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Anticonvulsant Drug Pharmacology of Alcohol Withdrawal Seizures
- Update on the Neurobiology of Alcohol Withdrawal Seizures

Up to one third of patients with significant alcohol withdrawal may experience alcohol withdrawal seizures. Although seizures in this setting are usually self-limited, they can be associated with status epilepticus and, therefore, are potentially serious (60). In the United States, benzodiazepines are considered the drugs of choice to treat alcohol withdrawal and to prevent the occurrence of seizures (6162). In Europe, carbamazepine, chlormethiazole, and valproate are often used (6364). Although benzodiazepines are protective in some animal models of alcohol withdrawal seizures (6566), they do not exhibit high potency (Table 1). The relatively modest activity of benzodiazepines is not surprising because alcohol withdrawal is associated with increases in α4 subunit–containing GABAA receptors, which are benzodiazepine insensitive (6768). Nevertheless, clinical experience demonstrates that benzodiazepines do reduce the risk of recurrent seizures in patients with an alcohol withdrawal seizure (62), so that in practice, no complete benzodiazepine resistance occurs. However, GABAA-receptor modulators, other than benzodiazepines, might be superior therapeutic agents. Chlormethiazole is a positive modulator of GABAA receptors, which has high efficacy in enhancing GABAA receptors containing α4 subunits (69) and has been shown to protect transiently against alcohol withdrawal seizures in mice withdrawn from exposure to inhaled ethanol (70). Although chlormethiazole may be a preferred agent from a theoretical point of view, it is not currently registered for sale in the United States.

As shown in Table 1, the sodium channel–blocking antiepileptic drugs carbamazepine and phenytoin are weak or ineffective in rodent models of alcohol withdrawal seizures, which corresponds with their lack of effectiveness in many other types of generalized seizures. In line with results from animal studies, there is little evidence that carbamazepine prevents alcohol withdrawal seizures and delirium in humans, although it may be useful to treat alcohol craving (1). Similarly, phenytoin is not effective in protecting against the occurrence of seizures in withdrawing alcoholics (71,72). Valproate is protective against alcohol withdrawal convulsions in mice (73). The intravenous formulation is gaining acceptance in the clinical management of status epilepticus so that it could potentially be used in prophylaxis against alcohol withdrawal seizures. Increasing interest is expressed in the potential of gabapentin as a treatment for alcohol withdrawal (7478) and of topiramate in alcohol dependence (79). Animal studies confirm that both drugs have protective activity against ethanol withdrawal seizures (8081), and evidence from a preliminary clinical trial suggests that topiramate is effective in preventing seizures in human subjects undergoing withdrawal (82).

TABLE 1. Potencies of Anticonvulsant Substances for Protection in Rodent Alcohol Withdrawal Seizure Models
  ED50 (mg/kg)
Substance Audiogenic seizures (rat) Handling-induced convulsions (mouse)
GABAA-receptor Modulators
Diazepam NE* 20
Lorazepam ∼1
Chlormethiazole ∼100§
Sodium-channel Modulators
Phenytoin 50|| NE
Carbamazepine 150** NE††
Antiepileptic Drugs: Other Antiepileptic Drugs
Gabapentin ∼50 (mouse)‡‡
Valproic acid 300§§
NMDA-receptor Antagonist
Dizocilpine (MK-801) 0.33||||


Adapted from N'Gouemo and Rogawski (9), with permission.

ED50, median effective dose; NE, not effective.

*Little et al. (91);
Crabbe (92);
Becker and Veach (66);
§Green et al. (70);
||Chu (93);
Gessner (94);
**Chu (95);
††Grant et al. (59);
‡‡Watson et al. (80);
§§Goldstein (73);
||||Morrissett et al. (96).

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