SEVRAGE ALCOOLIQUE ET ANTIPSYCHOTIQUES

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1 SEVRAGE ALCOOLIQUE ET ANTIPSYCHOTIQUES Question : Devrait-on éviter les antipsychotiques chez les patients en sevrage alcoolique qui sont agités ou en délirium tremens? AUTEURE : Geneviève Gagnon (MAI 2009) P : patients en sevrage alcoolique I : antipsychotiques C : benzodiazepines O : contrôle des symptômes, convulsions Contexte La question du pico m est venue alors qu un patron optait, dans le cas d un patient en sevrage alcoolique aux prises avec des hallucinations (délirium? hallucinose?), pour l haloperidol plutôt que les benzodiazépines. J ai voulu vérifier s il était acceptable d opter pour un médicament de cette classe, sachant qu avec ceux-ci, qu il existe un risque de réduire le seuil convulsif chez des patients déjà à risque de convulsions. Recherche Dans Cochrane, avec alcohol, alcohol withdrawal, delirium tremens, alcoholism... Je poursuis dans d autres banques de données avec les mêmes termes de recherche. Résultats Cochrane 1. Ntais C, Pakos E, Kyzas P, Ioannidis JPA. Benzodiazepines for alcohol withdrawal. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD Fifty-seven trials, with a total of 4,051 people were included. Despite the considerable number of randomized controlled trials, there was a very large variety of outcomes and of different rating scales and relatively limited quantitative synthesis of data was feasible. Benzodiazepines offered a large benefit against alcohol withdrawal seizures compared to placebo (relative risk [RR] 0.16; 95% confidence interval [CI] 0.04 to 0.69; p = 0.01). Benzodiazepines had similar success rates as other drugs (RR 1.00; 95% CI 0.83 to 1.21) or anticonvulsants in particular (RR 0.88; 95% CI 0.60 to 1.30) and offered a significant benefit for seizure control against nonanticonvulsants (RR 0.23; 95% CI 0.07 to 0.75; p = 0.02), but not against anticonvulsants (RR 1.99; 95% CI 0.46 to 8.65). Changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment were similar with benzodiazepines versus other drugs, although some small studies showed isolated significant differences for other, less commonly, used scales. Data on other comparisons were very limited, thus making quantitative synthesis for various outcomes not very informative.

2 Page 2 Sur les 57 études, les suivantes ont inclus un antipsychotique : Borg 1986 : convulsions 0.11 [ 0.01, 1.90 ] Golbert 1967 succès thérapeutique 0.59 [ 0.25, 1.37 ], «any succes» (inclue les anti-convulsivants ) 0.59 [ 0.25, 1.37 ], delirium 1.04 [ 0.52, 2.09 ], mortalité (inclue les anti-convulsivants) : 0.58 [ 0.03, ] Kaim 1972 : Rien de significatif quand aux convulsions, au délirium, à la mortalité, à l abandon du traitement suite à des effets secondaires. Lepola 1984 : Rien de significatif quand à l efficacité globale du traitement et aux effets secondaires. Lucht 2003 Overall 1973 Palestine 1976 (haloperidol) Pena-Ramos 1977 Pena-Ramos 1977 Globalement, études très hétérogènes, qui montrent que les benzo sont préférables quand un patient convulse, mais les données ne sont pas assez solide pour permettre de conclure qu elles sont préférables à un autre traitement pour le contrôle des autres symprômes. Dare Mayo-Smith M F. Pharmacological management of alcohol withdrawal: a metaanalysis and evidence-based practice guideline. JAMA.1997;278(2): OBJECTIVE: To provide an evidence-based practice guideline on the pharmacological management of alcohol withdrawal. DATA SOURCES: English-language articles published before July 1, 1995, identified through MEDLINE search on "substance withdrawal--ethyl alcohol" and review of references from identified articles. STUDY SELECTION: Articles with original data on human subjects. DATA ABSTRACTION: Structured review to determine study design, sample size, interventions used, and outcomes of withdrawal severity, delirium, seizures, completion of withdrawal, entry into rehabilitation, adverse effects, and costs. Data from prospective controlled trials with methodologically sound end points corresponding to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were abstracted by 2 independent reviewers and underwent meta-analysis.

