Episode 71. Pushing P! Phenobarbital for Alcohol Withdrawal Syndrome


Alcohol withdrawal syndrome (AWS) is a disease commonly treated in the emergency department, with
~5% of cases leading to delirium tremens.

  1. In patients with a history of AWS, decreased GABA-A receptor sensitivity to GABA agonists may cause
    benzodiazepine (BZD) monotherapy to be ineffective.
  2. Patients may experience increase in morbidity and mortality due to escalated doses of benzodiazepines.
  3. There are likely a subset of patients that respond poorly to benzodiazepines, therefore requiring alternative
    mechanisms to treat AWS.
  4. Phenobarbital (PB) has some theoretical benefits over benzodiazepines alone from a mechanistic
    a. Chronic alcohol use leads to down regulation of GABA-A receptors and up-regulation of NMDA
    b. Abrupt withdrawal of alcohol use leads to greater NMDA receptor-mediated excitatory activity,
    which may be inhibited more effectively with phenobarbital rather than benzodiazepines.

DosePrior to benzodiazepines 5-10 mg/kg over 30 minutes Can split up into multiple doses if concerned about respiratory depression   After receiving benzodiazepines •          130-260 mg PRN Q30 minutes to clinical effect(Max ~10-15 mg/kg)
Mechanism of ActionBind to the GABA receptor at a different binding site than BZDs, increasing the time the GABA-mediated chloride channels remain open. •          inhibitor of excitatory AMPA glutamates receptors
PK/PDOnset: IV ~5 minutes Duration:  6-12 hours Half-life:  80-120 hours      Renal Excretions: 21% Therapeutic Blood levels: 15-40 ug/mL           
Adverse EffectsHypotension, respiratory depression, ataxia, lethargy
Drug Interactions and warningsWarning with loading doses in patient that are hypotensive and received large doses of benzodiazepines
CompatibilityCompatible with NS, D5W, and LR  

Overview of Evidence
Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
Ibarra, 2019Retrospective observational/ n=78Lorazepam protocol  only (LZP)   PB x 1 + LZP protocol  (PB+LZP)No difference in daily lorazepam requirements or hospital LOS   PB+LZP group had pts d/c within 72 hrs   No patient in PB group experience intubation or hypotension
Nisavic, 2019Retrospective observational/ n=562BZD only fixed dosing   PB- Based Protocol (IM load + PO taper)No difference in AWS-related seizures , ICU admission, over-sedation, LOS, and hallucinations   Delirium in BZP group   In BZPàPB crossover pts, PB led to rapid improvement of BZP resistant AWS symptoms
Nelson, 2019Pre-post observational/ n=300IV diazepam alone (DZP)   IV LZP + IV PB (LZP + PB)   IV PB alone (PB)No difference in ICU admission, ICU LOS, and need for intubation.   PB associated with ED LOS but BZP requirements
Tidwell, 2019Pre-post observational/ n=120BZD only CiWA- Protocol   PB Taper ± Benzo PRNPB ICU+ Hospital LOS   PBtotal lorazepam requirements   PB had less patient intubated
Sullivan, 2018Retrospective observational/ n=209BZD only CIWA- Protocol   PB + BZD CIWA ProtocolNo difference in ICU admission, intubation, hypotension, ED LOS, CIWA score at ED discharge   PB group had hospital LOS and Max CIWA score at 24 hrs
Rosenson, 2013RCT/ n=102PB 10 mg/kg IV x1 + PRN benzodiazepines   Placebo + PRN benzodiazepinesPB had ICU admission   PB had continuous infusion lorazepam   PB had total lorazepam requirements   No difference in ICU or hospital LOS


  1. Phenobarbital. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved September 28, 2019, from http://www.micromedexsolutions.com/
  2. Sullivan SM et al. Am J Emerg Med. 2019 Jul;37(7):1313-1316.
  3. Rosenson J et al. J Emerg Med 2013;44:592–8 [e2].
  4. Nisavic M et al. Psychosomatics. 2019 Sep – Oct;60(5):458-467.
  5. Ibarra F Jr et al. Am J Emerg Med. 2019 Jan 30. pii: S0735-6757(19)30075-0
  6. Nelson AC et al. Am J Emerg Med. 2019 Apr;37(4):733-736.
  7. Tidwell WP et al. Am J Crit Care. 2018 Nov;27(6):454-460

Related FOAM Posts

ToxCard: Phenobarbital for Alcohol Withdrawal


Jimmy L. Pruitt III, PharmD, BCPS, BCCCP

The Pharm So Hard Podcast is a show focused primarily on emergency medicine and hospital pharmacy related topics. To empower healthcare providers with the knowledge and skills they need to provide evidence-based, safe care for critically ill patients.

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