Abstract
We would like to thank Deveau and colleagues 1 for their article exploring the use of phenobarbital compared with benzodiazepines for the management of alcohol withdrawal syndrome (AWS) in patients with primary neurologic injury. Authors found that phenobarbital did not increase the risk of oversedation when compared with benzodiazepines, suggesting it is a viable option for treatment in this patient population. Their study presents an important and novel perspective on managing AWS in a complex patient population. However, the differences between treatment groups, along with the distinct pharmacokinetic and pharmacodynamic properties of phenobarbital, are critical factors that may influence both the efficacy and safety outcomes observed in this study and must be carefully considered when interpreting its findings.
First, the article’s title implies a comprehensive assessment of safety; however, the reported outcomes focus solely on the incidence of oversedation. While this is an important consideration in managing AWS, other critical safety endpoints, such as bradycardia, hypotension, or respiratory depression, are well-documented adverse effects of phenobarbital 2 and are notably absent. In particular, the risk of respiratory depression may be heightened by concomitant opioid use, and 41% of patients in the phenobarbital group received intravenous opioids for sedation compared with 11% in the benzodiazepine group. These interactions deserve careful attention in any safety comparison.
In a population with primary neurologic injury, electroencephalogram (EEG) monitoring is critical to detect subclinical seizures, assess nonconvulsive status epilepticus, and monitor overall brain function to guide treatment decisions and prognostication. Yet, phenobarbital has been shown to influence EEG readings by reducing the amplitude of spikes, 3 potentially masking the presence of AWS-related seizures. With a prolonged half-life averaging ~79 hours, and even longer in patients with hepatic impairment such as cirrhosis, 4 the impact of phenobarbital on both EEG interpretation and clinical status may extend well beyond the initial dosing window. As a result, the effects of phenobarbital must be carefully considered when interpreting EEG results and evaluating neurological recovery in this population.
It is unclear whether patients in the phenobarbital group received benzodiazepines prior to or concomitantly with phenobarbital initiation. Phenobarbital and benzodiazepines have synergistic effects via their action on GABA-A receptors; benzodiazepines increase the frequency of chloride channel opening, whereas phenobarbital increases the duration. These pharmacodynamic interactions could significantly affect outcomes related to both efficacy and safety. Without clear reporting on benzodiazepine use, it is difficult to isolate the effects of phenobarbital alone, limiting the ability to directly apply the study’s findings to clinical practice.
Comprehensive safety outcomes are important considerations in AWS and we applaud Deveau et al for bringing a component of this complex clinical question to the forefront. We encourage future research to consider a more comprehensive approach to evaluating safety outcomes to draw more definitive conclusions for this complex issue.
