Benzodiazepine-Refractory Alcohol Withdrawal

Background: Severe alcohol withdrawal syndrome (AWS) accounts for only 10% of the roughly 500,000 annual cases of AWS episodes that require pharmacologic treatment. AWS is characterized by an imbalance between inhibitory GABA and excitatory NMDA receptor stimulation secondary to chronic ethanol intake. Treatment is typically centered around supportive care and symptom-triggered benzodiazepines. However, some patients are refractory to benzodiazepines, defined as > 10 mg lorazepam equivalents in 1 hour or > 40 mg lorazepam equivalents in 4 hours. Doses exceeding this threshold provide little benefit and put patients at risk for increase morbidity and mortality, over sedation, ICU delirium, respiratory depression and hyperosmolar metabolic acidosis. 

What are Some Other Options for Benzodiazepine-Refractory Alcohol Withdrawal?

 

 

What is the Evidence for Each of These Medications?

Phenobarbital

• 296 Patients
• 1 Prospective Trial [1]
  • One prospective RCT with phenobarbital 10mg/kg vs placebo (+symptom-triggered lorazepam for both groups) showed significant decrease in both ICU admission rate and continuous lorazepam infusion use (1 single center trial, results have not been duplicated)
• 1 Retrospective Trial [2]

Propofol

• 225 Patients
• 5 Retrospective Trials [3 – 7]
• 1 Case Series [8]
• 3 Case Reports [9 – 11]

Dexmedetomidine

• 6 Retrospective Trials [6 – 7; 12 – 15]
• 4 Case Reports/Case Series [16 – 19]
• 1 Prospective Trial [20]
• Dexemedetomidine does not protect against withdrawal seizures and should not be used as monotherapy

Ketamine

• 1 Retrospective Review [21]

Clinical Bottom Line

• Phenobarbital, propofol, and dexmedetomidine have been shown to reduce benzodiazepine requirements in AWS
• Nothing has proven to shorten AWS duration or ICU LOS
• Dexmedetomidine does not protect against withdrawal seizures and should not be used as monotherapy

References:

1. Rosenson J et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med. 2013;44:592-598.e2. PMID: 22999778
2. Michaelsen IH et al. Phenobarbital versus diazepam for delirium tremens: a retrospective study. Dan Med Bull. 2010; 57 (8) A4169. PMID: 20682133
3. Sohraby R et al. Use of propofol-containing versus benzodiazepine regimens for alcohol withdrawal requiring mechanical ventilation. Ann Pharmacother. 2014;48:456-461. PMID: 24436457
4. Lorentzen K et al. Use of propofol infusion in alcohol withdrawal-induced refractory delirium tremens. Dan Med J. 2014;61:A4807. PMID: 24814732
5. Wong A et al. Management of benzodiazepine-resistant alcohol withdrawal across a healthcare system: benzodiazepine dose escalation with or without propofol. Drug Alcohol Depend. 2015;154:296-299. PMID: 2605315
6. Lizotte RJ et al. Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal. Clin Pharmacol. 2014;6:171-177. PMID: 25382987
7. Ludtke K et al. Retrospective review of critically ill patients experiencing alcohol withdrawal: dexmedetomidine versus propofol and/or lorazepam continuous infusions. Hosp Pharm. 2015;50:208-213. PMID: 26405310
8. McCowan C, Marik P. Refractory delirium tremens treatedwith propofol: a case series. Crit Care Med. 2000;28:1781-1784. PMID: 10890619
9. Hughes DW et al. Propofol for benzodiazepine-refractory alcohol withdrawal in a non-mechanically ventilated patient. Am J Emerg Med. 2014;32:112.e3-112.e4. PMID: 24075805
10. Coomes TR, Smith SW. Successful use of propofol in refractory delirium tremens. Ann Emerg Med. 1997;30:825-828. PMID: 9398785
11. Mahajan R et al. Use of propofol as adjuvant therapy in refractory delirium tremens. Ind Psychiatry J. 2010;19:58-59. PMCID: PMC3105562
12. Crispo AL et al. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy. 2014;34:910-917. PMID: 24898418
13. Frazee EN et al. Influence of dexmedetomidine therapy on the management of severe alcohol withdrawal syndrome in critically ill patients. J Crit Care. 2014;29:298-302. PMID: 24360597
14. Rayner SG et al. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care. 2012;2:12. PMID: 22620986
15. VanderWeide LA et al. Evaluation of early dexmedetomidine addition to the standard of care for severe alcohol withdrawal in the ICU: a retrospective controlled cohort study. J Intensive Care Med 2016; 31(3): 198 – 204). PMID: 25326428
16. Baddigam K et al. Dexmedetomidine in the treatment of withdrawal syndromes in cardiothoracic surgery patients. J Intensive Care Med. 2005;20:118-123. PMID: 15855224
17. Darrouj J et al. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Ann Pharmacother. 2008;42:1703-1705. PMID: 18780809
18. Muzyk AJ et al. The use of dexmedetomidine in alcohol withdrawal. J Neuropsychiatry Clin Neurosci. 2012; 24: E45-E46. PMID: 23037682
19. Rovasalo A et al. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psychiatry. 2006;28:362-363. PMID: 16814639
20. Mueller SW et al. A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Crit Care Med. 2014;42:1131-1139. PMID: 24351375
21. Wong A et al. Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. Ann Pharmacother. 2015;49:14-19. PMID: 25325907

For More on This Topic Checkout:

• Justin Morgenstern at First 10 in EM: Management of Delirium Tremens
• Josh Farkas at Pulmcrit/EMCrit: Phenobarbital Monotherapy for Alcohol Withdrawal – Simplicity and Power
• Bryan Hayes at ALiEM: Ketamine for Severe Ethanol Withdrawal – A New Hope?

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

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