‘There was pap looking wild, and skipping around every which way and yelling about snakes. He said they was crawling up his legs; and then he would give a jump and scream, and say one had bit him on the cheek.... He started and run round and round the cabin, hollering “Take him off! take him off! he's biting me on the neck!”
If Pappy in Mark Twain's book Huckleberry Finn were brought to the local emergency department in 1840 for his psychomotor agitation, hallucinations, and altered mental status, he might have received the typical 19th-century therapy for delirium tremens (DTs)—bloodletting, opium, and bed rest.
Skip forward roughly 160 years to the beginning of the 21st century. Medical intervention to treat DTs started with hydration and rapidly escalating doses of benzodiazepine (usually diazepam). Benzodiazepines were generally deemed safer than barbiturates in this setting despite the fact that even massive doses (e.g., 200 mg diazepam) were sometimes ineffective and could paradoxically increase agitation. Barbiturates were typically reserved for use as a secondary agent when benzodiazepines were not effective.
But this primary dependence on benzodiazepines to treat alcohol withdrawal and DTs may be slowly changing. Intensivist Josh Farkas, MD, presented a compelling argument for using phenobarbital as a first-line agent in many cases in a superb series of posts in his PulmCrit blog. (https://emcrit.org/category/pulmcrit/; see box.)
Dr. Farkas said chronic alcohol use causes the down-regulation of inhibitory GABA receptors in the central nervous system and the up-regulation of excitatory glutamate receptors. When ethanol consumption is stopped or decreased, the combination of enhanced stimulation and impaired inhibition results in the psychomotor agitation and autonomic hyperactivity characteristics of alcohol withdrawal.
Benzodiazepines work only at the GABA receptors, causing sedation by increasing the frequency with which the receptor's chloride channels open. Phenobarbital, on the other hand, increases GABA activity while also inhibiting glutamate-mediated stimulation, hitting both mechanisms responsible for the signs and symptoms of alcohol withdrawal, Dr. Farkas wrote. This may explain why some withdrawal patients who are resistant to large doses of benzodiazepines respond readily when a barbiturate is added.
Unlike most benzodiazepines, phenobarbital has predictable efficacy and pharmacokinetics. A 10 mg/kg IV dose of phenobarbital will reliably result in a serum level at the low end of the therapeutic range (15-40 mcg/ml). This should not cause respiratory depression as long as no benzodiazepines or other drugs are on board and no other complicating medical conditions are present. If benzodiazepines have been given first, however, one loses the ability to administer a predictably safe and reliable initial loading dose of phenobarbital without risking oversedation.
The terminal half-life of phenobarbital is quite long (three to four days), and the medication will taper itself once an effective blood level has been achieved. Small intravenous or oral doses of a benzodiazepine or phenobarbital can be given and titrated to effect if additional sedation is needed.
Several potential pitfalls could complicate a barbiturate-only or barbiturate-first approach to treating alcohol withdrawal, however. The initial phenobarbital dose of 10 mg/kg IV might no longer be safe if a patient had ingested a sedative or respiratory depressant before presentation. Similarly, further alcohol consumption at home could result in excessive sedation if a patient with mild to moderate alcohol withdrawal improved with phenobarbital and was discharged. It is crucial to be sure of the diagnosis and not miss concomitant complicating medical conditions such as CNS infection with any patient presumed to be in alcohol withdrawal. Treating meningitis with phenobarbital is not generally considered good form.
Few studies have evaluated the safety and efficacy of phenobarbital as the primary treatment for alcohol withdrawal and DT, so I was excited when I came across one.
Patient Outcomes Associated with Phenobarbital Use with or without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review
Hammond DA, Rowe JM, et al.
This paper aimed to evaluate phenobarbital use with and without concomitant benzodiazepine therapy according to indication, dosing, and patient outcomes. The authors identified only one paper that used an initial phenobarbital dose of 10 mg/kg IV and that they considered good-quality evidence. Patients with suspected acute alcohol withdrawal syndrome in that prospective, randomized, double-blind, placebo-controlled study were randomized to receive a single IV dose of phenobarbital 10 mg/kg or normal saline. (J Emerg Med 2013;44:592.) All 198 participants were placed on the institutional symptom-guided lorazepam-based protocol for alcohol withdrawal syndrome. The authors found that the patients who received phenobarbital had a decreased rate of admission to the ICU without increased incidence of adverse events. It should be noted that Riggan, et al., criticized this study for being underpowered, utilizing subjective outcome measures, not providing important clinical patient information, and not controlling for multiple confounding medications. (J Emerg Med 2016;50:895.)
The mechanistic arguments for using phenobarbital as the primary treatment for alcohol withdrawal syndrome are persuasive, but not enough good evidence shows that doing so on a widespread basis would be safe and effective. I predict that over the next few years we will see more studies examining this question. In the meantime, read Dr. Farkas' PulmCrit posts. (See box.) See what you think. When managing alcohol withdrawal syndrome; the current dogma may not be best in show.
Read Dr. Josh Farkas' articles on treatment for alcohol withdrawal here:
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- Phenobarbital Monotherapy for Alcohol Withdrawal: Reloaded; http://bit.ly/PulmCrit1.
- Phenobarbital Monotherapy for Alcohol Withdrawal: Simplicity and Power; http://bit.ly/PulmCrit2.
- Treating Delirium Tremens: Pharmacokinetic Engineering with Diazepam and Phenobarbital; http://bit.ly/PulmCrit3.