Update: What evidence is available on the off-label use of dexmedetomidine for alcohol withdrawal syndrome?

Dexmedetomidine in alcohol withdrawal

Dexmedetomidine is used as an adjunctive agent in alcohol withdrawal syndrome.1 Chronic alcohol intake ultimately causes down-regulation of the gamma-aminobutyric acid (GABA) receptor and up-regulation of N-methyl-D-aspartate (NDMA).2,3 Abrupt discontinuation of alcohol leads to hyperstimulation of the central nervous system because of the lack of GABA inhibition and because of excess excitatory activity due to glutamate and norepinephrine. Benzodiazepines are most commonly used to treat alcohol withdrawal because they work directly on GABA receptors. Symptoms of alcohol withdrawal include insomnia, tremulousness, anxiety, nausea, vomiting, headache, diaphoresis, palpitations, increased body temperature, tachycardia, and hypertension. Seizures and delirium tremens are severe manifestations. Unlike benzodiazepines, dexmedetomidine does not work on GABA receptors.2 As an alpha-2-adrenergic agonist, dexmedetomidine inhibits release of norepinephrine to decrease sympathetic activity such as tachycardia and hypertension.1,3 In addition, dexmedetomidine has anxiolytic and sedating activity which may be beneficial in alcohol withdrawal.

A frequently asked question (FAQ) was published in December 2016 with information on the off-label use of dexmedetomidine for alcohol withdrawal syndrome (available here).4 That FAQ was an update of a December 2013 FAQ (available here).5 At the time the 2016 FAQ was published, the author found that the existing literature supported dexmedetomidine to reduce short-term benzodiazepine use and improved hemodynamic parameters (eg, blood pressure and heart rate) in patients who do not respond adequately to benzodiazepines alone.4 However, the literature was mostly of low quality (eg, retrospective cohorts and case series) with limited prospective, randomized trials. Recently, there has been increased interest in this topic due to a 2020 guideline published by the American Society of Addiction Medicine (ASAM). The purpose of this FAQ is to summarize the ASAM guideline recommendations and to summarize studies published since the 2016 FAQ.

Guideline Recommendations

American Society of Addiction Medicine

The ASAM published a guideline on alcohol withdrawal management in 2020.3 Benzodiazepines are recommended as first-line agents for patients with moderate (Clinical Institute of Withdrawal Assessment for Alcohol, revised scale [CIWA-Ar] scores 10 to 18) or severe (CIWA-Ar scores ≥ 19) alcohol withdrawal. Dexmedetomidine is recommended for use in certain patients receiving inpatient management of alcohol withdrawal. For patients in whom symptoms are not controlled with use of benzodiazepines alone, the guideline recommends that alpha-2-adrenergic agonists, including clonidine and dexmedetomidine, can be used in addition to benzodiazepine therapy to help control autonomic hyperactivity and anxiety. However, the ASAM recommends that these agents are not used for prevention or treatment of withdrawal-related seizures or delirium. Additionally, dexmedetomidine is recommended for patients in the intensive care unit (ICU) who are experiencing resistant alcohol withdrawal. Resistant alcohol withdrawal is defined generally as patients who experience “severe or complicated withdrawal despite having received high doses of benzodiazepines.”

In the commentary, the ASAM states that alpha-2-adrenergic agonists and beta-agonists can be used with benzodiazepines for persistent hypertension or tachycardia.3 The guideline warns that administration of these agents may give the false appearance that the hyperadrenergic signs of alcohol withdrawal are adequately treated; however, they do not address the underlying pathophysiology of alcohol withdrawal. Monitoring for bradycardia is required when dexmedetomidine is used.

Evidence cited by the guideline

In support of the guideline recommendation to use dexmedetomidine as an adjunct to benzodiazepines in the ICU, the ASAM guideline cites systematic reviews of mostly observational trials6-9 and 2 randomized, controlled trials.10,11 Overall, the guideline states that these studies found improved sedation quality, decreased 24-h benzodiazepine requirements, and higher rates of bradycardia with use of dexmedetomidine.3,10,11 The randomized controlled trials are thoroughly summarized in the 2016 FAQ (available here) and briefly summarized here. The randomized controlled trial by Mueller et al (2014) was a small, single-center study of 24 patients with severe alcohol withdrawal.10 Patients received high dose (1.2 mcg/kg/h) or low dose (0.4 mcg/kg/h) dexmedetomidine or placebo as adjunctive therapy. Use of dexmedetomidine (both high and low doses combined) resulted in lower 24-h lorazepam requirements after study drug use (-56 mg vs -8 mg; p=0.037); however, 7-day lorazepam requirements were not significantly different (159 mg vs 181 mg). The number of patients experiencing moderate or severe agitation in the first 24 hours was similar between groups. Bradycardia was more common with dexmedetomidine compared to placebo (25% vs 0%; p=not significant). The second randomized controlled trial by Bielka et al (2015) included 72 patients who received dexmedetomidine 0.2 to 1.4 mcg/kg/h (titrated to target sedation level of -2 to 0 on Richmond Agitation Sedation Scale and CIWA-Ar score <15) plus benzodiazepines vs benzodiazepines alone for alcohol withdrawal.11 The addition of dexmedetomidine reduced median 24-h diazepam requirements (20 mg vs 40 mg; p<0.001) and the median ICU cumulative diazepam dose (60 mg vs 90 mg; p<0.001). In addition, the median percentage of time in the target sedation range was greater in the dexmedetomidine group vs benzodiazepines alone (90% vs 64.5%; p<0.001). Bradycardia was more common with dexmedetomidine (31% vs 6%; p=0.03).