3 Page 3 DATA SYNTHESIS: Benzodiazepines reduce withdrawal severity, reduce incidence of delirium (-4.9 cases per 100 patients; 95% confidence interval, -9.0 to -0.7; P=.04), and reduce seizures (-7.7 seizures per 100 patients; 95% confidence interval, to -3.5; P=.003). Individualizing therapy with withdrawal scales results in administration of significantly less medication and shorter treatment (P<.001). beta- Blockers, clonidine, and carbamazepine ameliorate withdrawal severity, but evidence is inadequate to determine their effect on delirium and seizures. Phenothiazines ameliorate withdrawal but are less effective than benzodiazepines in reducing delirium (P=.002) or seizures (P<.001). CONCLUSIONS: Benzodiazepines are suitable agents for alcohol withdrawal, with choice among different agents guided by duration of action, rapidity of onset, and cost. Dosage should be individualized, based on withdrawal severity measured by withdrawal scales, comorbid illness, and history of withdrawal seizures. beta- Blockers, clonidine, carbamazepine, and neuroleptics may be used as adjunctive therapy but are not recommended as monotherapy. Résultats : Risk difference with benzodiazepine versus placebo for delirium: -4.9 cases of delirium per 100 patients (95% CI: -9.0, -0.7, P=0.04). Risk difference with benzodiazepine versus placebo for seizures: -7.7 cases of seizures per 100 patients (95% CI: -12.0, -3.5, P<0.001). Risk difference with long-acting as opposed to short-acting benzodiazepines for seizure: -6.7 cases of seizure per 100 patients (95% CI: -13.0, 0.0, P=0.07). Risk difference with phenothiazine versus placebo for delirium: 0.0 cases of delirium per 100 patients (95% CI: -5.8, +6.6, P=0.92). Risk difference with phenothiazine versus cross-tolerant medication for delirium: +6.6 cases of delirium per 100 patients (95% CI: 2.4, 10.8, P=0.002). Risk difference with phenothiazine versus placebo for seizure: +4.6 cases of seizure per 100 patients (95% CI: -2.6, +11.9, P=0.19). Risk difference with phenothiazine versus cross-tolerant medication for seizure: cases of seizure per 100 patients (95% CI: 6.2, 16.6, P<0.001). Beta-blockers, clonidine and carbamazepine ameliorate withdrawal severity, but evidence is inadequate to determine their effect on delirium and seizures. Individualising therapy with withdrawal scales results in the administration of significantly less medication and shorter treatment. On ne parle pas du résultat de la comparaison de l haloperidol avec un placebo ou une benzo, quoiqu on mentionne cet agent dans l abstract.

4 Page 4 2. Franck J. Pharmacotherapy for alcohol withdrawal syndrome. (dans Treating Alcohol and Drug Abuse.) Wiley-VCH Veriag GmbH and Co KGaA, 2003: «The aim of this chapter is to present an overview of published clinical drug trials on withdrawal treatment for the respective groups of agents. Furthermore, recent metaanalyses in the area are summarized to compare the effectiveness of different agents in alleviating the symptoms of alcohol withdrawal and reducing the risk of withdrawal seizures and delirium.» «Eighty-two randomized controlled trials were found on drug treatment of alcohol withdrawal in clinical patient groups, i.e., patients who presented for care in hospitals or other health care facilities. The corresponding number of studies of delirium tremens was 13. Two of the studies fell within both of these categories and are therefore presented twice. Conclusions are presented for three meta-analyses of pharmacotherapy in alcohol withdrawal published since No meta-analyses addressing the treatment of delirium tremens were found.» «Strong evidence from placebo controlled studies shows that benzodiazepines, betareceptor antagonists, calcium antagonists, carbamazepine, and clonidine reduce unspecific withdrawal symptoms more effectively than placebo does. Only the benzodiazepine group has a documented effect as a preventive treatment against withdrawal seizures or delirium tremens. Hence, evidence is lacking to support the recommendation of other drugs as monotherapy in alcohol withdrawal. The studies of nitrous oxide treatment are difficult to interpret because of several methodological problems, but nitrous oxide appears to reduce unspecific withdrawal symptoms. There is insufficient evidence to show that nitrous oxide could prevent the origin of seizures or delirium. Few randomized controlled clinical trials have investigated pharmacological treatment in fully developed delirium tremens. Published studies have consistently small patient databases. The state of knowledge is insufficient. On the basis of proven clinical experience, most textbooks recommend benzodiazepines and chlormethiazole as first-line agents for treating delirium tremens. Chlormethiazole has more potentially serious side effects than benzodiazepines, mainly respiratory depression and increased airway secretion.» Donc peu d études avec des antipsychotiques et des données insuffisantes pour se prononcer en faveur d un tel traitement dans les cas de sevrages alcooliques. 1. Williams D, McBride A J. The drug treatment of alcohol withdrawal symptoms: a systematic review. Alcohol and Alcoholism.1998;33(2): Brièvement : «The quality of methodological design was often poor. Further research using better methods is required to allow comparison of different drugs in the treatment of alcohol withdrawal symptoms. On the evidence available, a longacting benzodiazepine should be the drug of first choice.»

