Background

Alcohol abuse is common in the United States with 14.1 million adults estimated to have some degree of alcohol use disorder. Emergency physicians will encounter this quite often, either as the primary presenting problem or as a complicating factor in a patient’s care. Unfortunately, alcohol consumption appears to be increasing, with the World Health Organization projecting ongoing increases through at least 2025. As a result, it is becoming increasingly important that we understand the serious and potentially life-threatening consequences of alcohol withdrawal syndrome (AWS) and the treatment options that exist in order to best manage these patients.

Regular consumption of alcohol results in a downregulation of the inhibitory GABA-receptors and upregulation of the excitatory glutamate receptors. Upon cessation of alcohol consumption, the lack of the depressant effect results in an unregulated state with AWS symptoms ranging from mild to severe. There are a multitude of treatment regimens available for treating AWS, with benzodiazepines as the typical mainstay of therapy. Prior to the abundance of benzodiazepines, barbiturates were heavily utilized. There is a resurgence of interest in utilizing phenobarbital for the treatment of AWS, either as a sole agent or in combination with benzodiazepines.

The following three journal club articles sought to investigate the potential clinical benefits for the use of phenobarbital in the emergency department (ED) for the treatment of AWS.

Articles reviewed

1. Staidle, et al. Phenobarbital and/or benzodiazepines for recurrent alcohol withdrawal: A self-controlled, retrospective cohort study. American Journal of Emergency Medicine. 54 (2022) 263-266.[Pubmed]

2. Nelson, et al. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. American Journal of Emergency Medicine. 37 (2019) 733-736. [Pubmed]

3. Rosenson, et al. Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-Blind Placebo-Controlled Study. The Journal of Emergency Medicine. Volume 44, No. 3, pp 592-598, 2013.[Pubmed]

Additional reading

4. Murphy, et al. Adjunctive Phenobarbital for Alcohol Withdrawal Syndrome: A Focused Literature Review. Annals of Pharmacotherapy. 2021, Vol. 55 (12) 1515-1524.[Pubmed]

STAIDLE ET AL

The authors of this study sought to evaluate treatment strategies for AWS in a patient population with high rates of recurrent ED visits related to alcohol abuse. Adult patients included in this study were grouped into three arms: phenobarbital only, benzodiazepine only, or combination therapy. In order to be included in the study, patients needed to have one previous encounter where they were treated with phenobarbital, followed by a separate encounter with only benzodiazepines. The primary outcome was admission or discharge, and bounce-back to the ED within 48 hours. Secondary outcomes were level of care on admission, ED length of stay, first and highest CIWA score, and adverse events. Limitations include single center retrospective study, lack of treatment protocols resulting in practice variation, and lack of randomization.

All three groups had similar rates or admission to the hospital and return to the ED. This finding would suggest that phenobarbital and benzodiazepines have similar efficacy in treating AWS in patients with frequent encounters for AWS. The authors did find that a significantly higher proportion of patients treated with combination therapy were admitted to the intensive care unit (ICU), as well as had a significantly longer length of stay in the ED, and more bouts of hypotension. Given the lack of a standardized treatment strategy, it is unclear if these findings are related to a synergistic effect of benzodiazepines and phenobarbital, or rather due to patient selection by practitioners.

Bottom Line: Patients with frequent presentations to the ED for treatment of AWS have similar outcomes when treated with benzodiazepines or phenobarbital but have worse outcomes when treated with a combination of the two.

NELSON ET AL

Nelson, et al. evaluated the effectiveness of three distinct AWS treatment protocols in their single-center, high volume urban ED. This study took place over the course of two years where multiple different AWS treatment strategies were developed depending upon drug shortages. Like the Staidle, et al. paper, the authors of this study were able to compare benzodiazepines only, phenobarbital only, and combination, in the treatment of AWS in adults presenting to the ED. The primary outcome was the rate of ICU admission, with the secondary outcomes being the rate of mechanical ventilation, the overall rate of hospitalization, length of hospital/ICU stay, the total dose of drugs, and the number of protocol violations. Limitations include a single-center retrospective study, the use of multiple types of benzodiazepines depending upon drug availability, and convenience sampling.

The primary outcome of ICU admission did not differ among the three treatment groups, but the phenobarbital group did have a higher admission rate, overall. There was no significant difference in rates of intubation, suggesting a similarly safe respiratory profile between phenobarbital and benzodiazepines. This study did find a benzodiazepine-sparing effect with utilizing a loading dose of phenobarbital, which may be clinically favorable. Overall, this study suggests that phenobarbital is both safe and effective in the treatment of AWS in the ED whether utilized as the sole agent or in combination with benzodiazepines.

Bottom Line: ICU admission for AWS did not differ as a result of the medication utilized in the ED, and the safety profile of phenobarbital appears similar to that of benzodiazepines.

ROSENSON ET AL

The authors of this paper investigated the use of a single dose of intravenous phenobarbital in addition to a symptom-guided strategy utilizing lorazepam in the treatment of adult patients presenting with AWS in a single-center urban ED. Unlike the other two studies, this was a prospective, randomized, double-blinded, placebo-controlled study. The primary outcome was initial and subsequent level of hospital care on admission (ICU vs telemetry vs floor). Secondary outcomes included vital signs, initial and maximum alcohol withdrawal clinical assessment score, as well as various other time measurements. Limitations include a single-center study, low percentage of enrollment, lack of a priori sample size, limited patient characteristics, practice variation of individual physicians, and use of an unvalidated withdrawal score.

This study found that a single dose of intravenous phenobarbital significantly decreased the rate of ICU admission, with no difference in admission to telemetry or floor. Additionally, the use of phenobarbital resulted in the decreased use of continuous lorazepam infusions and the total dose of lorazepam administered. There were no significant rates of differences in the other secondary outcomes. This study suggests a benefit to utilizing phenobarbital in the treatment of AWS as it appears to reduce the rate of ICU admissions, although these results have not been replicated in studies to date. These findings continue to support the safety profile of phenobarbital, as well as its benzodiazepine-sparing effects.

Bottom Line: A single loading dose of 10 mg/kg intravenous phenobarbital and a protocol-driven benzodiazepine strategy lowered rates of ICU admission with no significant increase in adverse events.

Emergency department visits for alcohol withdrawal syndrome are common and appear to be increasing.
Multiple treatment strategies exist with heavy practice variation amongst providers and limited data to suggest optimal regimens.
Phenobarbital has a favorable pharmacologic profile for treating alcohol withdrawal and may be especially useful in benzodiazepine-resistant cases.
Phenobarbital appears to be safe, either as a sole agent or in combination with benzodiazepines.