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ramato era comparado con el placebo, y despus re- visamos la eficacia en los ensayos donde era comparadocon otros frmacos.

Mtodo. Una sntesis cuantitativa de los datos sellev a cabo ponderando por el inverso de la varianza enun modelo de efectos aleatorios.

Resultados. En base a tres ensayos clnicos controla-dos, el topiramato es ms eficaz que el placebo en: re-duccin del porcentaje de los das de consumo elevado(23,2%, intervalo de confianza [IC] del 95%: 15,7 a 34,4),incremento del nmero de das de abstinencia (diferenciamedia: 2,9 das, IC del 95%: 2,5 a 3,3) y descenso del

logaritmo de los niveles de -GT (diferencia media:0,075, IC del 95%: 0,048 a 0,118). Dos ensayos sugirieronque el topiramato es tambin ms eficaz que la naltrex-ona y un estudio abierto refiri mejores resultados parael disulfirn que para el topiramato.

Conclusiones. el topiramato puede ser utilizado parael tratamiento en la dependencia etlica; los efectos ad-

versos tales como las parestesias o el insomnio deben ser tenidos en cuenta cuando se prescribe topiramato. La do-sis ptima precisa investigacin adicional.Palabras clave:Dependencia alcohlica. Topiramato. Metaanlisis. Naltrexona. Disulfirn.

INTRODUCTION

Topiramate is an anticonvulsant known both for its usein the treatment of epilepsy and in the prevention of headaches. Recently, its utility is being tested in other con-ditions such as bulimia nervosa, binging disorders,1 smokingaddiction,2 and alcohol dependence. 3

The neuropharmacological actions of topiramate in-clude facilitation of the neurotransmitter gamma-

aminobutyric (GABA) inhibitory action in its non-benzo-diazepine receptor and the reduction of the glutamateexcitatory action in the alpha-amino-3 hydroxy-5metylisoxazole-4 propionic (AMPA) receptor and the

Introduction. Several controlled clinical trials havestudied the efficacy of topiramate in the treatment of alco-holism. In this paper, we have performed a meta-analysis of those trials in which topiramate was compared with placeboand then we reviewed its efficacy in trials in which it wascompared with other drugs.

Method. A quantitative synthesis of data was per-formed using inverse variance weighting in a random ef-fects model.

Results. Based on three placebo-controlled trials, topi-ramate is more efficacious than placebo in reducing thepercentage of heavy drinking days (23.2%, 95% confidence

interval [CI]: 15.7 to 34.4), increasing the number of days of abstinence (mean difference: 2.9 days, 95% CI: 2.5 to 3.3),and lowering the logarithm of -GT levels (mean difference:0.075 95% CI: 0.048 to 0.118). Two trials suggested thattopiramate is also more efficacious than naltrexone, andone open-label study reported better results for disulfiramthan for topiramate.

Conclusion. Topiramate can be used in alcohol depen-dence. Adverse effects such as paresthesia or insomniashould be taken into account when prescribing topiramate.Its optimal dosage requires further research.Key words:Alcohol dependence. Topiramate. Meta-analysis. Naltrexone. Disulfiram

Actas Esp Psiquiatr 2010;38(1): 8 -12

Topiramato en el tratamiento de ladependencia etlica: un metaanlisis

Introduccin. Algunos ensayos clnicos controladoshan estudiado la eficacia del topiramato para eltratamiento del alcoholismo. En este artculo, primerorealizamos un metaanlisis de los ensayos donde el topi-

Originals

Topiramate in the treatment of alcoholdependence: a meta-analysis

1 Mental Health UnitHospital LaredoCantabria (Spain)

2CIBER Epidemiology and Public HealthBarcelona (Spain)

3Epidemiology and Computational BiologyUniversity of CantabriaSantander (Spain)

Correspondence:Javier LlorcaFacultad de MedicinaAvda. Herrera Oria s/n39011 Santander (Spain)E-mail : llorcaj@unican.es

B. Arbaizar1T. Dierssen-Sotos2,3

I. Gomez-Acebo2,3J. Llorca2,3

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kainate receptors. 4,5 In this way, it seems to reduce themesolimbic cortical activity of dopamine. This would bethe principal mechanism to decrease alcohol consumptionreward effects.6,7

Since 2003, several controlled clinical trials have stud-ied the value of topiramate in the treatment of alco-holism. In this article, we have reviewed these trials andmeasured the efficacy of topiramate in the clinical trialswith placebo.

