Should chlordiazepoxide and diazepam be avoided when treating alcohol withdrawal syndrome in patients with hepatic insufficiency?

Introduction: Chlordiazepoxide and diazepam are first-line treatments for patients with alcohol withdrawal. However, their use is discouraged in hepatic insufficiency due to concerns that impaired metabolism may prolong their half-lives and those of their active metabolites, increasing the risk of prolonged sedation to an unacceptable level.

The activity of chlordiazepoxide and its metabolites: Findings presented here suggest that chlordiazepoxide has minimal sedative activity-its effect is primarily dependent on its metabolites. Chlordiazepoxide metabolism occurs through hepatic oxidation, so its biotransformation to its metabolites can be markedly delayed in patients with hepatic insufficiency. Because unmetabolized chlordiazepoxide has little activity, this delay may lead to the administration of a considerable cumulative dose before a therapeutic response occurs. This could result in the accumulation of a substantial reservoir of unmetabolized chlordiazepoxide ("dose-stacking"). This reservoir would undergo slow biotransformation to chlordiazepoxide metabolites, even after dosing is discontinued. The chlordiazepoxide metabolite demoxepam has a markedly longer half-life (14-95 h) than chlordiazepoxide (6.6-28 h), which may be further prolonged by hepatic insufficiency. Therefore, if chlordiazepoxide dose-stacking occurs in patients with hepatic insufficiency, demoxepam may also accumulate. This can result in a delayed, profound, and prolonged sedative effect.

The activity of diazepam and its major metabolite: The major metabolite of diazepam, desmethyldiazepam, is no more sedating than diazepam itself. As a result, the rapid onset sedative effect of diazepam-reaching its peak within 5 min when administered intravenously and within 120 min when administered orally-is unaffected by hepatic insufficiency. This allows accurate titration of diazepam to avoid prolonged sedation, even with compromised liver function.

Discussion: The widely accepted assertion that the increased risk of prolonged sedation when using chlordiazepoxide to treat alcohol withdrawal in patients with hepatic insufficiency is primarily due to the prolonged half-lives of chlordiazepoxide and its metabolites appears incorrect. It primarily results from a delayed onset of action and peak effect, driven by slowed chlordiazepoxide metabolism and the greater activity of its metabolites compared to the parent drug. These factors combine to increase the risk of dose-stacking. Dose-stacking is readily avoided with diazepam use in patients with hepatic insufficiency because its rapid time-to-peak effect is unaffected.

Conclusions: Although it has long been recommended that diazepam be avoided for the treatment of alcohol withdrawal in patients with hepatic insufficiency, the findings presented here suggest that it can be used as long as the dosing interval exceeds the time-to-peak effect and the patient is assessed for sedation before each dose-measures incorporated into front-loading and symptom-triggered treatments. In contrast, chlordiazepoxide may cause prolonged sedation in patients with hepatic insufficiency-even with close monitoring-due to unrecognized dose-stacking.