Alcohol withdrawal syndrome (AWS) is a disease commonly treated in the emergency department, with
~5% of cases leading to delirium tremens.
- In patients with a history of AWS, decreased GABA-A receptor sensitivity to GABA agonists may cause
benzodiazepine (BZD) monotherapy to be ineffective.
- Patients may experience increase in morbidity and mortality due to escalated doses of benzodiazepines.
- There are likely a subset of patients that respond poorly to benzodiazepines, therefore requiring alternative
mechanisms to treat AWS.
- 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.
|Dose||Prior 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 Action||Bind 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/PD||Onset: IV ~5 minutes Duration: 6-12 hours Half-life: 80-120 hours Renal Excretions: 21% Therapeutic Blood levels: 15-40 ug/mL|
|Adverse Effects||Hypotension, respiratory depression, ataxia, lethargy|
|Drug Interactions and warnings||Warning with loading doses in patient that are hypotensive and received large doses of benzodiazepines|
|Compatibility||Compatible with NS, D5W, and LR|
|Overview of Evidence|
|Author, year||Design/ sample size||Intervention & Comparison||Outcome|
|Ibarra, 2019||Retrospective observational/ n=78||Lorazepam 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, 2019||Retrospective observational/ n=562||BZD 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, 2019||Pre-post observational/ n=300||IV 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, 2019||Pre-post observational/ n=120||BZD only CiWA- Protocol PB Taper ± Benzo PRN||PB ↓ ICU+ Hospital LOS PB↓ total lorazepam requirements PB had less patient intubated|
|Sullivan, 2018||Retrospective observational/ n=209||BZD only CIWA- Protocol PB + BZD CIWA Protocol||No 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, 2013||RCT/ n=102||PB 10 mg/kg IV x1 + PRN benzodiazepines Placebo + PRN benzodiazepines||PB had ↓ ICU admission PB had ↓continuous infusion lorazepam PB had ↓ total lorazepam requirements No difference in ICU or hospital LOS|
- Phenobarbital. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved September 28, 2019, from http://www.micromedexsolutions.com/
- Sullivan SM et al. Am J Emerg Med. 2019 Jul;37(7):1313-1316.
- Rosenson J et al. J Emerg Med 2013;44:592–8 [e2].
- Nisavic M et al. Psychosomatics. 2019 Sep – Oct;60(5):458-467.
- Ibarra F Jr et al. Am J Emerg Med. 2019 Jan 30. pii: S0735-6757(19)30075-0
- Nelson AC et al. Am J Emerg Med. 2019 Apr;37(4):733-736.
- Tidwell WP et al. Am J Crit Care. 2018 Nov;27(6):454-460