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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.

Pharmacology

Dose
Prior to benzodiazepines
-
5-10 mg/kg over 30 minutes
o 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 patients that are hypotensive and received large
doses of benzodiazepines
Compatibility Compatible with NS, D5W, and LR
evidence-based medicine
Other pearls found at:
-
Pharmacyfriday.com

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 experienced
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 BZD group
In BZD→PB crossover pts, PB led to
rapid improvement of BZD 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 ↓
BZD 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
-
BZD= Benzodiazepines, DZP= diazepam, ED= emergency department; ICU=Intensive care unit; LOS=length of stay; LZP=lorazepam; PB=

Conclusions

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