phenobarbital for alcohol withdrawal

Alcohol withdrawal syndrome (AWS) and its complications are common reasons for ICU admission. Clinical practice guidelines recommend benzodiazepines as first-line treatment in this setting, but increasing evidence suggests that phenobarbital is both safe and effective in patients with moderate to severe AWS (commonly defined using Clinical Institute Withdrawal Assessment for Alcohol–revised [CIWA-Ar] score >15 and 20, respectively; Figure 1) or those at high risk for severe or complicated clinical course based on regular, heavy alcohol use or history of numerous episodes of AWS with delirium tremens or seizures (choice A is correct).

Ethanol binds to the γ-aminobutyric acid (GABA) ionotropic receptor family A (GABAA) receptor, augmenting the effects of the inhibitory neurotransmitter GABA. It also antagonizes N-methyl-D-aspartate (NMDA) receptors, decreasing action of the excitatory neurotransmitter glutamate. Together, these mechanisms cause ethanol’s sedative effect on the central nervous system. Chronic alcohol exposure reduces endogenous GABA levels and results in both GABAA receptor downregulation and NMDA receptor upregulation. Abrupt alcohol cessation in this setting can lead to neuronal hyperactivity and AWS due to NMDA pathway overactivation. Clinical manifestations of AWS include tremor, increased autonomic activity, insomnia, agitation, tachypnea, headache, diaphoresis, anorexia, nausea, vomiting, fever, and visual, tactile, and auditory hallucinations. Left untreated for 24 to 48 h, these symptoms typically progress to delirium (commonly referred to as delirium tremens) and increasing risk of seizures. Benzodiazepines also bind to GABAA receptors and increase GABA effects, but the low circulating GABA levels and decreased GABAA receptor sites seen in chronic alcohol use can lead to benzodiazepine resistance and refractory AWS.

Phenobarbital binds to GABAA receptors through a different mechanism, working synergistically with benzodiazepines, and does not require endogenous GABA to produce its effects. It also inhibits NMDA-type glutamate receptors, making it an attractive adjunct or alternative to benzodiazepines to treat severe or high-risk AWS. A systematic review and meta-analysis of 7 studies examining phenobarbital use in AWS requiring ICU admission demonstrated shorter hospital but similar ICU lengths of stay and reduced risk of intubation compared with benzodiazepines alone. Clinical application of these findings, however, should be tempered by recognition of significant methodologic heterogeneity with conflicting trial results, varied phenobarbital dosing protocols, and absence of prospective randomized clinical trial data in the ICU setting. Phenobarbital appears to be most effective when administered as an initial loading dose, with subsequent administration guided by a symptom-based protocol. Phenobarbital is metabolized by the liver, with prolonged serum levels when cirrhosis is present, and should generally be avoided in the setting of active hepatic encephalopathy.

Use of the centrally acting α-2 agonist dexmedetomidine to treat inadequately controlled AWS symptoms has been increasing, because of its ability to reduce catecholamine-mediated autonomic symptoms without respiratory depression. Dexmedetomidine can reduce CIWA-Ar scores and may shorten ICU lengths of stay when used as an adjunct to benzodiazepines; however, it is associated with increased frequency of bradycardia and hypotension compared with benzodiazepines alone. As its efficacy as monotherapy to prevent delirium tremens and seizures in severe AWS has not been studied, dexmedetomidine should be used in combination with benzodiazepines and not alone to treat severe AWS (choice B is incorrect). There is evidence suggesting that gabapentin and carbamazepine may have a role in the management of mild alcohol withdrawal, but there is limited evidence supporting their effectiveness in patients with severe symptoms and delirium tremens (choices C and D are incorrect).123456

Footnotes

  1. SEEK Questionnaires ↩

  2. Le Daré B, Lagente V, Gicquel T. Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects. Drug Metab Rev. 2019;51(4):545-561. PubMed ↩

  3. Polintan ETT, Danganan LML, Cruz NS, et al. Adjunctive dexmedetomidine in alcohol withdrawal syndrome: a systematic review and meta-analysis of retrospective cohort studies and randomized controlled trials. Ann Pharmacother. 2023;57(6):696-705. PubMed ↩

  4. Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989;84(11):1353-1357. PubMed ↩

  5. The ASAM clinical practice guideline on alcohol withdrawal management. J Addict Med. 2020;14(3S suppl 1):1-72. PubMed ↩

  6. Umar Z, Haseeb Ul Rasool M, Muhammad S, et al. Phenobarbital and alcohol withdrawal syndrome: a systematic review and meta-analysis. Cureus. 2023;15(1):e33695. PubMed ↩