5 Page 5 BestBets 1. Should benzodiazepines always be first choice in Alcohol Withdrawal? In [Adult patients with withdrawal symptoms] is[chlordiazepoxide better than chlormethiazole] at [treating withdrawal symptoms]? Donc, la question est de savoir si les benzo constituent la meilleure option thérapeutique. On a cherché dans Medline, avec plusieurs termes de recherche, mais pas de mots s approchant d un semblant d antipsychotique. On a surtout cherché avec «chlormethiazole» et «chlordiapoxezide» On conclut que «Benzodiazepines or Chlormethiazole can be given but there is more evidence availble to support administering a benzodiazepine.» Donc on ne répond pas vraiment à ma question ici. Trip Database 1. Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, Jara G, Kasser C, Melbourne J. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004 Jul 12;164(13): «NEUROLEPTIC AGENTS No placebo-controlled trials of neuroleptic agents in AWD were identified. The trials reviewed earlier demonstrated that neuroleptic drug therapy is inferior to sedativehypnotic drug use in reducing mortality and duration. Nevertheless, neuroleptic agents, especially haloperidol, are commonly used with sedativehypnotic drugs to calm patients with AWD. However, neuroleptic agents have the potential to cause a variety of serious adverse effects, particularly when used in very high doses, which may be required to control severe agitation. Chlorpromazine, promazine, and other low-potency typical antipsychotic agents have been reported to have the greatest effect on lowering seizure threshold. Chlorpromazine and thioridazine are the most common offenders for causing hypotension, and thioridazine may also prolong the QTc interval, increasing risk for torsade de pointes and sudden death. All neuroleptic agents are thought to have the potential for causing neuroleptic malignant syndrome, and cases have been reported in patients with AWD who have received neuroleptic drugs. No studies were identified describing the use of newer atypical antipsychotic agents, such as risperidone, olanzapine, and quetiapine, for AWD. These agents are at least as efficacious as typical antipsychotic agents for other indications and have a preferable adverse effect profile.»

6 Page 6 2. Delirium Tremens: Treatment & Medication dans E-medecine On ne parle pas de l haloperidol, on note qu une benzo demeure le meilleur choix et qu il faut éviter les phénothiazines. PubMed 1. [No authors listed]. Alcohol withdrawal syndrome: how to predict, prevent, diagnose and treat it. Prescrire Int Feb;16(87): «An oral benzodiazepine is the best-assessed treatment for a single episode of generalised seizures or hallucinations during alcohol withdrawal. (15) In randomised comparative trials benzodiazepines were more effective than neuroleptics in preventing delirium-related mortality.» 2. McKeon A, Frye MA, Delanty M. The alcohol withdrawal syndrome. J Neurol Neurosurg Psychiatry Aug;79(8): Epub 2007 Nov 6. «A practice guideline fromthe American Society of Addiction Medicine has advised against the use of neuroleptic agents as the sole pharmacological agents in the setting of delirium tremens, as they are associated with a longer duration of delirium, higher complication rate and, ultimately, a higher mortality.8 However, neuroleptic agents have a role as a selected adjunct to benzodiazepines when agitation, thought disorder or perceptual disturbances are not sufficiently controlled by benzodiazepines. Although haloperidol is well established in this setting, chlorpromazine is contraindicated as it is epileptogenic» Conclusion et commentaire Le traitement de base d un sevrage alcoolique symptomatique se fonde sur le concept de «cross-tolerance» entre les benzo et l alcool, et les études qui existent sur ce sujet appuient leur utilisation, tant pour les symptômes autonomiques que pour le délirium et l hallucinose. Il y a peu de données sur l utilisation de neuroleptiques dans les sevrages alcooliques, il semble néanmoins sécuritaire d administrer de petites doses de ceux-ci, à l exclusion de la classes des phénothiazines, en traitement d appoint lorsque le patient présente une grande agitation.