Barbiturates Versus Benzodiazepine for the Treatment of Severe Alcohol Withdrawal Syndrome: A Systematic Review and Meta-Analysis of Clinical Trials

Context: The utility of phenobarbital in the treatment of severe alcohol withdrawal is contentious. Objective: The aim was to conduct a meta-analysis of existing observational and randomized controlled trials investigating the efficacy and safety of phenobarbital versus commonly used benzodiazepine in the setting of severe alcohol withdrawal. Data Sources: A search of PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials published between 1976 and September 2021 was performed using medical subject headings: “severe alcohol withdrawal”, “delirium tremens” (DT), “phenobarbital” (PB), “barbiturate”, “critical care”, “ICU”, “Trial”, “human” and “English”. We selected English-language clinical trials (observational and randomized controlled trials (RCT)) evaluating the efficacy and safety of phenobarbital (PB) compared to benzodiazepine (BZD) for the treatment of severe alcohol withdrawal syndrome (AWS) in the acute care setting. Study Appraisal and synthesis methods: Data extraction and critical appraisal were carried out independently by two authors (EC and YM) using predefined data fields. The outcome variables analyzed included (a) history of DT; (b) initial CIWA-AR score; (c) drug dosages delivered; (d) duration of medical treatment of severe AWS; (e) other adjunct medication use; (f) intensive care unit (ICU) length of stay (LOS); (g) hospital LOS; (h) readmission rate; (i) DT or seizures; (j) other complications including endotracheal intubation and mechanical ventilation. These outcomes were unanimously decided to be important as they influence the practical management of severe AWS within hospitals and institutions. Heterogeneity amongst the outcome variables of these trials was determined by Cochran’s Q statistics and I² index. The meta-analysis was prepared in accordance with PRISMA guidelines. Results: Seven studies consisting of 1 prospective RCT and 6 retrospective trials were identified. Results from all the included studies show similar variables between BZD and PB group: mean age, percentage of patients with previous DT, and median Clinical Institute Withdrawal Assessment for Alcohol Revised (CIWA-AR) scores. There were no statistically significant differences in ICU and hospital LOS when comparing the BZD and PB groups. The prevalence of DT and adjunct medication usage was higher in the BZD group; however, statistically insignificant in the meta-analysis. The pooled prevalence of intubation was similar between the two treatment groups. Lastly, Hawa et al. reported higher alcohol-related re-admission in the BZD group. Conclusions: Based on our findings, the use of PB as the primary treatment, or when used in addition/as adjunct to BZD, offers several advantages in the treatment of severe AWS. These include trend toward improved DT and seizures in severe AWS, shortened ICU and hospital LOS, and less use of adjunct medications. Further RCTs are needed to investigate PB as the primary treatment of AWS that presents with severe features.