Benzodiazepines have long been the cornerstone of alcohol withdrawal management. However, phenobarbital is an overlooked treatment despite its safety and efficacy.
Better Than a Benzo: Phenobarbital for Management of Alcohol Withdrawal Syndrome
Claiming the lives of 88,000 individuals each year, alcohol-related death is the third most preventable cause of death in the United States.1
Alcohol use disorder (AUD) has complex downstream effects on the body. It has inhibitory effects on the brain, resulting in the upregulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and inhibition of the excitatory neurotransmitter N-methyl-d-aspartate (NMDA). Stimulation of GABA hyperpolarizes the cell membrane, increasing calcium influx, and ultimately slowing down neurotransmission.2 Inhibition of NMDA occurs by preventing it from binding to glycine thus barring its ability to function in the brain. Over time, tolerance may result after chronic ingestion and the body will try to overcome the neurotransmitter imbalance by increasing expression of NMDA and downregulating GABA. 2 For as long as the individual continues to consume alcohol, the body will maintain this new homeostasis. However, if alcohol consumption is suddenly ceased, for example, due to hospital admission, the balance is no longer sustained and the disproportionate upregulation of NMDA and downregulation of GABA result in alcohol withdrawal syndrome (AWS).
Abrupt alcohol cessation manifests in alcohol withdrawal (AWD). Tremors may begin within 5 hours, peaking at 24-48 hours.3 Autonomic hyperactivity including elevated pulse, heightened blood pressure, increased respiratory rate, diaphoresis, nausea, and vomiting may occur. 2, 3 Severe alcohol withdrawal symptoms occur 12-24 hours after cessation, resulting in hallucinations and seizures. The most severe form of AWD, delirium tremens, may occur 2-3 days after the last drink. 2 Delirium tremens may progress to multiorgan failure if left untreated and carries a 5%-15% mortality rate.4
There is a multitude of treatment options for alcohol withdrawal, but perhaps one medication is more attractive than the rest: Phenobarbital. Unlike benzodiazepines which only bind to GABA receptors and enhance receptor activity to the neurotransmitter, phenobarbital mimics GABA at high doses, activates chloride channels, and suppresses glutaminergic activity. 4 It has a longer duration of action (oral = 10-12 hours) and longer half-life (53-118 hours), making it an ideal therapy when given in the early stages of AWD to prevent severe AWS, including delirium tremens.5 Numerous dosing strategies have been evaluated, including scheduled and as-needed administration. Due to the long half-life, phenobarbital has a self-tapering effect, eliminating the need for a tapering strategy or prescription at hospital discharge.
Review of the Literature
Determining the most appropriate phenobarbital dosing regimen for a patient can be a complex decision. There are advantages to using phenobarbital in both the ICU and ED settings. Here, we summarize key evidence for phenobarbital and highlight which patients are most likely to benefit from therapy.
In 2019, Massachusetts General Hospital published their experience with using a phenobarbital-based regimen (n=143) compared to a benzodiazepine-based regimen (n=419) in patients with AUD and AWS on the general medical floor, based on provider preference. No significant differences were found in the primary outcome (development of alcohol withdrawal-related complications) or secondary safety outcomes (over-sedation). There was a higher rate of delirium in the benzodiazepine-group, but this did not reach statistical significance. The authors concluded that a phenobarbital-based regimen for AWS was associated with comparable efficacy and safety to a benzodiazepine-group regimen. 4
It is important to note the majority of patients did not receive any benzodiazepines prior to initiation of phenobarbital. 4 Patients who have received doses of benzodiazepines may be at increased risk of respiratory compromise; however, this does not preclude them from phenobarbital therapy, and a lower starting dose may be appropriate.
In 2013, a study from Alameda County Medical Center randomized 198 patients to either a single loading dose of IV phenobarbital prior to a standard, benzodiazepine symptom-triggered protocol or placebo. 102 patients were included in the final analysis which showed a statistically significant difference in the primary outcome (ICU admission rate). There were no differences in telemetry admission, floor admission, or median ICU or total hospital length of stay.6
A single dose of IV phenobarbital combined with a symptom triggered lorazepam based alcohol withdrawal protocol may have important implications for patient disposition. Notably, a similar number of patients in either group received study drugs but were discharged from the ED. This may provide an opportunity to administer phenobarbital in the ED with the intent to load and discharge, taking advantage of its unique pharmacokinetic properties. Future studies should evaluate whether a phenobarbital loading dose impacts the need for hospital admission in less severe AWS.
Weight-based loading doses of phenobarbital allow patients to rapidly achieve therapeutic concentrations and subsequent AWS symptom control. Questions often arise regarding which weight to use, especially in obese patients. It is reasonable to use ideal body weight for all patients to avoid the potential for over-sedation. You can always give more, but you can’t take it away.
Loading doses of phenobarbital should be based on a number of factors, ranging from 6-8 mg/kg (medium risk of AWD with severe risk of respiratory compromise) to 12-15 mg/kg (high risk of AWD with minimal risk of respiratory compromise). 4 Routine monitoring of phenobarbital serum levels is likely not needed due to the predictable, linear pharmacokinetics, but may be considered in obese patients.
Phenobarbital administered to AWS patients in the ED setting (10 mg/kg) has been shown to reduce the need for ICU admission.6 EM and critical care specialties should collaborate to develop local, phenobarbital-based AWS protocols with the focus on impacting patient disposition.
- Weight-based loading doses of phenobarbital promote rapid alcohol withdrawal (AWD) symptom control
- Medium risk of AWD with severe risk of respiratory compromise: 6-8mg/kg Phenobarbital loading dose
- High risk of AWD with minimal risk of respiratory compromise: 12-15mg/kg Phenobarbital loading dose
- When in doubt, use 10mg/kg
- Alcohol Facts and Statistics. 18 Feb. 2020
- Schmidt, K. J., Doshi, M. R., Holzhausen, J. M., Natavio, A., Cadiz, M., & Winegardner, J. E. (2016). Treatment of Severe Alcohol Withdrawal. Annals of Pharmacotherapy, 50(5), 389–401.
- Publishing, Harvard Health. Alcohol Withdrawal. Apr. 2019
- Nisavic M, Nejad SH, Isenberg BM, et al. Use of Phenobarbital in Alcohol Withdrawal Management – A Retrospective Comparison Study of Phenobarbital and Benzodiazepines for Acute Alcohol Withdrawal Management in General Medical Patients. Psychosomatics. 2019;60(5):458-467
- Phenobarbital. In: Lexi-drugs online [database on the Internet]. Hudson (OH): Lexicomp, Inc.; 2016 [updated 23 Jun 20; cited 30 Jun 20].
- Rosenson J, Cements C, Simon B, et al. Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-Blind Placebo-Controlled Study. Journal of Emergency Medicine. 2013. 44(3):592-598.