How to Use Phenobarbital for Treatment of Alcohol Withdrawal Syndrome

TL;DR

Phenobarbital is a good alternative or adjunct for treatment of alcohol‌‌ withdrawal syndrome. It has particular benefits for patients with severe‌‌ alcohol withdrawal.

High risk patients are those with prior seizure,‌‌ delirium tremens, ICU‌‌ admission, benzodiazepine infusion, or failure to respond to typical‌‌ treatments.

Tread careful when patients have other medical problems requiring‌‌ hospitalization, cirrhosis, CYP interactions, or if excessive benzodiazepines‌‌ have already been given.

Treatment strategies:

1. (severe) 10 mg/kg IV phenobarbital followed by benzodiazepine symptom triggered
2. (severe) 10 mg/kg IV phenobarbital followed by phenobarbital symptom triggered
3. 65 mg, 130 mg, or 260 mg IV or oral q30 minutes - symptom triggered

• Dosing is always based on ideal body weight (IBW)
• Max dosage should NOT exceed 30 mg/kg
• Doses should be reduced by 25-50% for patients with hepatic dysfunction, depressed mental status, or concomitant sedative use such as opioids or excessive benzos

Safety

• Phenobarbital has a wide range of therapeutic levels for safety.
• Typically patients will require 5-30 mg/kg IBW for full treatment effect when‌‌ phenobarbital is used as monotherapy. Less may be required if concurrent benzodiazepines are being used.
• The risk of respiratory depression is not unfounded, but multiple studies‌‌ have demonstrated safety of the above dosing strategies for patients with‌‌ alcohol withdrawal. Furthermore, although we don't use phenobarbital as frequently for seizures these days, a typical load would be 20 mg/kg.

Introduction

This article focuses on how to use phenobarbital as an alternative or adjunctive therapy for patients with severe alcohol withdrawal. It covers patient selection, dosing regimens, adverse effects - including the concern for respiratory depression, medication interactions, and therapeutic benefits over benzodiazepine protocols.

Hospital admissions and emergency department visits for alcohol withdrawal are common. Most of the time patients are well treated with modest dosing of a benzodiazepine and consultation with a substance abuse team. Treatment is more complicated when the patient has severe withdrawal. Up to 15% of patients with severe alcohol withdrawal will have life threatening seizures or delirium tremens.

Benzodiazepines are the cornerstone treatment for alcohol withdrawal. Phenobarbital fell out of favor in the 1990s due to medication interactions, societal issues with barbiturate addiction, and drug company sponsorship. Despite the shift in practice, there was no major evidence to suggest that benzos were superior to phenobarbital. In fact, there are now data showing that 10% of patients with severe alcohol withdrawal are refractory to benzodiazepines but remain responsive to phenobarbital.

Benzodiazepines remain a reasonable option for treatment of alcohol withdrawal, and phenobarbital is an excellent adjunct or replacement in select patients at high risk for seizure, delirium tremens (DTs), intubation, or ICU admission.

In patients with severe alcohol withdrawal, phenobarbital alone or in‌‌ combinations with benzodiazepines has significant benefits including reduced ICU‌‌ admission, intubation, need for benzodiazepine infusion, and benzodiazapine‌‌ requirements.

Patient selection

The best use case for phenobarbital is in patients with a clear diagnosis of‌‌ severe alcohol withdrawal, risk factors for severe alcohol withdrawal, no suspected alternative diagnoses, no major drug‌‌ interactions, and no cirrhosis.

Risk factors for severe alcohol withdrawal include the following:

• Prior ICU admission for alcohol withdrawal
• Requiring benzodiazapine infusion
• Requiring intubation
• Prior documented delirium tremens
• Prior documented or confirmed seizure with alcohol cessation
• Long standing heavy alcohol use without cessation (drinking for > 1 year >10 standard drinks per day)
• High initial alcohol level

Benzodiazepine resistance occurs in up to 20% of patients with severe alcohol withdrawal (Wong 2015). It is non-formally defined by receiving >40 mg diazepam equivalents within one hour (Langlois 2020). In this case, phenobarbital should be strongly considered AND you should think very carefully about potential missed alternative diagnoses.

