Phenobarbital for Severe Alcohol Withdrawal Syndrome (Aguilar & Bowen 3/12/2025)

 A recording of this presentation is available HERE. 

My notes:

• 10.9% of US adults have alcohol use disorder (AUD) at some point in their lifetime (!!)
• AUD costs the US $249 billion/year
• 178,000 excess deaths due to AUD in the US 2021
• Compared to opioids, higher rates of alcohol use, misuse, ED visits, and deaths see below)

Alcohol Withdrawal Syndrome (AWS)

• 500,000/year episodes of AWS requiring pharmacological treatment
• 5-20% of people admitted to the hospital have AWS
• highest risk of seizures in first 1-2 days of AWS, DTs 4-6 days with looooooooong tail
• Reminder of difference between hallucinosis vs. DTs (autonomic instability)

Neuropharmacology of Alcohol

Dopamine>> reward>> addiction

GABA agonism during intoxication>> sedation

Chronic use>> GABA downregulation, Glutamate upregulation

Lots of other neurotransmitters involved: opiate R, serotonin R, cannabinoid R, etc

When we take away alcohol (after chronic use), our GABA system is completely depleted, and our glutamate is "going wild"

Phenobarbital is a barbiturate

• GABA agonism, suppresses glutamate
• PO>> onset 60 minutes, IV>> onset 5 minutes
• metabolized in the liver, excreted renally
• 1/2 life ~79 hours (range 53-118 hours)
• this prolonged half life allows for a built in taper
• has a predictable pharmacokinetics at 10mg/kg (deal body weight), though no RCTs that study "ideal drug level" for AWS
• no documented barbiturate resistant alcohol withdrawal

Traditional treatment of AWS is with benzodiazepines. We know benzos can cause paradoxical agitation and delirium. In addition, a lack of endogenous GABA in chronic alcohol use can make benzos less useful.

What does the current  literature say about Phenobarbital vs benzos?

• Retrospective cohort study, 42-bed ICU, 120 participants (2018, Am J of Critical Care)
•  shorter ICU stays (2.4 vs 4.4), shorter hospital stays (4.3 vs 6.9).  lower rate of mechanical ventilation (2% vs 23%), fewer adjunctives including precedex (7% vs 28%)
• RCT with ED pts requiring admission – single dose phenobarb vs symptom-based BZD, 102 participants (2013 Journal of Emergency Medicine)
• decreased ICU admission rates (8% vs 25%), decreased BZD use
• Retrospective cohort over 2 years, 606 participants (2021, Cureus)
• shorter hospital stay (2.8 vs 3.6), lower all-cause 30-day readmission (11%  vs 19%), fewer 30-day ED visits
• 2 different Metanalyses (2021) findings: may shorten hospital LOS, unclear if shortens ICU LOS but does decrease ICU admission, benzo sparing, may result in less intubation

Some suggestion that we should move away from CIWA for scoring AWS. One proposed alternative is RASS scoring, which should be familiar to people who work in ICUs

Proposed Phenobarbital Protocol DRAFT

Notes:

• For HIGH risk patients (CIWA>20 OR CIWA>16 with Risk factors)
• 10-12 mg/kg (IDEAL body weight) loading dose
• Use ideal body weight calculator (MD Calc)
• should happen in monitored setting (ED vs. ICU) only
• For patients who may be at lower risk for AWS, consider lower dose than the loading dose (e.g. 130mg, 260mg IV/IM) q30 minutes-1 hour
• Patients who have already been treated with benzos CAN receive phenobarbital but should be lower dose (due to risks of sedation)

References:

1. SAMHSA Center for Behavioral Health Statistics and Quality. (2022). National Survey on Drug Use and Health (Table 5.9A—Alcohol use disorder in past year: among people aged 12 or older; by age group and demographic characteristics, numbers in thousands, 2021 and 2022, Issue. https://www.samhsa.gov/data/sites/ default/files/ reports/ rpt42728/NSDUHDetailedTabs2022/NSDUHDetailedTabs2022/NSDUHDetTabsSect5pe2022.htm#tab5.9a  

2. Centers for Disease Control and Prevention. (February 29, 2024). Excessive Alcohol Deaths. Retrieved April 1 from https://www.cdc.gov/alcohol/features/excessive-alcohol-deaths.html#:~:text=About%20178%2C000%20people%20die%20from,or%20488%20deaths%20per%20day

3. Fixed-Dose Phenobarbital Versus As-Needed Benzodiazepines for the Management of Alcohol Withdrawal in Acute Care General Internal Medicine https://pubmed.ncbi.nlm.nih.gov/38151248/#:~:text=There%20was%20no%20difference%20in,%25%2C%20P%20%3D%200.03).

4. National Institute on Alcohol Abuse and Alcoholism. (2024). Alcohol-related emergencies and deaths in the United States. Retrieved April 1 from https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states

5. Maldonado, J. R. (2017). Novel Algorithms for the Prophylaxis and Management of Alcohol Withdrawal Syndromes-Beyond Benzodiazepines. Crit Care Clin, 33(3), 559-599. 

6. Tidwell, W. P., Thomas, T. L., Pouliot, J. D., Canonico, A. E., & Webber, A. J. (2018). Treatment of Alcohol Withdrawal Syndrome: Phenobarbital vs CIWA-Ar Protocol. Am J Crit Care, 27(6), 454-460. 

7. Rosenson, J., Clements, C., Simon, B., Vieaux, J., Graffman, S., Vahidnia, F., . . . Alter, H. (2013). Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-blind Placebo-controlled Study. The Journal of Emergency Medicine, 44(3), 592-598.e592. 

8. Hawa, F., Gilbert, L., Gilbert, B., Hereford, V., Hawa, A., Al Hillan, A., . . . Al-Sous, O. (2021). Phenobarbital Versus Lorazepam for Management of Alcohol Withdrawal Syndrome: A Retrospective Cohort Study. Cureus, 13(2), e13282. 

9. Murphy, J. A., Curran, B. M., Gibbons, W. A., & Harnica, H. M. (2021). Adjunctive Phenobarbital for Alcohol Withdrawal Syndrome: A Focused Literature Review. Annals of Pharmacotherapy, 55(12), 1515-1524. 

10. Hammond, D. A., Rowe, J. M., Wong, A., Wiley, T. L., Lee, K. C., & Kane-Gill, S. L. (2017). Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review. Hospital Pharmacy, 52(9), 607-616.