(April 5, 2023)

Executive Summary

Droperidol is a first generation antipsychotic (so-called typical antipsychotics, same class as haloperidol) that acts as a D2 dopamine receptor antagonist. Droperidol also has some histamine and serotonin antagonist properties (17). 

• It has a significant potential role in the ED because of its efficacy to treat a variety of clinical conditions, including undifferentiated agitation, migraine, vertigo, nausea, vomiting, cannabinoid hyperemesis, and pain (17, 3, 5, 7, 9, 16, 19). 

  • Droperidol or olanzapine are considered first-line medications to treat acute severe agitation in psychiatric patients, and both can be used in combination with benzodiazepines (9, 19). 

• Its use differs amongst geographical locations, clinicians and ED protocols. Some EDs do indicate it on a daily basis, others don't; this phenomena is explained to a great degree because of the US-FDA Black Box Warning issued in 2001 (23). This warning has been deeply questioned (11, 17, 12, 18, 20), this is why droperidol has been regaining popularity and its use has been increasing over the last decade (18). Nonetheless it should not be used on patients with long QT syndrome or at an increased risk of QT prolongation. 

Adult dose for undifferentiated agitation in the ED

5-10mg IM

Adult dose for migraine, acute vertigo, nausea or vomiting and cannabinoid hyperemesis
1.25-2.5mg IV or IM

Adult dose for undifferentiated agitation in the ED (7, 19)

5-10mg IM

• Time to adequate sedation is usually 10 to 20 min with a time to peak effect of 30 min (IM).

• If used IM, may repeat dose in 30 min (max 20 mg in 24 hours).

• If used IV, may repeat dose in 5 min (max 20 mg in 24 hours)

• May be administered as monotherapy or in combination with a benzodiazepine.
  
  

Adult dose for migraine, acute vertigo, nausea or vomiting and cannabinoid hyperemesis (23, 3, 5, 16)

1.25-2.5mg IV or IM

• For nausea and vomiting an initial dose of 0.625mg IV or IM may be sufficient, with an additional dose of 1.25mg if necessary.

• For acute migraine headache the appropriate starting dose is 2.5mg IV or IM.

Indications

• US FDA-labeled (23):

  • Nausea and vomiting treatment and prevention (post-operative, post-procedural)

• Off-label: 

  • Agitation

  • Acute vertigo

  • Cannabinoid hyperemesis syndrome

  • Headache (migraine)

  • Chronic and neuropathic pain

Usage in the Emergency Department

• Headache

  • A dose of 2.5mg to 2.75 mg IM or IV has been proven effective for treating acute migraine headaches. The minimum effective dose is 2.5 mg IV/IM, based on a review of data from 1946 to 2014 (13). Higher doses were associated with an increased risk of side effects, such as akathisia, drowsiness, and anxiety (6).
    
    

• Agitation

  • Droperidol has been shown to be effective for agitation management, with a faster onset of action, less additional sedation and less respiratory depression compared to the use of midazolam and/or haloperidol.

  • The study DORM (Droperidol OR Midazolam)(7) showed that 10 mg of droperidol IM was as effective as 10 mg of Midazolam in reducing the duration of violent behavior (20 min vs 24 min respectively), that it required less additional sedation (33% vs 62%) and was associated with less respiratory depression among intoxicated and agitated patients. 

  • The combination of droperidol 5 mg IV and midazolam 5 mg IV was even more effective in handling agitation at 10 minutes, and required fewer additional doses or alternative drugs to achieve sedation, compared with monotherapy with droperidol 10 mg IV or Olanzapine 10 mg IV (15). 

  • Considering the favorable data towards droperidol, there are a significant number of comparative studies on different approaches, both solo and in combination with other drugs, to treat agitation. The 2022 ACEP Task Force for Severe Agitation (19) evidence review concludes that ketamine, droperidol, olanzapine, and midazolam have overall similar efficacy as monotherapy in treating undifferentiated agitation.
    
    

• Nausea and vomiting

  • Droperidol 1.25mg is effective in treating postoperative nausea and vomiting, as well as other antiemetics such as ondansetron (2). It showed a synergistic effect when used together with ondansetron (droperidol 1.25mg IV + ondansetron 4mg IV)(10). It is approved by the US-FDA for this indication.
    
    

• Acute vertigo

  • Despite the very limited number of studies that have studied droperidol for the treatment of vertigo, or studies that have compared it with other drugs, some experts still consider droperidol as a safe and effective treatment for this condition in current practice (21).

