Carbamazepine and Valproate as Adjuncts in the Treatment of Alcohol withdrawal Syndrome

Florian Eyer; Meike Schreckenberg; Daniela Hecht; Krisztina Adorjan; Tibor Schuster; Norbert Felgenhauer; Rudi Pfab; Tim Strubel; Thomas Zilker


Alcohol Alcohol. 2011;46(2):177-184. 

In This Article

Abstract and Introduction


Aims: To compare the clinical course, incidence of withdrawal seizures (WS) or delirium tremens (DT) and side effects during treatment of alcohol withdrawal in patients treated with either carbamazepine (CBZ) or valproate (VPA) as an adjunct to clomethiazole and clonidine therapy.
Methods: Retrospective analysis of charts of two cohorts of inpatients treated during 2000–2009: CBZ 374 patients, VPA 453 patients.
Results: At baseline, those treated with VPA and those treated with CBZ were similar except for a trend to younger age and a higher incidence of previous WS in the CBZ group. The median duration of pharmacological treatment (91 vs. 76 h; P < 0.001) and the length of stay (8 vs. 6 days; P < 0.001) as well as the need for intensive care treatment (7 vs. 2%; P = 0.001) were significantly higher in the CBZ than the VPA group. Additionally, withdrawal-related complications such as WS occurred more often in the CBZ group (9.6 vs. 5.5%; not significant after adjusting for potential confounders); the incidence of DT in the CBZ group was insignificantly higher (6.6 vs. 4.4%; P = 0.52). Admittance with seizures and older age were predictors of WS and DT, respectively. Adverse drug reactions, mainly affecting the central nervous system, were significantly more frequent with CBZ than VPA (7.6 vs. 2%; P < 0.001).
Conclusion: During alcohol withdrawal, VPA may offer some benefits compared with CBZ due to favorable tolerability, possibly less incidence of WS and a shorter duration of pharmacological treatment.


The alcohol withdrawal syndrome (AWS) involves a range of neurotransmitter circuits that are implicated in alcohol tolerance reflecting a homeostatic readjustment of the central nervous system (CNS) (De Witte et al., 2003; Nutt, 1999), involving reduced brain γ-aminobutyric acid (GABA) levels, GABA-receptor sensitivity (Dodd et al., 2000; Gilman et al., 1996) and activation of glutamate systems (Glue and Nutt, 1990; Sanna et al., 2004; Tsai et al., 1995; Tsai and Coyle, 1998). These alterations are believed to be mainly responsible for the occurrence of withdrawal seizures (WS) and/or delirium tremens (DT) and have considerable impact on morbidity and mortality of AWS (Ferguson et al., 1996; Mayo-Smith et al., 2004; Saitz, 1995; Victor, 1966).

Both benzodiazepines (BZD) and clomethiazole (CMZ) have proved to be effective in ameliorating AWS symptoms, preventing seizures and forestalling progression to DT, and therefore, are considered first-line agents in the treatment for AWS (Brewer, 1995; Mayo-Smith, 1997; Schuckit et al., 1995). While effectiveness is supported by extensive literature, their use is limited by their potential for abuse, psychomotor sedation, cognitive impairment and pharmacological interaction with alcohol (Ait-Daoud et al., 2006; Lum et al., 2006). In the light of these limitations, antiepileptic drugs (AEDs) have attracted attention in the past two decades, and lamotrigine, topiramate, gabapentin, pregabalin, vigabatrin, oxcarbazepine, levetiracetam, carbamazepine (CBZ) and valproate (VPA) have emerged as possible alternatives or adjuncts to BZD or CMZ (Ait-Daoud et al., 2006; Bonnet et al., 2009; Croissant et al., 2009; De Sousa, 2010; Krebs et al., 2006; Lum et al., 2006; Malcolm et al., 2001; Muller et al., 2010). CBZ and VPA have the advantage that they have been in widespread clinical use for the treatment of AWS for around three decades (Bastie, 1970; Brune and Busch, 1971) and because their clinical effectiveness in ameliorating AWS has been shown in controlled studies (Lucht et al., 2003; Lum et al., 2006; Malcolm et al., 2001; Reoux et al., 2001). Both of these drugs may be as effective as BZD or CMZ in reducing the severity of AWS (at least in mild-to-moderate forms) and are even more potent regarding their anti-seizure property (Lambie et al., 1980; Stuppaeck et al., 1992; Wilbur and Kulik, 1981).

Treatment of moderate-to-severe AWS in our department has traditionally been performed using a symptom-triggered detoxification protocol (see METHODS section) with the adjunctive use of CBZ to prevent WS, even if the evidence of using AEDs during AWS is inconsistent (Brathen et al., 2005; Minozzi et al., 2010; Polycarpou et al., 2005). However, increasing data from the literature suggested that additional CBZ treatment may be more frequently related to intolerable side effects and may be less effective compared with VPA to prevent WS or progression of AWS to DT (Bayard et al., 2004; Hillbom et al., 1989; Longo et al., 2002; Lum et al., 2006; Malcolm et al., 2001; Reoux et al., 2001). This led us to adapt our established treatment protocol in 2006, replacing CBZ with VPA but using an otherwise unchanged treatment regimen.

The objective of this study was to compare two historical cohorts of inpatients suffering from moderate-to-severe AWS who received either CBZ or VPA in addition to a standardized symptom-triggered therapy. This investigation mainly focuses on the incidence of complications (WS, DT) and acceptability of these drugs as well as some clinical parameters characterizing the course of AWS.


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