Phenobarbital monotherapy vs benzodiazepines for alcohol withdrawal syndrome: a multicenter propensity-matched comparative effectiveness study

Alcohol withdrawal syndrome (AWS) is a common and potentially severe condition among hospitalized patients, with complications such as seizures and delirium tremens contributing to significant morbidity and healthcare utilization. Although benzodiazepines remain the recommended first-line therapy, increasing interest has emerged in phenobarbital as an alternative pharmacologic strategy. However, large comparative studies evaluating phenobarbital monotherapy relative to benzodiazepines remain limited. Using the TriNetX Global Collaborative Network, we identified hospitalized adults with AWS treated with phenobarbital monotherapy or benzodiazepines. Patients receiving phenobarbital were required to have no concurrent benzodiazepine exposure. Clinical outcomes were compared after 1:1 propensity score matching for demographic characteristics, comorbid conditions, psychiatric and substance use disorders, medication exposures, and laboratory values. Effect estimates were reported as relative risks (RRs) with 95% confidence intervals. After propensity score matching, 4712 patients were included in each cohort. Admission to a critical care setting was significantly higher among patients treated with phenobarbital (RR 1.85, 95% CI 1.66–2.06; p < 0.001). There were no significant differences in mechanical ventilation (RR 0.82, 95% CI 0.66–1.03; p = 0.08), vasopressor use (RR 0.83, 95% CI 0.47–1.46; p = 0.46), aspiration pneumonitis (RR 0.73, 95% CI 0.51–1.04; p = 0.075), or in-hospital mortality (RR 0.74, 95% CI 0.53–1.05; p = 0.092) among both groups. Phenobarbital use was associated with significantly lower risks of seizures (RR 0.70, 95% CI 0.58–0.85; p < 0.001) and delirium tremens (RR 0.52, 95% CI 0.41–0.65; p < 0.001), as well as a lower risk of escalation to additional sedative therapy (RR 0.89, 95% CI 0.84–0.94; p < 0.001).Phenobarbital monotherapy was associated with significantly lower risks of seizures, delirium tremens, and escalation to additional sedative therapy compared with benzodiazepines. Despite a higher risk of critical care utilization, there were no significant differences in mechanical ventilation, vasopressor use, aspiration pneumonitis, or in-hospital mortality. These findings support phenobarbital as a viable alternative treatment strategy for hospitalized patients with alcohol withdrawal syndrome.