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Old Drug, New Indication: Phenobarbital for Severe Alcohol Withdrawal Syndrome

By Cameron Mertz

 

CASE PRESENTATION

  • 62 y.o. male with history of opiate use disorder, hepatitis C, and alcohol use disorder with prior withdrawal seizures BIBEMS after a witnessed fall with head strike after a seizure

  • Upon arrival to the hospital ambulance bay, the patient had another tonic-clonic seizure that ceased by time that patient was brought into the ED. 


Physical Exam

BP 177/96 | Pulse 113 | Temp 36.6 ℃ (97.9℉) (temporal) - 38.6 ℃ (101.5℉) (axillary)| SpO2 95% on RA

Hematoma on R forehead. Abrasion to R forehead with some dried blood around nares. C-collar in place with midline trachea and no crepitus. No c/t/l spinal step offs or deformities, difficult to determine tenderness due to patient confusion. GCS 10 (opens eyes spontaneously, no verbal response, localizes to pain). Tremor noted in bilateral hands at rest.

ED Course

  • The patient had a third tonic-clonic seizure after being roomed in the ED, which ceased after about 30 seconds without pharmacotherapy. 

  • The patient was then given 240 mg of phenobarbital and started on a 440 mg IV infusion.

  • The patient was evaluated for other causes of seizure: RVP -, no leukocytosis, UA negative, CT head was negative, CXR negative, CT max face revealed nondisplaced fracture of L mandible (see image)

  • The patient was ultimately admitted to the floor and required no benzodiazepines per the RASS protocol


Clinical Question: In what scenario should barbiturates, namely phenobarbital, be used in treating alcohol withdrawal seizures instead of (or in conjunction with) benzodiazepines?


Summary of Evidence

  • The American Society of Addiction Medicine recommends benzodiazepines (BZDs) as the first-line treatment for alcohol withdrawal seizures due to their efficacy in reducing seizure incidence and severity [1]. However, in recent years, several studies have provided evidence suggesting PB may be just as effective as BZDs with some potential advantages [2]. 

  • PB has a dual MOA, upregulating GABA and suppressing excitatory glutamate signaling. Additionally, PB 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 [3]. In contrast, many BZDs have a relatively short half-life, which requires frequent redosing which can strain ED resources.

  • A 2013 randomized prospective study evaluated patients presenting to an urban emergency department with acute alcohol withdrawal [4]. The patients were randomized to receive either a single dose of intravenous PB (10 mg/kg in 100 mL normal saline) or placebo, in addition to a standardized lorazepam-based alcohol withdrawal protocol.  In comparison with BZDs, patients who received PB had fewer ICU admissions (PB vs. placebo, 8% vs. 25%, [95% confidence interval (CI) 4–32%]) and there were no differences in adverse outcomes such as intubation, further seizures, or need for restraints.  The decision to admit patients to the ICU or to implement continuous lorazepam infusions was based on provider judgment rather than a standardized protocol and may limit the generalizability of the results. Additionally, the institution used a modified CIWA called the AWCA scale, which has not been externally validated and may limit the external generalizability of the findings in institutions using different alcohol withdrawal protocols.

  • A recent retrospective cohort study looked exclusively at patients presenting to the ED with a primary diagnosis of AWS [5]. There were 97 patients who received PB treatment and 112 patients who received BZDs only treatment.  The mean hospital LOS was significantly higher in the non-PB group (4 days) compared to the PB group (3 days) (p = 0.048). Some limitations of this study include its mostly white male patient population and the fact that treatment choices were made at the discretion of the providers, and it is possible that providers were more likely to use PB in patients that they expected to have more serious AWS.  Lastly, patients in the PB group were more likely to have a history of severe AWS and this could have resulted in some selection bias.

Recommendations

  • PB is both a safe and effective alternative to BZD therapy for patients with AWS, particularly those with severe withdrawal symptoms such as seizures. Recommended regimen: 10 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.

  • The Prediction of Alcohol Withdrawal Severity Scale (PAWSS) is a clinical tool that can be used to identify patients most at risk for developing severe AWS and whom would most likely benefit from PB treatment [6].  The development of AWS in patients admitted for traumatic injuries has been reported in around 1% of these patients.  Trauma patients who developed AWS had longer hospital stays, unplanned ICU admissions, and need for ventilation when compared to trauma patients who did not develop AWS [7]. This underscores the need for early assessment for alcohol withdrawal risk factors and potential prophylactic treatment.

  • Drawbacks: There is a theoretical risk of PB induction of hepatic enzymes, influencing co-administered medications but the short course of PB is unlikely to have a clinically relevant effects of the metabolism of these drugs [8]. There is also the risk of oversedation and respiratory depression leading to mechanical ventilation and/or aspiration pneumonia, although the available data indicates that this is rare and even suggests that PB use may decrease the risk for these adverse outcomes when compared to BZDs or hybrid therapy [9].

References

  1. American Society of Addiction Medicine. The ASAM Clinical Practice Guideline on Alcohol Withdrawal Syndrome. Published online January 23, 2023. Accessed August 24, 2024. https://www.asam.org/quality-care/clinical-guidelines/alcohol-withdrawal-management-guideline

  2. Punia K, Scott W, Manuja K, Campbell K, Balodis IM, MacKillop J. SAEM GRACE: Phenobarbital for alcohol withdrawal management in the emergency department: A systematic review of direct evidence. Acad Emerg Med Off J Soc Acad Emerg Med. 2024;31(5):481-492. doi:10.1111/acem.14788

  3. Ebeling-Koning NE, Goodman D, Amaducci AM, et al. Load and go: Assessing safety outcomes of patients discharged from the emergency department after receiving phenobarbital for alcohol withdrawal. J Am Coll Emerg Physicians Open. 2024;5(3):e13178. doi:10.1002/emp2.13178

  4. Rosenson J, Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med. 2013;44(3):592-598.e2. doi:10.1016/j.jemermed.2012.07.056

  5. Sullivan SM, Dewey BN, Jarrell DH, Vadiei N, Patanwala AE. Comparison of phenobarbital-adjunct versus benzodiazepine-only approach for alcohol withdrawal syndrome in the ED. Am J Emerg Med. 2019;37(7):1313-1316. doi:10.1016/j.ajem.2018.10.007

  6. Wood E, Albarqouni L, Tkachuk S, et al. Will This Hospitalized Patient Develop Severe Alcohol Withdrawal Syndrome?: The Rational Clinical Examination Systematic Review. JAMA. 2018;320(8):825-833. doi:10.1001/jama.2018.10574

  7. Ahmed N, Kuo Y. Risk of alcohol withdrawal syndrome in hospitalized trauma patients: A national data analysis. Injury. 2022;53(1):44-48. doi:10.1016/j.injury.2021.08.017

  8. Oks M, Cleven KL, Healy L, et al. The Safety and Utility of Phenobarbital Use for the Treatment of Severe Alcohol Withdrawal Syndrome in the Medical Intensive Care Unit. J Intensive Care Med. 2020;35(9):844-850. doi:10.1177/0885066618783947

  9. Malone D, Costin BN, MacElroy D, Al-Hegelan M, Thompson J, Bronshteyn Y. Phenobarbital versus benzodiazepines in alcohol withdrawal syndrome. Neuropsychopharmacol Rep. 2023;43(4):532-541. doi:10.1002/npr2.12347

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