Dosing

There is a lack of consensus regarding the best dosing strategy for‌‌phenobarbital in alcohol withdrawal. The medication comes in IV formulation and‌‌as tablets (65 mg, 130 mg, or 260 mg). There is a wide therapeutic range. Patients typically require 5-30 mg/dL IBW for adequate treatment effect. For patients with severe withdrawals, bolus dosing has been studied as a one time adjunct to benzodiazpeines and also in combination with phenobarbital symptom triggered dosing.

Be aware that in the current practice environment, both of these formulations will likely have to come all the way from the pharmacy. They are not typically stocked in the ED pyxis, for example.‌‌If you order a symptom triggered PRN dose, then pharmacy will typically send multiple doses.

For patients who are in florid withdrawals and have high risk features use one of the following

1. 10 mg/kg IV phenobarbital followed by benzodiazepine symptom triggered
2. 10 mg/kg IV phenobarbital followed by phenobarbital symptom triggered
3. 65 mg, 130 mg, or 260 mg IV or oral q30 minutes - symptom triggered

Keep the following in mind

• Dosing is always based on ideal body weight (IBW)
• Max dosage should NOT exceed 30 mg/kg
• Doses should be reduced by 25-50% for patients with hepatic dysfunction, depressed mental status, or concomitant sedative use such as opioids or excessive benzos

If a patient has severe withdrawals, but doesn't meet ICU admission criteria, then‌‌my practice is to give the 10 mg/kg bolus and then continue with a benzodiazepine symptom‌‌triggered strategy. This is to avoid confusion with admitting teams.

Safety

There is well founded concern about respiratory depression from phenobarbital, but the doses of phenobarbital used for treating alcohol withdrawal is between 5 mg/kg and 30 mg/kg (Oks 2020). Even when‌‌combined with benzodiazepines, phenobarbital hasn't been shown to result in‌‌increased rates of intubation or respiratory failure (see studies below).‌‌Compared to other barbiturates, such as thiopental, phenobarbital does not have‌‌nearly as large of a respiratory depression effect.

If a patient has risk factors for respiratory depression or failure, then it is‌‌reasonable to use a smaller bolus dose (5-8 mg/kg IBW) or use a symptom‌‌triggered strategy without bolus up front. Some risk factors to consider would‌‌include concomittant benzodiazepine use, opioid use, respiratory pathology, and‌‌reduced mental status.

My practice

For now, I typically only use phenobarbital in patients who are admitted to the hospital, but there has been evidence that it is a reasonable treatment option for patients discharged from the emergecy department who only had mild alcohol withdrawal.

I usually just stick with benzodiazepines if the patient has mild-moderate‌‌ alcohol withdrawal. For patients with high risk features I give the 10 mg/kg up‌‌ front. Our hospital dose not have a protocol for nurses to use phenobarbital for‌‌ symptom triggered dosing - so I don't order this for patients going to the‌‌ floor. In the ICU I generally switch any patient with more than the most mild‌‌ withdrawals to phenobarbital. ICU delirium is just such a major issue, that I‌‌ prefer to make all efforts to minimize that risk - and I think phenobarb is a‌‌good way to do that for these patients.

It's worth noting that there are a lot of alcohol withdrawal mimics. Phenobarbital is a seven day commitment, if you're concerned for alternative etiologies (such as sepsis...), then it may not be the best up front choice. Also, keep in mind that it has many drug interactions and is hepatically metabolized (reduce dose).

Further reading

Prospective/RCT studies‌‌

Rosenson 2013‌
‌Hendey 2011‌
‌Young 1987

Retrospective ICU based studies

‌‌Oks 2020
‌‌Nguyen 2020‌‌
Tidwell 2018
‌‌Duby 2014‌
‌Gold 2007

Retrospective ED based studies‌‌

Ibarra 2020
‌‌Nelson 2019‌‌
Sullivan 2018

Retrospective Non-ICU based studies

‌‌Nisavic 2019
‌‌Ives 1991