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Introduction

  • 1.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.

Key Points

  • Alcohol withdrawal syndrome is common in the ED, with ~5% of cases progressing to delirium tremens.
  • Decreased GABA-A receptor sensitivity can make benzodiazepine monotherapy ineffective, and dose escalation raises morbidity and mortality.
  • Phenobarbital binds GABA at a site distinct from benzodiazepines and inhibits excitatory glutamate receptors, addressing NMDA-mediated activity that benzodiazepines may not control.
  • It can be loaded weight-based (5–10 mg/kg) or given PRN (130–260 mg); its long 80–120 h half-life self-tapers, and it reduces benzodiazepine requirements (Rosenson 2013 RCT lowered ICU admission).

Pharmacology

ParameterDetail
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 glutamate receptors
FormulationsIV/IM/PO
PK/PDOnset: IV ~5 minutes
Duration: 6-12 hours
Half-life: 80-120 hours
Renal Excretion: 21%
Therapeutic Blood levels: 15-40 mcg/mL
Adverse EffectsHypotension, respiratory depression, ataxia, lethargy
Drug Interactions and WarningsWarning with loading doses in patients that are hypotensive and received large doses of benzodiazepines
CompatibilityCompatible with NS, D5W, and LR

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 experienced 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 BZD group
In BZD→PB crossover pts, PB led to rapid improvement of BZD 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 ↓ BZD requirements
Tidwell, 2019Pre-post observational / n=120BZD only CIWA-Protocol
PB Taper ± Benzo PRN		PB ↓ ICU + Hospital LOS
PB ↓ total lorazepam requirements
PB had less patients intubated
Sullivan, 2018Retrospective observational / n=209BZD 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, 2013RCT / n=102PB 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

BZD = Benzodiazepines; DZP = diazepam; ED = emergency department; ICU = Intensive care unit; LOS = length of stay; LZP = lorazepam; PB = Phenobarbital; ↓ = statistically significant decreased; ↑ = statistically significant increased

Conclusions

  • Phenobarbital offers a mechanistic rationale in severe alcohol withdrawal: it binds the GABA receptor at a site distinct from benzodiazepines (prolonging chloride-channel opening) and also inhibits excitatory AMPA glutamate receptors, potentially addressing the NMDA-mediated excitatory activity that benzodiazepines alone may not control.
  • It can be used either before benzodiazepines as a weight-based load (5–10 mg/kg) or after benzodiazepines as PRN dosing (130–260 mg), and its long 80–120 hour half-life allows the drug to self-taper without a separate weaning regimen.
  • Across the reviewed studies, phenobarbital was consistently associated with reduced benzodiazepine (lorazepam) requirements, and in the Rosenson 2013 randomized controlled trial a single phenobarbital load lowered ICU admission and the need for continuous lorazepam infusion.
  • Effects on ICU admission, length of stay, and intubation were mixed across the largely observational evidence, and loading doses warrant caution in hypotensive patients who have already received large benzodiazepine doses given the risks of hypotension and respiratory depression.

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
Tags: 5-10 mg/kg 130-260 mg GABA benzodiazepines

Source PDF

Phenobarbital for EtOH Withdrawal 2.0- pharmacy friday-jlp2. KRW1.pdf