Title: Comparison of a single dose of phenobarbital combined with CIWA protocol versus CIWA protocol alone for the management of acute alcohol withdrawal syndrome

Author(s): Carmen Bowers, PharmD; Martha Whinery, PharmD; Matthew Gatchel, PharmD

Email:  cbowers1@mercy.com

Introduction: The American Society of Addiction Medicine’s 2020 Clinical Practice Guidelines recommend a symptom-triggered benzodiazepine-based approach, commonly referred to as CIWA protocol, as the standard of care for the treatment of acute alcohol withdrawal syndrome (AAWS). However, CIWA-guided benzodiazepines increase the risk for central nervous system depression. These guidelines also include phenobarbital as an alternative treatment, although it is only recommended when benzodiazepines are contraindicated or as an adjunct therapy. Due to its long half-life, a single dose of phenobarbital could potentially decrease the amount of benzodiazepines required and lower the risk of central nervous system depression. The objective of this study was to compare the efficacy and safety between a single dose of phenobarbital given within 24 hours of emergency department presentation combined with CIWA protocol versus CIWA protocol alone in patients with acute alcohol withdrawal syndrome.

Methods: A retrospective chart review was conducted on adult patients with confirmed or suspected acute alcohol withdrawal syndrome from September 1, 2021 to September 1, 2023. Patients who received CIWA-guided benzodiazepines in addition to a single dose of phenobarbital (Pheno+CIWA; n = 50) were compared to patients who received CIWA-guided benzodiazepines without phenobarbital (CIWA alone; n = 50). The primary outcome was the total amount of benzodiazepines administered during hospital stay per patient. Secondary outcomes included intensive care unit and hospital length of stay, in hospital mortality, dose and route of phenobarbital, average dose of phenobarbital, and requirement for adjunctive sedatives or anxiolytics. Safety outcomes included incidence and time to onset of seizures and delirium tremens, incidence of hypotension with requirement for vasopressors, incidence and method of oxygen supplementation, respiratory rate, and oxygen saturation.

Results: Comparing the CIWA alone group to the Pheno+CIWA group, there was no statistically significant difference in the amount of benzodiazepines administered during hospital stay per patient (p = 0.9477). Additionally, there were no statistically significant differences in intensive care unit length of stay (p = 0.358) or hospital length of stay (p = 0.268). With respect to in hospital mortality, there was no statistically significant difference between the two groups (p = 0.4949). Out of 100 total patients there were two fatalities, both occurring in the CIWA-guided benzodiazepine group. In the phenobarbital group, 66% of patients received 130 mg of phenobarbital with doses ranging from 65 mg to 260 mg. Lastly, there was no statistically significant difference with respect to need for adjunctive sedatives between the two groups (p = 0.2298).

Discussion/Conclusion: Although no statistically significant differences were observed for any primary or secondary outcomes, selection bias, a small population size, and potential underdosing of phenobarbital may have contributed to these findings. Future studies should be conducted to evaluate the efficacy, safety, and optimal dosing of a single dose of phenobarbital in combination with symptom-guided benzodiazepines for the treatment of AAWS.