Substance Use and Related Disorders
Daniel M. Pearlman, MD
Resident
Memorial Healthcare System
Coral Springs, Florida
Alejandro Rodulfo, MD
Consultation Liaison Psychiatrist
Memorial Healthcare System
Hollywood, Florida
Kyle A. Hultz, PharmD
Emergency Medicine/Critical Care Clinical Specialist
Memorial Regional Hospital
miami, Florida
Omair H. Abbasi, MD, FAPA, FACLP
Program Director
Memorial Healthcare System
Hollywood, Florida
.jpg "Jorge L. Sotelo, FACLP, FAPAP photo")
Jorge L. Sotelo, FACLP, FAPAP
Medical Director
Memorial Healthcare System
Miami, Florida
Background: Alcohol withdrawal syndrome (AWS) is a common and potentially fatal condition. Although benzodiazepines are considered first-line, institution-specific protocols vary and there is considerable debate about whether phenobarbital represents a better alternative/adjunct. This topic has received renewed attention in light of several recent benzodiazepine shortages. Indeed, 4 systematic reviews addressing it were published in 2023 alone. We aimed to clarify the existing evidence base by integrating their findings.
Methods: We searched MEDLINE through March 2024 for RCTs and systematic reviews +/- meta-analysis comparing phenobarbital with benzodiazepines for AWS.
Results: We identified 2 RCTs and 6 systematic reviews (2 with meta-analysis). One RCT comparing phenobarbital (mean509mg, range 260-910mg) vs lorazepam (mean4.2mg, range 2-8mg) in mild/moderate AWS found no difference in CIWA score changes, admission rates, length of stay, or 48-hour post-discharge CIWA scores; post-discharge was phenobarbital + placebo vs lorazepam + chlordiazepoxide (Hendey, 2011). This supports several authors' conclusion that phenobarbital, t1/2=80-120hours), has the advantages of not requiring a post-discharge-controlled-substance prescription (avoiding risks of non-adherence, diversion, overdose when combined with alcohol) and decreases the risk of severe withdrawal emerging post-discharge. The second RCT found that a single intravenous dose of phenobarbital (10 mg/kg) with symptom-triggered-lorazepam decreased ICU admissions rate (8% vs 25%), decreased use of continuous lorazepam infusion (4% vs 31%), and decreased total lorazepam used (26mg vs 49mg) compared to symptom-triggered-lorazepam alone. There were no between-group differences in adverse events, including intubation rate, mechanical restraints, bedside sitter, or seizures (Rosenson, 2013). Systematic reviews concluded that existing data is limited but indicates phenobarbital (especially adjunctive) yields neutral (Pourmand, 2023; Lee, 2023; Umar, 2023; Punia, 2023) or potentially superior (Hammond, 2017) outcomes to benzodiazepines, especially in severe/benzodiazepine-refractory cases (Mo, 2016). Several highlighted chronic alcohol abuse desensitizes and downregulates GABAA receptors to benzodiazepines but not phenobarbital, which binds GABAA receptors at a unique site (directly opening the chloride channel and prolonging this effect vs benzodiazepines while only increase the likelihood the channel opens) and also inhibits glutamatergic excitotoxicity via NMDA/AMPA receptors. Beyond the 2 RCTs, reviews included 3-10 observational studies. Meta-analyses did not yield meaningful data given substantial heterogeneity.
Conclusions: High-quality evidence is limited to 2 RCTs from over a decade ago. Considering these alone or along with the observational studies, the overall evidence nonetheless (1) supports using phenobarbital adjunctively for benzodiazepine-refractory/severe AWS; (2) is insufficient to determine whether phenobarbital or benzodiazepines are superior, and (3) contradicts the widely held belief that phenobarbital administration increases the risk of intubation and ICU admission.
Lee et al. Phenobarbital treatment of alcohol withdrawal in the emergency department: A systematic review and meta-analysis.Acad-Emerg-Med.2023-Nov.
Pourmand et al. Evaluation of phenobarbital based approach in treating patient with alcohol withdrawal syndrome: A systematic review and meta-analysis.Am-J-Emerg-Med.2023-Jul;69:65-75
Hammond et al. Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review.Hosp-Pharm.2017-Oct;52(9):607-616.
Hendey et al. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal.Am-J-Emerg-Med.2011May;29(4):382-5.
Rosenson et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study.J-Emerg-Med.2013;44(3):592-598.e2.
*Additional citations available upon request.
