ToxCard: Phenobarbital for Alcohol Withdrawal

Authors: Alyssa Thomas, MD (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center); Ann-Jeannette Geib, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: Cynthia Santos, MD (@Cynthia Santos, MD); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

Case:

A 48-year-old male presents to the emergency department by police for loitering around the bus stop. On further questioning, he admits to drinking two 6-packs of beer daily, but his girlfriend kicked him out last night so his last drink was >18hrs ago.  He endorses a history of alcohol withdrawal.

VS: BP: 158/103 HR 110 RR 15 O2 100% on room air T 99.9

On review of the EMR, you see that he was recently discharged a few weeks ago after being admitted to the intensive care unit for alcohol withdrawal refractory to benzodiazepines.

Questions:

What is the pathophysiology of alcohol withdrawal?

How does phenobarbital work to treat alcohol withdrawal?

Can phenobarbital be used as monotherapy for acute alcohol withdrawal?

Background:

Alcohol withdrawal syndrome (AWS) refers to the neurological and autonomic symptoms that occur after chronic alcohol use, which can vary in severity.³ 

Pathophysiology of alcohol withdrawal⁴ 

• Alcohol binds to both the γ-aminobutyric acid (GABA_A) receptor-chloride complex and the N-methyl-d-aspartate (NMDA)-glutamate receptor.⁴
• When alcohol binds to the GABA_A receptor, the result is enhanced inhibition through an agonistic effect, whereas binding to NMDA results in an antagonistic effect blocking excitation.⁴
• Over time, chronic alcohol use causes a change in the GABA receptor complex, which is why more alcohol is needed to achieve the same effect = tolerance. Additionally, there is compensatory upregulation of excitatory NMDA receptors.⁴
• When alcohol is removed, the result is loss of inhibition at the GABA receptor and also an increase in uncontrolled excitation from the NMDA receptor, causing autonomic excitability and psychomotor agitation, a.k.a AWS.⁴

Clinical Presentation of AWS:³ 

Current Management:² 

• Benzodiazepines are often considered the mainstay of treatment.
• Symptom-triggered dosing of benzodiazepines has been shown to be superior to fixed dosing using an alcohol assessment scale (i.e. CIWA-Ar)
• Mild
  • Oral benzodiazepines usually effective
  • Diazepam preferred due to its quicker time to peak when compared to Lorazepam and longer half-life; caution in patients with hepatic disease.

• Moderate
  • IV Diazepam (10-20mg) or IV Lorazepam (2-4mg) boluses, escalating as needed
• Severe
  • More IV Benzodiazepines
  • IV Phenobarbital
  • Propofol

What about phenobarbital for alcohol withdrawal? 

Phenobarbital¹  

• A long-acting sedative hypnotic that works at the GABA_A  receptor.
• Binds to GABAA receptors causing an increase in the duration of time that the cell membrane chloride channel is open resulting in prolonged depolarization and prolonged inactivity.
• Has a long half-life (~80 hours), which can be ideal for treating withdrawal, but does put patients at risk for over-sedation if doses are escalated.
• Toxic effects mimic alcohol intoxication ranging from somnolence and slurred speech to coma and respiratory depression.

Can we use phenobarbital as monotherapy for alcohol withdrawal? 

There were three articles from 2019 that look at phenobarbital as a monotherapy for acute alcohol withdrawal syndrome (Tidwell et al,⁷ Nelson et al,⁵ Nisavic et al⁶). They each had different populations, study designs, and phenobarbital protocols, making it difficult to compare.

Things to consider from the pathophysiology of AWS, mechanism of phenobarbital and the three studies described: 

• Phenobarbital may not be superior to benzodiazepines, but may be an acceptable alternative.
  • Paradoxical agitation and Delirium with BZD
  • AWS resistant to BZDs
• The phenobarbital dosing and assessment of severity of alcohol withdrawal differed so more studies will need to be done with a uniform approach.
• These studies have shown phenobarbital to be safe as a monotherapy. Respiratory depression did not seem to differ when compared to benzodiazepines groups.
• Phenobarbital is best used when benzodiazepines are refractory

How to use phenobarbital for alcohol withdrawal syndrome? 