• • A small study demonstrated 93% of effectiveness for the treatment of acute peripheral vertigo at 30 minutes with 2.5mg of droperidol IM (3).

Droperidol is a first-generation antipsychotic that has prominent dopamine antagonism. Its effects include(4, 8): 

• Antagonism of dopamine D2 and D3 receptors

• Antagonism of serotonin 5-HT2A receptors

• Antagonism of alpha-1 and alpha-2 adrenergic receptors

• Antagonism of histamine H1 receptors

• Enhancement of μ opioid receptors (analgesic contributor)

• Sodium channel blocking activity (analgesic contributor)

• Potassium channels blocking activity (QT widening risk)

Pharmacology

• It has a rapid onset of action (3 to 10 minutes), with a maximum effect at 30 minutes (1, 23), and its onset time is similar in both intramuscular and intravenous administration. This makes it useful in situations where no intravenous access is available (1).

• The effect of droperidol lasts between 2 to 4 hours.

• It has hepatic metabolism and excretion of inactive metabolites by the urine and feces.

• US-FDA Black Box Warning issued in 2001, label citation (23)

• “Cases of QT prolongation and/or torsade de pointes have been reported in patients receiving droperidol at doses at or below recommended doses.  Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Due to its potential for serious proarrhythmic effects and death, droperidol should be reserved for use in the treatment of patients who fail to show an acceptable response to other adequate treatments, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS).

• Cases of QT prolongation and serious arrhythmias (e.g., torsade de pointes) have been reported in patients treated with droperidol. Based on these reports, all patients should undergo a 12-lead ECG prior to administration of droperidol to determine if a prolonged QT interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, droperidol should NOT be administered. For patients in whom the potential benefit of droperidol treatment is felt to outweigh the risks of potentially serious arrhythmias, ECG monitoring should be performed prior to treatment and continued for 2-3 hours after completing treatment to monitor for arrhythmias.

• Droperidol is contraindicated in patients with known or suspected QT prolongation, including patients with congenital long QT syndrome.

• Droperidol should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, or administration of other drugs known to increase the QT interval). 

• Other risk factors may include age over 65 years, alcohol abuse, and use of agents such as benzodiazepines, volatile anesthetics, and IV opiates. Droperidol should be initiated at a low dose and adjusted upward, with caution, as needed to achieve the desired effect.”

A copious amount of clinical data, review articles and society statements have emerged over the last decade defending droperidol safety when used properly and in the doses that usually are sufficiently needed in the ED (11, 18). 

Society positions, review articles, expert opinion:

1. 2021 ACEP - American College of Emergency Physicians

   • 2021 Severe Agitation in the ED Task Force Report
     ACEP Task Force Report on Hyperactive Delirium with Severe Agitation in Emergency Settings, 2021

   • 2021 Policy Statement
     ACEP - Use of Droperidol in the Emergency Department 2021

2. 2020 EM-RAP - Emergency Medicine Reviews and Perspectives

Droperidol is Back by Reuben Strayer

3. 2019 FOAMcast - An Emergency Medicine Podcast

   • FOAMCAST 2019 Droperidol (and Haloperidol) Review by emergency physicians Jeremy Faust and Lauren Westafer

   • Droperidol and Butyrophenones on Spotify

4. 2015 American Academy of Emergency Medicine (AAEM)

   • 2015 Safety of Droperidol Use in the ED Position Statement

Pregnancy

• AU-TGA pregnancy category: C

• US-FDA pregnancy category: C
  
  

Lactation

• There are no published data about droperidol on its excretion on breast milk, but available molecular data on its pharmacokinetic characteristics (high plasma protein binding, large volume of distribution and short half-life), make it very unlikely its excretion into breast milk in significant amounts (22).

• Therefore it should be considered safe during breastfeeding  at least in small and short term doses usually given in the ED.  

1. Cressman WA, Plostnieks J, Johnson PC. Absorption, metabolism and excretion of droperidol by human subjects following intramuscular and intravenous administration. Anesthesiology. 1973;38(4):363-369. doi:10.1097/00000542-197304000-00010
   Anesthesiology (Open Access)

2. Fortney JT, Gan TJ, Graczyk S, et al. A comparison of the efficacy, safety, and patient satisfaction of ondansetron versus droperidol as antiemetics for elective outpatient surgical procedures. S3A-409 and S3A-410 Study Groups. Anesth Analg. 1998;86(4):731-738. doi:10.1097/00000539-199804000-00011
   Pubmed

