Phenobarbital: The Sobering Truth

A quick note: “Ativan” is the trade name for the benzodiazepine drug “Lorazepam”, though we end up using the word “ativan” when in the department for a host of reasons, two of them being that it is easier to say and that when asking for this drug, nurses are more accustomed to this name compared to “lorazepam”.

Case

A 51 year old male patient presents to the emergency room complaining of nausea and vomiting. When you go in the room, the patient appears anxious and is picking at their skin. As an astute clinician you ask the patient to stick out their tongue and you see a constant, non-fatigable tremor. You then learn that the patient is 10 hours from their last drink, and prior to presentation drank a bottle of vodka a day. Because you are a phenomenal resident, you are concerned for alcohol withdrawal syndrome (AWS), and you calculate the patient’s CIWA is 16. You present this patient to your senior resident who suggests using phenobarbital to control the patient’s alcohol withdrawal. As you get ready to put in the order, the attending comes back to the desk and asks you to instead use lorazepam. 

Which drug is best?

When you search “alcohol withdrawal syndrome” (AWS) in UpToDate, you will find that benzodiazepine monotherapy is listed as the gold standard for acute treatment. In very broad and simplified strokes this is what is recommended: With CIWA scores taken every 10-15 minutes, while patient’s have severe symptoms – give IV valium (for patients with healthy livers) or IV lorazepam (for patients with less healthy livers) until the CIWA is less than 8. Then the CIWA is taken every hour. If the CIWA remains elevated, patients are admitted, and if the CIWA is consistently is stabilized the patient can be discharged with a librium taper. ^​1–4​

The question therefore becomes what are the potential pitfalls of benzodiazepine monotherapy. According to Endicott et al., benzodiazepine monotherapy for alcohol withdrawal is associated with risks of respiratory depression, dependence, delirium, and refractory alcohol withdrawal in which patients fail to respond to escalating doses of benzodiazepines, and the all too scary propylene glycol toxicity (propylene glycol is used as a diluent in many IV benzodiazepines).^​5,6​

Phenobarbital, like benzodiazepines, works on the GABA receptors to promote chloride influx into neurons and hyperpolarize the cell membrane – this means it would take a lot more stimulus to depolarize these cells.

In a study by Sullivan et al. in 2019, phenobarbital combination therapy was compared to benzodiazepine monotherapy. The study was a retrospective cohort study in an academic ED; the objective was to compare a phenobarbital-adjunct vs. benzodiazepine only approach to management of alcohol withdrawal in the ED with regard to the need for the ICU, severity of symptoms on ED discharge, and complications. The authors concluded that adjunctive phenobarbital use in the ED for AWS was equivalent to benzodiazepine monotherapy in regards to ICU admission, severity of symptoms, and complications. However, the study wasn’t randomized: phenobarbital was administered to sicker patients and achieved similar outcomes.  This may indirectly imply that the phenobarbital is superior.^​7​

In the 2013 study by Rosenson et al., phenobarbital combination therapy was again compared to benzodiazepine monotherapy. This was a prospective, randomized, double-blind, placebo-controlled study. The objective was to investigate whether a single dose of IV phenobarbital combined with a standardized lorazepam alcohol withdrawal protocol decreases ICU admission in ED patients with AWS. Patients were randomized to receive either a single dose of IV phenobarbital (10 mg/kg in 100 mL normal saline) or placebo (100 mL normal saline). The authors concluded that a single dose of IV phenobarbital combined with a symptom-guided lorazepam-based alcohol withdrawal protocol resulted in decreased ICU admission and did not cause increased adverse outcomes.^​8​

Finally, Hendy et al., performed a  prospectively, randomized, double-blind study, at an academic and community ED with the objective to compare phenobarbital versus lorazepam monotherapy in the treatment of alcohol withdrawal in the ED and at discharge at 48 hours. The authors concluded that ED phenobarbital monotherapy is as effective as lorazepam monotherapy. Patients treated with phenobarbital can be safely discharged from the ED without additional prescriptions. ^​9​

Based on this evidence (albeit short and sweet), you could argue that phenobarbital combination therapy should be used if you anticipate admission and phenobarbital monotherapy should be used if you anticipate discharge. However larger, randomized control trials with standardized protocols are required to make definitive recommendations. There is still a lot to learn about phenobarbital compared to benzodiazepine monotherapy/combination therapy (in fact the maximal dose in treatment of AWS is still unclear), but many FOAMed resources have commented on the purported benefits of phenobarbital compared to benzodiazepines. One of our favorites include this emDocs ToxCard article on some of the evidence.^​10​ The Internet Book of Critical Care also has a great algorithm for on which patients are ideal for phenobarbital and how to titrate it to effect.^​11​ As always, stay skeptical of evidence and practice good clinical judgement.

Cite this post: Kirsten Boone, MD. “Phenobarbital: The Sobering Truth”. GW EM Blog. 10/18/2023. Available at: https://gwemblog.com/phenobarbital-the-sobering-truth/.

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