Barbituates in the Management of Alcohol Withdrawal Syndrome

January 2020


You’re slogging through another morning shift in the Behavioral Health pod. Your
overnight colleague signed you out a rock garden, including a patient with alcohol use
disorder who is”awaiting sobriety.” After seeing a couple of new patients, you head up to
the cafeteria for a leisurely breakfast. After you finish your hash browns and sausage and
grab a cup of Jason Wagner coffee from the 8th floor, you return to the BHP. One of your
sign-out patients is now tremulous, diaphoretic, and agitated, and you ask the nurse to
check a set of vitals. She finds the patient to be tachycardic and hypertensive, and you
diagnose the patient with alcohol withdrawal.

Because TCC is “blowing up” (per the comm center charge nurse), you elect to keep the
patient in the BHP to begin treatment. Throughout the remainder of your shift, you
administer escalating doses of IV lorazepam with minimal improvements in the patient’s
symptoms. Before you know it, it’s 3 PM, and the oncoming team arrives to take sign-out.
As you discuss the alcoholic patient, the oncoming resident asks, “What about
phenobarb?” She pulls up EMCrit on her iPad and starts scrolling through posts to find
Josh Farkas’s “phenobarb-only” protocol. You admit that you haven’t read much about the
use of phenobarbital in alcohol withdrawal, although you have seen a few tweets about it,
and wish the oncoming team best of luck before high-tailing it out the side door.

Later that night, while catching up on charts, you notice that the withdrawal patient is
now in the MICU and intubated on a propofol infusion. Was there anything you could
have done differently to get ahead of his withdrawal symptoms? What’s the deal with
phenobarbital, anyway? You decide to start searching the literature…

PICO Question

Population: Adult patients with signs of alcohol withdrawal syndrome requiring

Intervention: Barbiturates (primarily phenobarbital) given by any route

Comparison: Standard management with benzodiazepines either given as part of a
protocol or at clinician discretion

Outcome: Need for ICU admission, need for hospital admission, need for intubation,
ICU and hospital length of stay, seizure frequency, or other adverse events

Search Strategy
Articles were chosen by members of the toxicology section. A specific search strategy
was not employed.


Article 1: Mo Y, Thomas MC, Karras GE Jr. Barbiturates for the treatment of alcohol
withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016 Apr;
32:101-7. Answer Key

Article 2: Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA.
Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment
protocols. Am J Emerg Med. 2019 Apr;37(4):733-736. Answer Key. 

Article 3: Rosenson J, Clements C, Simon B, Vieaux J, Graffman S, Vahidnia F, Cisse B,
Lam J, Alter H. Phenobarbital for acute alcohol withdrawal: a prospective randomized
double-blind placebo-controlled study. J Emerg Med. 2013 Mar;44(3):592-598. Answer Key.

Article 4: Tidwell WP, Thomas TL, Pouliot JD, Canonico AE, Webber AJ. Treatment of
Alcohol Withdrawal Syndrome: Phenobarbital vs CIWA-Ar Protocol. Am J Crit Care.
2018 Nov;27(6):454-460. Answer Key.

Bottom Line

Benzodiazepines have long been the mainstay of therapy for alcohol withdrawal
syndrome. Unfortunately, this class of drugs has several limitations, including lack of
activity at NMDA receptors, risk of a paradoxical reaction (Tae 2014), a subset of
patients who fail to respond (Hack 2006); lorazepam in particular has been associated
with the development of delirium among ICU patients. Barbiturates (particularly
phenobarbital) have been proposed as alternative and possibly superior agents given that
they lack these limitations and have several additional appealing characteristics
(including predictable pharmacokinetics and a wide therapeutic index). We therefore
sought to evaluate the clinical evidence for and against barbiturate use in the management
of alcohol withdrawal.

Two retrospective, observational studies were reviewed, one conducted in the medical
ICU of a large teaching hospital in Nashville, Tennessee (Tidwell 2018), the other in the
ED of Denver Health Medical Center (Nelson 2013). In the former study, use of a
phenobarbital protocol for management of alcohol withdrawal was associated with a
decrease in mean ICU length of stay of 2 days (95% CI -3.0 to -0.9 days) and decreased
need for mechanical ventilation (relative risk of 0.07, 95% CI 0.01 to 0.53). In the latter
study, phenobarbital had no effect on ICU admission rates (the primary outcome, but use
of phenobarbital alone resulted in significantly higher overall hospital admission rate
(54%) compared with diazepam alone (35%), with a much smaller difference when
compared with those receiving phenobarbital and lorazepam (47%); no difference in
intubation rates of days requiring a ventilator was seen between groups.

Such nonrandomized, essentially before and after data should be interpreted with caution.
Lack of blinding in particular likely had a significant impact on outcomes, as many ED
physicians in the latter study may have been less familiar with using phenobarbital and hence may have been more likely to admit patients receiving it. Additionally, other
confounding interventions could have been instituted during the studies, confounding the
effects on measures outcomes. Unfortunately, only one randomized controlled study was
identified (Rosenson 2013) relevant to our clinical question. This double-blinded, single
center study compared giving a single dose of IV phenobarbital (10 mg/kg) with placebo,
given in the ED, followed by a lorazepam-based alcohol withdrawal protocol. Patients
who received phenobarbital were less likely to be admitted to the ICU (absolute risk
reduction 17%, 95% CI 4% to 32%), with no difference in telemetry or floor admission
rates and no difference in adverse outcomes.

Finally, a systematic review of barbiturates in alcohol withdrawal was identified and
reviewed (Mo 2016). This review identified seven articles with a great deal of clinical
and methodological heterogeneity. Overall, this review suggests that barbiturates are safe
and effective at managing alcohol withdrawal syndrome, but in and of itself does not
demonstrate clear superiority to other strategies.