• The ideal IV loading dose for alcohol withdrawal syndromes is not known, and cannot be made based solely on the current literature, as studies vary widely in their populations, indications, dosing protocols, outcome measures, and comparison groups.
• We believe a reasonable starting point is 260 mg IV over 15 minutes if being used as monotherapy and 130 mg if being used as an adjunct. If being used as monotherapy, the loading dose may be repeated in 6 hours. However, these doses should be titrated to effect and reduced as needed.
• Dosing should be reduced if the patient has significant renal or hepatic impairment, or concomitant use of significant amounts of sedative-hypnotics, including benzodiazepines. 
• One placebo-controlled trial used 10 mg/kg Phenobarbital as initial therapy in the ED, with decreased ICU admission rates and need for lorazepam infusion.  There was no reported difference in adverse events.⁸
• Keep track of cumulative phenobarbital dose as oversedation requiring intubation or resulting in hemodynamic compromise is a very real risk. The maximum daily dose is 20 mg/kg in an adult.⁹
• Phenobarbital should be given in a large vein, as it has tissue irritant effects.
• Patients should receive appropriate cardiovascular and respiratory monitoring, especially when patients are receiving high doses of phenobarbital, or when phenobarbital is being used with benzodiazepines.  Clinicians should be prepared to address airway, respiratory, or cardiovascular depression.
• That said, ethanol withdrawal is a dynamic clinical situation that deserves frequent reassessment and appropriate monitoring.

Summary 

• Alcohol is an agonist to GABA receptors, but antagonist to NMDA receptors.
• Chronic ETOH use results in changing of the GABA receptor
• Abstinence of alcohol results in a loss of inhibition and uncontrolled excitation = AWS
• Benzodiazepines are the current mainstay of treatment
• Phenobarbital acts at the GABA receptor in a different fashion than BZD, it increases flow of chloride ions through the receptor channel independent of GABA.
• Recent studies comparing BZDs to Phenobarbital have mixed protocols and assessments, but thus far phenobarbital does not appear to be inferior to BZDs
• When treating with Phenobarbital,  load with 130-260 mg IV and adjust the dose as needed if the patient has significant renal or hepatic impairment, or concomitant use of significant amounts of sedative-hypnotics, including benzodiazepines

References

1. Barbiturates-Long Acting. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/. Last updated 23 August 2019. Accessed 17 November 2019.
2. Farkas, Josh. The Internet Book of Critical Care: Alcohol Withdrawal. 5 November 2016. https://emcrit.org/ibcc/etoh/. Accessed November 18, 2019.
3. Gold JA, Nelson LS. Ethanol Withdrawal. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank’s Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1163&sectionid=65098404. Accessed November 16, 2019.
4. Hamilton RJ. Withdrawal Principles. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank’s Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1163&sectionid=65090912. Accessed November 18, 2019.
5. Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. The American Journal of Emergency Medicine. 2019;37(4):733-736. doi:10.1016/j.ajem.2019.01.002.
6. 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. doi:10.1016/j.psym.2019.02.002.
7. Tidwell WP, Thomas TL, Pouliot JD, Canonico AE, Webber AJ. Treatment of Alcohol Withdrawal Syndrome: Phenobarbital vs CIWA-Ar Protocol. American Journal of Critical Care. 2018;27(6):454-460. doi:10.4037/ajcc2018745.
8. [Rosenson J, Clements C, Simon B, Vieaux J, Graffman S, Vahidnia J, et al. Phenobarbi-
   tal for acute alcohol withdrawal: a prospective randomized double-blind placebo- controlled study. J Emerg Med 2013;44:592–8.]
9. FDA Prescribing information; WEST-WARD PHARMACEUTICALS, Eatontown, NJ 07724 USA; Revised June 2011. 462-353-01 https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display; Accessed 07/26/2020.