Literature Review

Since the publication of the 2016 FAQ, 2 additional studies have been published. Both studies were retrospective cohort studies. A summary of the 2 trials are presented in the Table. One trial found the combination of propofol and dexmedetomidine numerically (but not statistically) improved the CIWA-Ar score compared to either agent alone; dexmedetomidine was also associated with numerically greater rates of bradycardia.12 However, the study was limited by a small sample size and drug dosing was not defined. The second study found an increased length of ICU stay associated with use of dexmedetomidine plus benzodiazepine compared to benzodiazepines alone.13 The authors hypothesized that this may have occurred due to the requirement to administer dexmedetomidine in the ICU or because of its effect on suppressing the signs and symptoms of withdrawal without treating the underlying pathophysiology. Although the authors accounted for several potential confounding variables in their analysis, the retrospective nature of the study may have led to additional confounding that was not anticipated.

Table. Dexmedetomidine for alcohol withdrawal.12,13

Study design

Subjects

Interventions

Results

Love & Zimmerman 202012

Retrospective cohort

N=62 patients in the ICU experiencing severe alcohol withdrawal receiving lorazepam

Propofol (n=39)

Dexmedetomidine (n=14)

Propofol + dexmedetomidine (n=9)

Primary

Change in CIWA-Ar score 24 h after starting medication (n=23 patients included in this analysis) were -4.7 (95% CI, -6.6 to -2.8), -4.4 (-7.4 to -1.4), and -10.4 (-13.5 to -7.3) in the propofol, dexmedetomidine, and combination groups, respectively (p=0.21)

Bradycardia (HR < 60 beats/min) occurred in 15.4%, 28.6%, and 11.1% of patients in the propofol, dexmedetomidine, and combination groups (p=0.40)

Hypotension (SBP < 90 mm Hg or DBP < 60 mm Hg) occurred in 38.5%, 21.4%, and 22.2% of patients in the propofol, dexmedetomidine, and combination groups (p=0.08)

Secondary

Length of hospitalization was 10.2, 11, and 7.1 days in the propofol, dexmedetomidine, and combination groups (p=0.14)

ICU LOS was 5.5, 5.1, and 4.1 days in the propofol, dexmedetomidine, and combination groups (p=0.65)

Time to extubation was 4.8, 4.4, and 4.1 days in the propofol, dexmedetomidine, and combination groups (p=0.98)

Yavarovich et al 201913

Retrospective cohort

N=438 patients in the ICU with AWS

Benzodiazepines alone (n=297)

Benzodiazepines + dexmedetomidine (n=141) (patients received dexmedetomidine within 1 hr of ICU admission)

Primary

In the unadjusted analysis, total ICU LOS was significantly higher in the dexmedetomidine + benzodiazepine group (88.7 h) vs benzodiazepines alone (36.3 h) (p<0.0001)

In the analysis adjusted for age, gender, BMI, AWS severity, and pre-ICU LOS, ICU LOS was longer with addition of dexmedetomidine vs benzodiazepines alone (ratio of relative mean number of ICU LOS hrs with dexmedetomidine compared to the non-dexmedetomidine group, 2.14; 95% CI, 1.78 to 2.57; p<0.0001) (difference, 42.9 h; 95% CI, 29.4 to 61.2 h)

Dexmedetomidine use increased ICU LOS vs benzodiazepines alone in both adjusted and unadjusted analyses based on severity of alcohol withdrawal (mild, moderate, or severe)

Abbreviations: AWS=alcohol withdrawal syndrome; BMI=body mass index; CI=confidence interval; CIWA-Ar=Clinical Institute Withdrawal Assessment for Alcohol, revised scale; DBP=diastolic blood pressure; HR=heart rate; ICU=intensive care unit; LOS=length of stay; SBP=systolic blood pressure.

Real-world use of dexmedetomidine

A 2016 survey of 94 US-based critical care pharmacists asked respondents about use of various agents for alcohol withdrawal.14 The survey found that dexmedetomidine is among the agents with the most barriers to its use. Surveyed pharmacists indicated that barriers included medication cost (58%) and the adverse events of bradycardia (50%) and hypotension (47%). Thirteen percent and 19% of respondents reported that dexmedetomidine was a protocol option for initial and adjunctive therapy, respectively, at their practice site. Dexmedetomidine was reportedly less commonly incorporated into institutional protocols than benzodiazepines, clonidine, haloperidol, and barbiturates (eg, phenobarbital). The survey also assessed the number of pharmacists who agreed with various reasons to use agents for alcohol withdrawal. The most common reasons for use of dexmedetomidine were: To reduce high or frequent doses of initial “GABA agonist” therapy (87.2%), to facilitate tracheal extubation after respiratory depression associated with initial “GABA agonist” therapy (89.4%), and to treat anxiety or agitation (83%).

