Are you using phenobarbital instead of benzodiazepines as the first-line monotherapy for patients in alcohol withdrawal in the Emergency Department (ED)? If not, you probably should be. Another old drug for a new indication, right? Well not exactly. Phenobarbital is indeed an older and relatively cheap drug (less than $20 per loading dose) that has gained some press recently for the treatment of acute alcohol withdrawal [1-3].

Why should you consider using phenobarbital as monotherapy rather than benzodiazepines?

Phenobarbital used to be one of the standard treatments for ethanol (EtOH) withdrawal prior to the introduction of benzodiazepines. However, there are key advantages over benzodiazepines.

1. Phenobarbital has a dual mechanism of action, binding both the GABA receptor and glutamate receptors in the CNS [3]. This helps EtOH withdrawal symptoms by up-regulating GABA activity and down-regulating excitatory glutamate activity.
2. Phenobarbital has a predictable metabolization with a long half-life of approximately 3-5 days, which allows the drug to self-taper after the initial loading dose and symptom control in the ED [1, 2]. This contrasts the relatively shorter half-life of many available benzodiazepines, which often require more frequent redosing.

Is phenobarbital safe for the treatment of EtOH withdrawal in the ED?

In short, yes. Several studies have indicated that dosing with phenobarbital (PO or IV) is safe and effective at decreasing the need for escalating doses of benzodiazepines for EtOH withdrawal [1-6]. In comparison to benzodiazepines, it demonstrated:

• Fewer episodes of hypotension and apnea [1-6]
• Decreased hospital and ICU stay duration in admitted patients [1]
• Decreased requirement for ICU level care [1]

Dosing regimens

• Common regimen: 10-15 mg/kg of IDEAL body weight (IBW) IV bolus over 30 minutes and administering 130-260 mg aliquots every 15-30 minutes for persistent symptoms [2]
  • Note that the patient’s IBW may be much lower than the actual body weight.
  • Use the MD Calc calculator for a patient’s IBW
  • Examples based on the average American height:
    • Male: 5’9” –> 71 kg IBW –> phenobarbital 710-1065 mg IV initial bolus
    • Female: 5’4” –> 55 kg IBW –> phenobarbital 550-825 mg IV initial bolus
• Alternative lower dosing regimen: 130-260 mg IV boluses with repeated dosing as needed [3]
• Maximum dose
  • No established maximum, but the absolute upper limit for dosing in epilepsy is 20-30 mg/kg [11]
  • Some sources recommend limiting the dose of phenobarbital in alcohol withdrawal to 15 mg/kg/day [3]
• Adjuncts: Benzodiazepines may be added without decreasing safely [1]

Do patients need phenobarbital dosing adjustments if they have liver dysfunction?

• Phenobarbital undergoes metabolization primarily in the liver, mostly by CYP2C9 [9].
• “Dose adjustment” is recommended by the manufacturer in hepatic dysfunction, but no value is provided [10].
  • Since there is no recommended dosing adjustment in patients with cirrhosis and liver dysfunction, a conservative approach starting with the 130 mg boluses and titrating to the minimum effective dose would likely be the safest approach.
• Clinical pearl: Hepatic encephalopathy is a strong contraindication to phenobarbital [9, 10].
  • Before administering a barbiturate to a cirrhotic patient for EtOH withdrawal, first ensure that hepatic encephalopathy is not the cause of the agitation or altered mental status.
  • Because patients with hepatic encephalopathy experience excess GABA stimulation, they are very sensitive to GABAergic medications (e.g., barbiturates or benzodiazepines).
  • Administration of benzodiazepines or barbiturates to these patients risk inducing a prolonged comatose state.

Is it safe to give phenobarbital to a patient who has already received benzodiazepines?

• The concern with concurrent phenobarbital and benzodiazepine administration is oversedation. There is a paucity of evidence for this question, although preliminary data suggests that it is safe without significant mortality risk [1].
• As a corollary, exercise caution when administering phenobarbital to patients at risk for sedation from any cause, such as hepatic encephalopathy, benzodiazepine abuse, and opioid abuse.
• Suggested approach: If benzodiazepines have already been given, consider using the alternative, more conservative, lower dose regimen protocol (130-260 mg doses) up to 10-15 mg/kg total with close monitoring after every up-titration. Avoid giving benzodiazepines concurrently during the phenobarbital up-titration period to minimize the risk of oversedation and apnea [11].

