Phenobarbital vs Diazepam for Alcohol Withdrawal: Similar Outcomes in Emulated Trial

Starting phenobarbital on the day of hospital admission for alcohol withdrawal syndrome (AWS) was not associated with differences in hospital length of stay or invasive mechanical ventilation use compared with diazepam, according to a comparative effectiveness study published in JAMA Internal Medicine.

The investigators noted that phenobarbital use for AWS is increasing, but its effectiveness and safety have largely been compared with lorazepam rather than with more pharmacokinetically similar long-acting, self-tapering benzodiazepines such as diazepam. The study aimed to emulate a clinical trial comparing patients randomized to phenobarbital vs diazepam.

Using the Premier Healthcare Database (October 2022 to August 2024), representing 754 US acute care hospitals, the investigators included adult inpatients with a primary diagnosis of AWS present on admission who started either drug on the day of admission. Of 24,643 patients (median age, 45 years; 75.1% male), 11,919 (48.4%) received phenobarbital and 12,724 (51.6%) received diazepam. Marginal mean length of stay, the primary effectiveness outcome, was 4.1 days with phenobarbital vs 4.3 days with diazepam (mean difference, −0.21 days; 95% CI, −0.42 to 0.00). Invasive mechanical ventilation, the primary safety outcome, occurred in 3.1% vs 2.7% of patients (risk difference, 0.4%; 95% CI, −0.7% to 1.4%).

Secondary outcomes, which assessed treatment escalation, complications of severe AWS, and resource utilization, also did not differ, except for self-directed discharge. Self-directed discharge was more frequent among patients started on diazepam (9.5% with phenobarbital vs 12.6% with diazepam; risk difference, −3.1%; 95% CI, −4.9% to −1.3%). The investigators used targeted maximum likelihood estimation with ensemble machine learning to estimate differences between groups.

The authors wrote that the results "may suggest near therapeutic equivalence" between phenobarbital and long-acting benzodiazepines and support the need for comparative clinical trials.

Source: Bradley T, Feeney M, Law AC, et al. Comparative effectiveness of phenobarbital vs diazepam for alcohol withdrawal syndrome. JAMA Intern Med. Published online October 12, 2026. doi:10.1001/jamainternmed.2026.4939