Controversy regarding use of dexmedetomidine for alcohol withdrawal

Although many advocate for the use of dexmedetomidine for alcohol withdrawal, controversy exists regarding its role in therapy because it does not affect the GABA receptors and therefore does not affect the underlying pathophysiology.2,15 Alpha-2 adrenergic agonists have not been shown to reduce clinically important outcomes such as seizures and delirium tremens when used as adjuncts in routine care.15 In addition, dexmedetomidine may increase cost, bradycardia, and hypotension.

Conclusion

Overall, evidence supporting use of dexmedetomidine as an adjunct agent for alcohol withdrawal symptoms is limited to low quality data of mostly retrospective studies and 2 randomized controlled trials. Although there are limited data supporting its use, the 2020 ASAM guideline recommends its use as an adjunct to benzodiazepine therapy for hyperactivity and anxiety symptoms that are not controlled with benzodiazepines alone, and for patients in the ICU experiencing resistant alcohol withdrawal symptoms.

References

  1. Glahn A, Proskynitopoulos PJ, Bleich S, Hillemacher T. Pharmacotherapeutic management of acute alcohol withdrawal syndrome in critically Ill patients. Expert Opin Pharmacother. 2020;21(9):1083-1092. doi: 10.1080/14656566.2020.1746271
  2. Long D, Long B, Koyfman A. The emergency medicine management of severe alcohol withdrawal. Am J Emerg Med. 2017;35(7):1005-1011. doi: 10.1016/j.ajem.2017.02.002
  3. Wong J, Saver B, Scanlan JM, et al. The ASAM clinical practice guideline on alcohol withdrawal management. J Addict Med. 2020;14(3S Suppl 1):1-72. doi: 10.1097/ADM.0000000000000668
  4. Gabay M. Is there updated information on the off-label use of dexmedetomidine (Precedex) for alcohol withdrawal syndrome? University of Illinois at Chicago Drug Information Group. Published December 2016. Accessed October 8, 2020. https://dig.pharmacy.uic.edu/faqs/2016-2/december-2016-faqs/
  5. Can dexmedetomidine be used off-label in the management of alcohol withdrawal syndromes? University of Illinois at Chicago Drug Information Group. Published December 2013. Accessed October 8, 2020. https://dig.pharmacy.uic.edu/faqs/2013-2/december-2013-faqs/
  6. Schmidt KJ, Doshi MR, Holzhausen JM, Natavio A, Cadiz M, Winegardner JE. Treatment of severe alcohol withdrawal. Ann Pharmacother. 2016;50(5):389-401. doi: 10.1177/1060028016629161
  7. Albertson TE, Chenoweth J, Ford J, Owen K, Sutter ME. Is it prime time for alpha2-adrenocepter agonists in the treatment of withdrawal syndromes? J Med Toxicol. 2014;10(4):369-381. doi: 10.1007/s13181-014-0430-3
  8. Linn DD, Loeser KC. Dexmedetomidine for alcohol withdrawal syndrome. Ann Pharmacother. 2015;49(12):1336-1342. doi: 10.1177/1060028015607038
  9. Brotherton AL, Hamilton EP, Kloss HG, Hammond DA. Propofol for treatment of refractory alcohol withdrawal syndrome: A review of the literature. Pharmacotherapy. 2016;36(4):433-42. doi: 10.1002/phar.1726
  10. Mueller SW, Preslaski CR, Kiser TH, et al. A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Crit Care Med. 2014;42(5):1131-1139. doi: 10.1097/CCM.0000000000000141
  11. Bielka K, Kuchyn I, Glumcher F. Addition of dexmedetomidine to benzodiazepines for patients with alcohol withdrawal syndrome in the intensive care unit: a randomized controlled study. Ann Intensive Care. 2015;5(1):33. doi: 10.1186/s13613-015-0075-7
  12. Love K, Zimmermann AE. Use of propofol plus dexmedetomidine in patients experiencing severe alcohol withdrawal in the intensive care unit. J Clin Pharmacol. 2020;60(4):439-443. doi: 10.1002/jcph.1539
  13. Yavarovich ER, Bintvihok M, McCarty JC, Breeze JL, LaCamera P. Association between dexmedetomidine use for the treatment of alcohol withdrawal syndrome and intensive care unit length of stay. J Intensive Care. 2019;7:49. doi: 10.1186/s40560-019-0405-1
  14. Dyal S, MacLaren R. The assessment and management practices of acute alcohol withdrawal: Results of a nationwide survey of critical care pharmacists. Hosp Pharm. 2019;54(1):22-31. doi: 10.1177/0018578718769241
  15. Hoffman RS, Weinhouse GL. Management of moderate and severe alcohol withdrawal syndromes. UpToDate website. Updated August 11, 2020. Accessed October 16, 2020. https://www.uptodate.com/contents/management-of-moderate-and-severe-alcohol-withdrawal-syndromes?search=alcohol%20withdrawal&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Prepared by:
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

November 2020

The information presented is current as of October 7, 2020.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.