Which patients treated with phenobarbital require admission?

There is a dearth of evidence about which patients require medical admission in the setting of phenobarbital administration. The American Society of Addiction Medicine has developed a tool to assist providers with disposition planning for patients with alcohol withdrawal syndrome for all-comers (not necessarily those treated with phenobarbital) [2]. Their recommendations are as follows:

• Outpatient management
  • Able to follow return precautions
  • Likely to continue with alcohol use disorder treatment
  • Supportive living environment
• Inpatient management
  • Requires frequent physician and nursing intervention
  • Heavy sedation requirements or active delirium tremens
  • Coexisting medical diagnoses that require inpatient management (severe electrolyte anomalies, infections, pancreatitis, hepatic encephalopathy, etc.)
  • History of severe withdrawals, pregnancy, or concurrent medical condition requiring treatment

Conclusion

Phenobarbital has gained significant popularity for use in EtOH withdrawal in the last few years. Several factors make it ideal for use in EtOH withdrawal, primarily its long half-life allowing for a multi-day, self-tapering effect. The most commonly recommended dosing regimen starts with a 10 mg/IBW kg bolus followed by titration every 30 minutes afterwards. Patients in the ED often can be safely phenobarbital-loaded and discharged, assuming hemodynamic stability, normal alertness, and resolution of withdrawal symptoms. More rigorous studies are needed determine dose thresholds that warrant hospital admission.

References

1. Rosenson J, Clements C, Simon B, et al. Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-blind Placebo-controlled Study. The Journal of Emergency Medicine. 2013;44(3):592-598.e2. doi:10.1016/j.jemermed.2012.07.056. PMID: 22999778
2. Wolf C, Curry A, Nacht J, Simpson SA. Management of Alcohol Withdrawal in the Emergency Department: Current Perspectives. Open Access Emerg Med. 2020;12:53-65. doi:10.2147/OAEM.S235288. PMID: 32256131
3. Long D, Long B, Koyfman A. The Emergency Medicine Management of Severe Alcohol Withdrawal. The American Journal of Emergency Medicine. 2017;35(7):1005-1011. doi:10.1016/j.ajem.2017.02.002. PMID: 28188055
4. Staidle A, Geier C. Phenobarbital and/or Benzodiazepines for Recurrent Alcohol Withdrawal: A Self-Controlled, Retrospective Cohort Study. The American Journal of Emergency Medicine. 2022;54:263-266. doi:10.1016/j.ajem.2022.02.020. PMID: 35219012
5. Lebin JA, Mudan A, Murphy CE, Wang RC, Smollin CG. Return Encounters in Emergency Department Patients Treated with Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal. J Med Toxicol. 2022;18(1):4-10. doi:10.1007/s13181-021-00863-2. PMID: 34697777
6. Hendey GW, Dery R, Barnes R, Snowden B, Mentler P. A Prospective, Randomized, Trial of Phenobarbital Versus Benzodiazepines for Acute Alcohol Withdrawal. The American Journal of Emergency Medicine. 2011;29(4):382-385. doi:10.1016/j.ajem.2009.10.010. PMID: 20825805
7. Hoffman PL, Grant KA, Snell LD, Reinlib L, Iorio K, Tabakoff B. NMDA Receptors: Role in Ethanol Withdrawal Seizures. Annals of the New York Academy of Sciences. 1992;654(1):52-60. doi:10.1111/j.1749-6632.1992.tb25955.x. PMID: 1321581
8. Young GP, Rores C, Murphy C, Dailey RH. Intravenous Phenobarbital for Alcohol Withdrawal and Convulsions. Annals of Emergency Medicine. 1987;16(8):847-850. doi:10.1016/S0196-0644(87)80520-6. PMID: 3619162
9. Patsalos PN, Spencer EP, Berry DJ. Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update. Therapeutic Drug Monitoring. 2018;40(5):526-548. doi:10.1097/FTD.0000000000000546. PMID: 29957667
10. Lewis CB, Adams N. Phenobarbital. In: StatPearls. StatPearls Publishing; 2023. Accessed April 16, 2023.
11. Farkas J. Alcohol withdrawal. EMCrit Project. Published March 29, 2023. Accessed April 18, 2023.