3. Irving C, Richman PB, Kaiafas C, Eskin B, Ritter A, Allegra J. Droperidol for the treatment of acute peripheral vertigo. Am J Emerg Med. 1999;17(1):109-110. doi:10.1016/s0735-6757(99)90037-2
   Pubmed

4. Drolet B, Zhang S, Deschênes D, et al. Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol. 1999;10(12):1597-1604. doi:10.1111/j.1540-8167.1999.tb00224.x
   Pubmed

5. Miner JR, Fish SJ, Smith SW, Biros MH. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med. 2001;8(9):873-879. doi:10.1111/j.1553-2712.2001.tb01147.x
   Pubmed

6. Silberstein SD, Young WB, Mendizabal JE, Rothrock JF, Alam AS. Acute migraine treatment with droperidol: A randomized, double-blind, placebo-controlled trial. Neurology. 2003;60(2):315-321. doi:10.1212/01.wnl.0000042477.63516.b2
   Pubmed

7. DORM Study - Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56(4):392-401.e1. doi:10.1016/j.annemergmed.2010.05.037
   Pubmed

8. Richards JR, Richards IN, Ozery G, Derlet RW. Droperidol analgesia for opioid-tolerant patients. J Emerg Med. 2011;41(4):389-396. doi:10.1016/j.jemermed.2010.07.005
   Pubmed

9. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61(1):72-81. doi:10.1016/j.annemergmed.2012.07.118
   Pubmed

10. Matsota P, Angelidi M, Pandazi A, Tzirogiannis KN, Panoutsopoulos GI, Kostopanagiotou G. Ondansetron-droperidol combination vs. ondansetron or droperidol monotherapy in the prevention of postoperative nausea and vomiting. Arch Med Sci. 2015;11(2):362-370. doi:10.5114/aoms.2015.50968
    AMS (Open Access)

11. Perkins J, Ho JD, Vilke GM, DeMers G. American Academy of Emergency Medicine Position Statement: Safety of Droperidol Use in the Emergency Department. J Emerg Med. 2015;49(1):91-97. doi:10.1016/j.jemermed.2014.12.024
    Pubmed

12. DORM II Study - Calver L, Page CB, Downes MA, et al. The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2015;66(3):230-238.e1. doi:10.1016/j.annemergmed.2015.03.016
    Pubmed

13. Thomas MC, Musselman ME, Shewmaker J. Droperidol for the treatment of acute migraine headaches. Ann Pharmacother. 2015;49(2):233-240. doi:10.1177/1060028014554445
    Pubmed

14. Furyk JS, Meek RA, Egerton-Warburton D. Drugs for the treatment of nausea and vomiting in adults in the emergency department setting. Cochrane Database Syst Rev. 2015;2015(9):CD010106. Published 2015 Sep 28. doi:10.1002/14651858.CD010106.pub2
    Pubmed Central (Open Access)

15. Taylor DM, Yap CYL, Knott JC, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69(3):318-326.e1. doi:10.1016/j.annemergmed.2016.07.033
    Pubmed

16. Lee C, Greene SL, Wong A. The utility of droperidol in the treatment of cannabinoid hyperemesis syndrome. Clin Toxicol (Phila). 2019;57(9):773-777. doi:10.1080/15563650.2018.1564324
    Pubmed

17. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: DROPERIDOL injection, solution. Updated in March 2023. Accessed April 5, 2023.
    DailyMed

18. Gaw CM, Cabrera D, Bellolio F, Mattson AE, Lohse CM, Jeffery MM. Effectiveness and safety of droperidol in a United States emergency department. Am J Emerg Med. 2020;38(7):1310-1314. doi:10.1016/j.ajem.2019.09.007
    Science Direct (Open Access)

19. Kramer KJ. The Surprising Re-emergence of Droperidol. Anesth Prog. 2020;67(3):125-126. doi:10.2344/anpr-67-03-14
    Pubmed Central (Open Access)

20. ACEP Task Force Report on Hyperactive Delirium with Severe Agitation in Emergency Settings. Approved by the ACEP Board of Directors, June 23, 2021.
    ACEP

21. ACEP Policy Statement. Use of Droperidol in the Emergency Department, 2021.
    ACEP (Open Access)

22. Cisewski D, Long B, Gottlieb M. Emergency medicine updates: Droperidol. Am J Emerg Med. 2022;53:180-184. doi:10.1016/j.ajem.2022.01.011
    AJEM (Open Access)

23. APILAM (Association for promotion of and cultural and scientific research into breastfeeding). e-lactancia. Droperidol. Updated June 2022. Accessed February 12, 2023.
    E-lactancia