Phenobarbital for Alcohol Withdrawal

Alcohol withdrawal. We’ve all seen it. The tachycardic, tremulous patient who went cold turkey and now, isn’t feeling so hot. You give benzodiazepine after benzodiazepine, without any clinical improvement. Before you know it, the patient has a seizure, requires intubation for airway protection, is placed on a benzodiazepine drip, and is admitted to the intensive care unit (ICU). Could this have been prevented? Possibly.

With over 15 million Americans meeting criteria for DSM-V alcohol use disorder, alcohol withdrawal (AW) is a common emergency department (ED) presentation.¹ AW ranges from mild to severe and can lead to life threatening delirium tremens (DTs), requiring ICU admission and significant utilization of health care resources and dollars. Lately, there has been discussion in the literature about alternative treatments for AW other than the first-line benzodiazepines. One of these medications, phenobarbital, can be used in the treatment algorithm of most seizure disorders, include those secondary to AW. In this brief overview, we will show you how phenobarbital can be an addition to your toolbox for the treatment of AW, both as monotherapy or in addition to benzodiazepines, and may lead to decreased ICU admissions.

Phenobarbital is a barbiturate that, like benzodiazepines and alcohol, targets gamma-aminobutyric acid (GABA) receptors in the central nervous system. There are many potential advantages of phenobarbital over more commonly used benzodiazepines (such as lorazepam, diazepam, and chlordiazepoxide) in the treatment of AW. One advantage is phenobarbital’s long half-life compared to benzodiazepines; the half-life of phenobarbital is 80-120 hours, compared to lorazepam’s half-life of 14-20 hours, with the duration of sedation being very similar between the two medications (4-10 hours for phenobarbital, 6-8 hours for lorazepam).² Phenobarbital’s long half-life helps treat the withdrawal when adverse outcomes, such as DTs, are most likely, thus helping to prevent seizures and life-threatening DTs.³ Phenobarbital also has a tapering effect as the medication wears off, which limits the need for additional outpatient prescriptions like chlordiazepoxide.³ This means a patient with uncomplicated AW with adequate symptom control after treatment with phenobarbital could potentially be discharged home with no prescriptions. In addition, since these patients do not require a discharge prescription of benzodiazepines to prevent continued withdrawal symptoms, they are protected from the dangers of misuse or overdose of these drugs, especially with concomitant continued alcohol abuse.

Another advantage of phenobarbital over benzodiazepines is the mechanism of action. Both phenobarbital and benzodiazepines work by inhibiting GABA receptors. Phenobarbital has an additional benefit of suppressing the excitatory glutamate receptors.³ In addition, phenobarbital is associated with less delirium and agitation, which can occur with benzodiazepines.⁴ Finally, phenobarbital should be considered in cases of severe AW, which are often refractory to benzodiazepines.³

Phenobarbital has also been shown to be safe in AW.⁵ A loading dose of 10-15mg/kg given over 30 minutes is unlikely to lead to serum levels associated with respiratory depression.^3,4 Phenobarbital has been used for alcohol withdrawal in Europe for decades and has been shown to be safe in people without severe hepatic impairment. A study by Hendey, et al, used phenobarbital in addition to benzodiazepines and did not find any additional adverse events when compared to benzodiazepine use alone.⁶ Phenobarbital, in addition to benzodiazepines, were also found to help reduce need for mechanical ventilation in the ICU setting and lead to shorter lengths of ICU stay in a study by Gold, et al.⁷  Rosenson and colleagues found in 2013 that a loading dose of 10mg/kg of phenobarbital, in addition to a lorazepam protocol, significantly reduced ICU admissions (8 vs 25%), in contrast to when lorazepam was used alone.⁸

Unfortunately, there has yet to be adequately powered randomized controlled trials (RCTs) comparing benzodiazepines to barbiturates in the treatment for AW. There have been several studies showing the safety of phenobarbital, both as monotherapy for AW, or in conjunction with benzodiazepines. Several studies have also shown similar, if not better, clinical outcomes of phenobarbital over convention benzodiazepines, and phenobarbital has not demonstrated an increase in adverse reactions compared to benzodiazepines.

So, how do you use phenobarbital for AW in the ED and admitted patient? Well, there are a couple of approaches. One is to load the patient with phenobarbital over a 30-minute period, with most studies and protocols using a 10mg/kg of ideal body weight loading dose. Loading doses are safe when phenobarbital is used alone, but should be used with caution when the patient has received other sedative medications, such as benzodiazepines, as over-sedation can occur.³ Another approach is to forego the loading dose and give boluses of 130mg IV over 3 minutes for mild symptoms, or 260mg IV over 5 minutes for moderate to severe symptoms. Phenobarbital doses of 130mg can be repeated every 30 minutes as needed and titrated to symptom relief, with a maximum of 1040mg in 24 hours. These doses have been used in European countries, as well as in multiple studies for patients of differing weights, and found to be effective.^5,6 Hendey, et al, found that most patients required three doses of phenobarbital for symptoms control, similar to benzodiazepines.⁶ Phenobarbital can also be given orally or intramuscularly, allowing for administration of this drug to patients who lack IV access. Phenobarbital should be avoided in patients with known allergy to barbiturates, and in those with severe hepatic impairment, as this drug is hepatically cleared. Patients should always be monitored for respiratory depression during the administration of this drug.

In conclusion, phenobarbital has been shown to be beneficial for the treatment of AW, both in the emergency and inpatient settings.^3,5,6,7 It is safe in patients without severe hepatic impairment, has a different mechanism of action and longer half-life than benzodiazepines, and leads to less delirium and agitation. Patients treated with phenobarbital for mild AW symptoms can be safely discharged from the ED without additional prescriptions, and the use of this drug may lead to less ICU admissions and more health care dollars saved overall.⁷ Prospective RCTs and studies with large populations are lacking, but phenobarbital can be another tool to add to your toolbox to fight off the dangerous complications of AW.

References

1. Substance Abuse and Mental Health Services Administration (SAMHSA). 2015 National Survey on Drug Use and Health (NSDUH). Table 5.6A - Substance Use Disorder in Past Year Among Persons Aged 18 or Older, by Demographic Characteristics: Numbers in Thousands, 2014 and 2015.  https://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015.htm#tab5-6a. Accessed April 10, 2018.
2. Charney DS, Mihic SJ, Harris RA. Hypnotics and Sedatives. In: Brunton L, Lazo J, Parker K, ed(s). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11^th edition. New York: McGraw-Hill; 2005:401-27.
3. Farkas J. Phenobarbital Monotherapy for Alcohol Withdrawal: Simplicity and Power. PulmCrit. https://emcrit.org/pulmcrit/phenobarbital-monotherapy-for-alcohol-withdrawal-simplicity-and-power/. Published October 18, 2015. Accessed April 2, 2018.
4. Ives TJ, Mooney AJ 3^rd, Gwyther RE. Pharmacokinetic dosing of phenobarbital in the treatment of alcohol withdrawal syndrome. South Med J. 1991 Jan;84(1):18-21.
5. Young GP, Rores C, Murphy C, et al. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987 Aug;16(8):847-50.
6. Hendey GW, Dery RA, Barnes RL, et al. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011 May;29(4):382-5.
7. 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 Mar;35(3): 724-30.
8. Rosenson J, Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized placebo controlled study. J Emerg Med. 2013 Mar;44(3):592-8.e2.

Derek Donovan, MD
Resident, Class of 2018
Department of Emergency Medicine
Dartmouth-Hitchcock Medical Center

Harman Singh Gill, MD
Assistant Professor of Emergency Medicine and Critical Care
Dartmouth-Hitchcock Medical Center