Background: Alcohol withdrawal syndrome (AWS) results from the sudden cessation of heavy alcohol use, causing symptoms such as tremors, anxiety, and agitation. Benzodiazepines remain first-line for alcohol withdrawal management according to American Society of Addition Medicine (ASAM) guidelines. Phenobarbital has a half-life of about 80 to 120 hours which allows for adequate control of withdrawal symptoms, and its self-tapering effect reduces the risk of medication abuse seen with benzodiazepines. The initial dosing of phenobarbital varies across institutions, typically starting at 130 mg or 260 mg, based on recommendations derived from clinical practice and studies such as Hendey et al. However, weight-based dosing strategies (ex. 10 mg/kg) have emerged with aims of achieving therapeutic serum concentrations and optimizing symptom control, as opposed to repeated smaller doses. The purpose of this study was to compare outcomes between patients that received an initial phenobarbital dose higher than 260 mg versus those that got a lower dose of 260 mg or less.
Methods: This IRB approved, retrospective chart review was conducted at a 711-bed academic medical center from 1/1/2020 to 9/26/2025. Adult patients who received phenobarbital were identified through a report from the electronic medical record. Patients were included if they had alcohol withdrawal documented within the chart. Patients were excluded if they were pregnant, incarcerated, had phenobarbital listed as a home medication, had a urine drug screen positive for barbiturates, any history of seizures not related to alcohol withdrawal, or were mechanically ventilated prior to phenobarbital administration. The primary outcome was stable or improved CIWA and/or RASS scores from baseline within the first 24 hours, defined as two consecutive CIWA and/or RASS scores equal to or below baseline. The secondary outcomes were the change in CIWA and/or RASS score after the first dose, improved or stable CIWA and/or RASS scores from 24-48 hours and 48-72 hours, cumulative benzodiazepine requirements, adjunctive medication requirements, hospital and ICU length of stay, and escalation of care. Comparative analyses of the primary and secondary outcomes were conducted using t-tests. Other appropriate statistical tests were utilized as needed.
Results: Of the 395 patients screened, 187 met inclusion criteria and were enrolled in the final analysis. Patients were grouped by initial phenobarbital dose; 118 received low-dose phenobarbital (≤260 mg) and 69 received high-dose phenobarbital (>260 mg). The primary outcome was achieved in 81 (80%) patients in the low-dose group compared with 59 (90%) in the high-dose group (p=0.111). No significant differences were found between the low-dose group and high-dose group for stable or improved CIWA and/or RASS scores at 24-48 hours (87% vs 90%; p=0.53) or 48-72 hours (94% vs 97%; p=0.71). Cumulative benzodiazepine requirements, adjunctive medication requirements, hospital length of stay, ICU length of stay, and escalation of care were similar between groups. Patients in the high-dose group demonstrated statistically significant greater reductions in CIWA scores following the initial dose compared to the low-dose group at 6 hours (mean change: 6.24 vs 0; p=0.005) and 24 hours (mean change: 8.05 vs 2.25; p=0.002).
Conclusions: Based on the results of this study, both low-dose and high-dose phenobarbital appear to have similar outcomes in the management of alcohol withdrawal. This study also found that higher initial phenobarbital doses were associated with more rapid symptom control in the first 24 hours without resulting in any additional complications or safety concerns. Establishing evidence-based protocols could improve standardization of care and optimize outcomes for patients with alcohol withdrawal.
