Episode 71. Pushing P! Phenobarbital for Alcohol Withdrawal Syndrome

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

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

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Pharmacology
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
Formulations	IV/IM/PO
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

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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

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References

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

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