Phenobarbital in Alcohol Withdrawal

Chronic alcohol abuse results in a down-regulation of inhibitory GABA receptors and an up-regulation of excitatory NMDA receptors.  Alcohol withdrawal occurs when ethanol stimulation is removed, resulting in an imbalance of GABA and NMDA activity.  Historically, there has been interest in using pharmacologic therapy, other than ethanol, to prevent or treat alcohol withdrawal and its complications, including delirium tremens and seizures.  While benzodiazepines are currently the mainstay of therapy, adjunctive treatment options may be useful in patients who display symptoms resistant to conventional therapy.

Historically, phenobarbital was a commonly used agent for alcohol withdrawal, but has since been replaced by benzodiazepines as the drug of choice in alcohol withdrawal due to phenobarbital’s narrow therapeutic window and risk for respiratory depression.  As a barbiturate anticonvulsant, phenobarbital works similarly to benzodiazepines by stimulating the GABA receptor, but there is evidence to suggest that phenobarbital may also augment benzodiazepine binding at the GABA receptor and inhibit the excitatory NMDA receptor.  Based on these mechanisms, phenobarbital may be an attractive adjuvant therapeutic option in alcohol withdrawal patients with a poor response or high tolerance to benzodiazepines.

The best evidence supporting phenobarbital as an adjunctive agent was published in a before-and-after study by Gold et al.  In this single-center retrospective study, alcohol withdrawal patients requiring ICU admission were compared before (June 2000-2003) and after (June 2003-2005) a new hospital protocol implementation using escalating doses of diazepam and adjunctive phenobarbital.  Per hospital policy, ICU admission was required in patients with a diazepam requirement of at least 200 mg in 4 hours or an individual dose of more than 40 mg for control of agitation.  The study included a total of 95 patients (54 pre and 41 post-protocol).  Post-protocol, patients received nearly double the amount of diazepam in the first 24 hours, triple the amount per hospitalization, and significantly more patients received adjunctive phenobarbital (58% vs. 17%, p<0.001).  Analysis demonstrated a significance decrease in mechanical ventilation in the post-protocol group (21.9% vs. 47.3%, p=0.008), however, this benefit did not translate to a shorter ICU length of stay or fewer nosocomial infections.  Due to the design of the study, it is unclear whether more aggressive diazepam dosing or phenobarbital as an adjunctive therapy reduced the need for intubation.

While the Gold study demonstrates exciting results, its retrospective design, small sample size, and other potential confounders limit widespread application of phenobarbital as an adjunctive agent.  As described in a case report by Hayner et al, phenobarbital may also be useful in reducing total benzodiazepine requirements in patients displaying propylene glycol toxicity from continuous lorazepam infusions.

There is no standard dosing for phenobarbital for alcohol withdrawal, although most evidence suggests using escalating doses of 65 mg, 130 mg, or 260 mg bolus doses every 15 minutes for severe agitation.  For maintenance therapy, a similar maintenance dose (65 to 130 mg) given 3-4 times daily may be considered.  Note that serum drug levels can be drawn (typical range for seizure prevention 15-40 mcg/mL), although there is not a specific therapeutic goal in alcohol withdrawal.  Patients receiving phenobarbital should be monitored for respiratory depression, which may be more common at higher doses than with benzodiazepines.  Finally, it is important to note that phenobarbital is a potent inducer of many hepatic CYP isoenzymes, which may result in subtherapeutic drug concentrations of some hepatically metabolized medications.

Additional Reading:

Gold JA, Rimal B, Nolan A, et al. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007;35(3):724-30. PMID 17255852

Hayner CE, Wuestefeld NL, Bolton PJ. Phenobarbital treatment in a patient with resistant alcohol withdrawal syndrome. Pharmacotherapy. 2009;29(7):875-8. PMID 19558262

Thanks to Sean Kane, PharmD for this post.