METHODS

Search strategy

We made a search in the MEDLINE/PubMed databasefor controlled clinical trials on the efficacy of topiramate inthe treatment of alcohol dependence. The last search wasdone on March 30, 2009. The abstracts were reviewed toidentify the controlled clinical trials on the subjects. Thereferences of these articles were also studied to identifystudies not located in the original search.

ARTICLE SELECTION

The studies were included if they were placebo-con-trolled and had focused on the evaluation of topiramatewith single drug therapy in the treatment of alcohol depen-dence. The studies controlled with other drugs were includ-ed in the systematic review, but not in the quantification.Studies aimed at patients with dual pathology and studiesthat re-analyzed previous data were excluded.

Data extraction

Data on the number of patients in the topiramategroup patients and on the control groups, follow-up time,

topiramate dose, days of high alcohol intake, changes inplasma levels of -GT, score on the Obsessive CompulsiveDrinking Scale [OCDS]), number of drinks per day and num-ber of abstinence days, and the principal adverse effects oc-curring during the trials were extracted.

Quantitative analysis

Effect measurements in the meta-analysis were: 1)percentage of days of elevated intake at the end of thefollow-up in the placebo group minus percentage of daysof elevated intake at the end of the follow-up in the top-

iramate group, 2) number of abstinence days in the topi-ramate group minus number of abstinence days in theplacebo group, 3) variations in the levels of -GT. Thechanges in the number of drinks per day were only col-

lected in two studies which is why this data was not ana-lyzed.

The results of the trials selected were combined andweighted by the inverse of the variance in a random effectsmodel (DerSimonian-Laird model). All of the statisticalanalyses were made with the Stata 10/SE program (StataCorporation, College, Station, Tx, USA).

RESULTS

Six articles defined as controlled clinical trials werelocated.3,8-12 One was excluded because it was a laborato-ry study in which the patients were voluntarily exposed toalcohol while taking topiramate. 12 Another study was anopen-label study comparing topiramate with disulfiran 10and one article was an open-label study compared withnaltrexone.11 One of the works compared topiramate withnaltrexone and placebo. 9 Finally, two studies comparedtopiramate with placebo. 3,8 Data were obtained from thestudies that compared topiramate with placebo or otherdrugs. However, the quantitative analysis was only per-formed with the three placebo-controlled studies (twomade by Johnson at al., 3,8 and another by Baltieri at al. 9Excluding the comparison made with naltrexone in thelatter, these studies were double blind. The principal char-acteristics of these studies are shown in table 1. Consider-ing the six articles together, topiramate was administeredto 418 patients, disulfiran to 50 patients, naltrexone to100, and placebo to 322. The topiramate dose rangedfrom 150-300 mg/day, and its follow-up ranged from 12to 38 weeks.

Table 2 collects the results of the review in these sixstudies.

Effect of topiramate on the days of elevatedintake

In the group with topiramate, the days of elevated in-take decreased 23.2% more than in the placebo group (95%confidence interval [CI]: 15.7-34.4; p < 0.001) and therewas no evidence of heterogeneity (Q = 0.75, 2 degrees of freedom p = 0.69). The results of one of the studies 9 alsosuggested that naltrexone had intermediate efficacy be-tween topiramate and the placebo in regards to day of ele-vated intake (table 2).

Effect of topiramate in the abstinence days

Patients with topiramate had 2.9 more days of absti-nence than the placebo group patients (95% CI: 2.5-3.3; p