Phenobarbital or diazepam for alcohol withdrawal?

Clinical takeaway: When choosing initial inpatient alcohol withdrawal treatment, weigh patient factors and local protocols, as hospital stay and mechanical ventilation outcomes were similar with phenobarbital and diazepam.

Phenobarbital use for hospitalized patients with alcohol withdrawal is growing, but much of the evidence supporting it comes from comparisons with lorazepam. Diazepam offers a more comparable alternative. Like phenobarbital, it is long acting, with effects that gradually diminish as the drug clears. A large multicenter study found no significant difference in hospital stay or invasive mechanical ventilation between patients initially treated with phenobarbital and those treated with diazepam.

Researchers analyzed data from 24,643 adults admitted primarily for alcohol withdrawal at 754 US hospitals between October 2022 and August 2024. Patients started phenobarbital or diazepam on admission day, including treatment in the emergency department. Those receiving both drugs that day were excluded. The analysis used statistical adjustment to approximate a randomized comparison, accounting for differences in illness severity, comorbidities, and initial treatment. About half of patients in each group subsequently received lorazepam or midazolam, so the comparison reflects initial treatment choice rather than exclusive use of either drug throughout hospitalization.

The results offer little reason to favor phenobarbital over diazepam to shorten hospitalization or reduce the need for mechanical ventilation. After adjustment, hospital stays averaged 4.1 versus 4.3 days, and ventilation rates were 3.1% versus 2.7%, respectively. However, fewer patients initially treated with phenobarbital left before recommended discharge (9.5% versus 12.6% with diazepam), raising the possibility of differences in treatment experience that warrant further investigation.

Mortality, delirium, seizures, ICU transfer, and hospital readmission also did not differ significantly. Patients receiving phenobarbital without other benzodiazepines on admission day had hospital stays about 11 hours shorter than those receiving diazepam alone, but mechanical ventilation rates did not differ.

“For doctors and healthcare systems, these results might mean they do not need to rush to completely replace diazepam protocols with phenobarbital, as both drugs appear to offer nearly similar benefits and risks,” said corresponding author Nicholas Bosch, MD, MSc, assistant professor of medicine at Boston University Chobanian & Avedisian School of Medicine, in a news release.

Source: Bradley T, et al. (2026 Oct 12) JAMA Intern Med. Comparative Effectiveness of Phenobarbital vs Diazepam for Alcohol Withdrawal Syndrome