Common Sense Has Finally Prevailed: The Reappearance of Droperidol

Most anesthesiologists who trained before 2001 used small doses of droperidol, a butyrophenone, as a low-cost prophylactic antiemetic.¹ This was with an understanding that the risks for extrapyramidal side effects or electrocardiographic QT prolongation were minimal with small doses (0.625-1.25 mg intravenously).¹ Multiple well-controlled, randomized, comparative clinical trials have validated droperidol to be as safe and effective as the more costly 5-HT3 or NK-1 receptor antagonists.^2,3 The QT interval prolongation associated with antiemetic doses of the drug were found to be of no clinical significance.⁴ Many clinical studies had affirmed the safety and efficacy of droperidol in reducing postoperative nausea and vomiting (PONV) following a wide variety of surgical procedures, including tonsillectomy in children,⁵ neurosurgery and many ambulatory surgical procedures.⁶

In December 2001, to the surprise of most practicing anesthesiologists, the FDA decided to issue a black box warning for droperidol. The FDA’s decision was based on a review of a few hundred patients receiving varying doses of droperidol—most in excess of the standard antiemetic dose—of whom 90 reportedly developed QT prolongation. Unfortunately, the FDA data analysis did not consider other reasons for QT prolongation. For example, some patients had cardiac disease or had received other drugs known to cause QT prolongation. In addition, the dosage of droperidol associated with the development of torsades de pointes was in the range of 200 to 300 mg, which is two orders of magnitude higher than the typical antiemetic dose of 0.625 to 1.25 mg.

While the rationale for the black box warning seemed to lack scientific foundation, after the warning was issued, it became nearly impossible to use droperidol in anesthesia practice. In fact, most hospital pharmacies decided not to stock the drug. The removal of droperidol from hospital formularies was usually done without any consultation with hospital anesthesiologists. For a patient to receive the drug in those hospitals where it was still available, they were required to undergo a screening ECG and then be monitored for two to three hours after the drug was administered, a policy that was not tenable in normal anesthetic practice.

After the FDA issued its black box warning, researchers from Washington University School of Medicine in St. Louis conducted an independent review of the data obtained from the FDA under the Freedom of Information Act. They concluded that the evidence supporting the black box warning was “poor.”⁷ In 2015, after conducting an extensive literature review, the American Academy of Emergency Medicine issued a position statement that supported the use of droperidol in the emergency setting. Its conclusion was that droperidol is an effective and safe medication for the treatment of nausea, headache and agitation.8 These literature reviews did not support any need for a screening ECG or continued monitoring for doses less than 2.5 mg, given either intramuscularly or intravenously.

Droperidol was reintroduced to the U.S. market in February 2019 by American Regent, with the required black box warning. Several months later, the company was reporting shortages of the drug, although the website currently states that it is available. To gauge the availability of droperidol in large practice hospitals in California, we conducted a survey of the 280 members of the California Society of Anesthesiologists Large Practice Forum group. In 48 hours, 161 members opened the survey and 65 replied, with 97% of the respondents indicating that they did not have droperidol in the OR pharmacy.

This communication will hopefully serve to inform anesthesia practitioners and hospital pharmacists that droperidol should be made available for routine antiemetic prophylaxis of surgical patients. However, anesthesiologists will likely need to request that it be stocked in the OR pharmacy. For those practitioners too young to remember droperidol, give it a try (0.625-1.25 mg intravenously about five to 15 minutes before the end of anesthesia). It is especially useful in patients with chronic pain in whom, in addition to its anti-PONV effects, it can enhance postoperative analgesia with a mechanism likely related to a partial block of postsynaptic alpha-adrenergic receptors. Hypotension has not been reported with the recommended antiemetic dosage. Good luck and be well.

The authors reported no relevant financial disclosures. Dr. White is a member of the editorial advisory board of Anesthesiology News. Dr. Brock-Utne is the corresponding author, and can be contacted at brockutn@stanford.edu.

Editor’s note: The views expressed in this commentary belong to the authors and do not necessarily reflect those of the publication.

References

1. White RE. Droperidol: a cost-effective antiemetic for over 30 years. Anesth Analg. 2002;95(4):789-790.
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.
3. Hill RP, Lubarsky DA, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol or placebo. Anesthesiology. 2000;92(4):958-967.
4. White PF. Prevention of postoperative nausea and vomiting—a multimodal solution to a persistent problem. N Engl J Med. 2004;350(24):2511-2512.

5. Flubacher P, Fournier N, Cherpillod J, et al. A randomized controlled trial of placebo, droperidol or ondansetron to prevent nausea and vomiting after tonsillectomy in children receiving dexamethasone. Anaesthesia. 2017;72(7):859-863.
6. Charton A, Greib N, Ruimy A, et al. Incidence of akathisia after postoperative nausea and vomiting prophylaxis with droperidol and ondansetron in outpatient surgery: a multicentre controlled randomised trial. Eur J Anaesthesiol. 2018;35(12):966-971.
7. Jackson CW, Sheehan AH, Reddan JG. Evidence-based review of the black-box warning for droperidol. Am J Health Syst Pharm. 2007;64(11):1174-1186.
8. Perkins J, Ho JD, Vilke GM, et al. American Academy of Emergency Medicine position statement: safety of droperidol use in the emergency department. J Emerg Med. 2015;49(1):91-97.