for TAC. These effect sizes are at least of the same order of magnitude as those reported for drinking variables for medicinal products approved in the EU for a different indication (maintenance of abstinence) and within the range reported for approved medicinal products in other CNS indications. In ESENSE 1, the mean number of HDDs decreased from 23 to 11 days/month and the mean TAC decreased from 102 to 44g/day in the nalmefene group at Month 6, a reduction of approximately 57% (MMRM). In the placebo group, the mean number of HDDs decreased from 23 to 15 days/month and the mean TAC decreased from 99 to 59g/day at Month 6, a reduction of approximately 40% (MMRM). In ESENSE 2, the mean number of HDDs decreased from 23 to 10 days/month and the mean TAC decreased from 113 to 43g/day in the nalmefene group at Month 6, a reduction of approximately 62% (MMRM). In the placebo group, the mean number of HDDs decreased from 22 to 11 days/month and the mean TAC decreased from 108 to 48g/day at Month 6, a reduction of approximately 55% (MMRM). National Institute for Health and Clinical Excellence (NICE) [Internet]. Alcohol dependence and harmful alcohol use: Appendix 17d – pharmacological interventions forest plots. 2011. Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psych 2012; 200:97-106. 44 g/day 43 g/day R R van den Brink W, Aubin HJ, Bladstrom A, Torup L, Gual A, Mann K. Alcohol Alcohol. 2013

Baclofène GABA-B receptor Baclofen GABA-B

Baclofène 30 mg/j Efficacité sur l’abstinence Aubin et al.

Alcohol-Dependence: The Current French Craze for Baclofen Rolland et al Addiction. 2012

Quelles doses ? Average : 147 mg/d de Beaurepaire Front Psychiatry. 2012;3:103.

Psychothérapie

Psychothérapie

Associations d’entraide