Physicians who remember using the drug droperidol are applauding its return to the market, while younger doctors who started practicing after it disappeared 20 years ago are asking why it’s creating such buzz.
In a recent twitter post, one physician polled colleagues about their views of droperidol:
“It worked & I miss it,” said 24%.
“I never got to use it,” responded another 29%.
The biggest group (44%) chose the answer option, “What’s Droperidol?”
Those who were familiar with the drug were largely enthusiastic about it, with one doctor commenting: “Miracle drug — makes crazy people normal and normal people crazy.” Another wrote: “Great antiemetic. Definitely miss having it in my tool kit.”
Droperidol was used for decades by anesthesiologists for postoperative nausea and vomiting but also in the emergency department as a sedative for undifferentiated agitation, explained Reuben J. Strayer, MD, associate medical director, Department of Emergency Medicine, Maimonides Medical Center, New York City.
“Before droperidol disappeared, I worked in a department where we saw 10 to 20 patients per day who required immediate sedation for agitation — mostly alcohol intoxication — but many other etiologies,” he said. “We used 5-10 mg of IM droperidol constantly, with excellent results.”
In 2001, however, the US Food and Drug Administration (FDA) placed a black box warning on droperidol over concerns about potential cardiac adverse effects. The fallout was swift, and droperidol vanished almost overnight from hospital formularies, leaving hospital staff to scramble for alternatives.
Long, Strange Trip
Droperidol is a dopamine antagonist related to the antipsychotic haloperidol (multiple brands). The onset of action is brisk: 5 to 10 minutes following intramuscular or intravenous injection, making it an attractive option in emergency medicine. It is also the shortest acting of the butyrophenone drug class, with a half-life of 2 hours and peak serum levels occurring 1 hour after administration.
Droperidol was first approved by the FDA in 1971 for nausea, anxiety, vomiting, and sedation. By the year 2000, 25 million doses were sold worldwide, and by 2001, droperidol had captured nearly one third of the market share for antiemetics.
That same year, however, the UK Medicines Control Agency raised a warning about a potential effect on cardiac QT interval prolongation associated with chronic high-dose usage in psychiatric patients, and the drug was quickly removed from the UK market. In fact, marketer Janssen-Cilag decided to discontinue its distribution globally.
Many physicians who had come to rely on droperidol protested that move. For example, in a 2001 correspondence in The Lancet, three European anesthesiologists noted that small intravenous doses of droperidol had been used for more than three decades to control postoperative nausea and vomiting (PONV), and that no safety concerns had been raised in that setting.
US clinicians initially were unaffected by Janssen’s decision as droperidol was marketed here by another company, Akorn Pharmaceuticals. But in December 2001, the FDA decided to strengthen the warnings and precautions and gave droperidol the dreaded black box warning.
“The black box warning made it quite difficult to use droperidol,” said Robert Glatter, MD, an emergency physician at Lenox Hill Hospital in New York City. “You had to do a screening ECG and then monitor the patient for 2 to 3 hours after the drug was given. It caused a lot of physicians to fear using the drug, and while a black box [warning] doesn’t ban a drug, it limits its clinical utility.”
Glatter also felt the data wasn’t sufficient to support the US action. “The FDA’s premise is based on a couple of hundred patients, of whom 90 developed QT prolongation,” he said, “but their data was based on patients who had other reasons for having QT prolongation. They had cardiac disease, or were on other drugs that can cause QT prolongation. So the data that they were basing this on is really flawed in my viewpoint.”
In addition, the doses of droperidol associated with the development of torsades de pointes were in the range of 200-300 mg, which is many times higher than the typical sedative dose of 5-10 mg.
“I’ve never seen a patient experience QT prolongation in all the years I’ve used the drug, and that’s hundreds of patients,” Glatter said.
As droperidol supplies dwindled in hospital formularies, physicians were forced to fill the gap with other agents. For sedation of agitated patients presenting to the ED, the most common replacement was haloperidol, which is primarily used as an antipsychotic and is not as effective for sedation, Glatter said. As a result, it needs to be accompanied by a sedative such as lorazepam (Ativan, Pfizer).
“These patients need behavioral control and the sedation you get with Ativan is not ideal because of its long half-life,” he said. “This means that patients have to remain in the ED to be monitored.”
The central nervous system penetration is poor initially, which leads to repeated dosing and, in turn, a longer period of sedation — “whereas droperidol has a very brisk penetrance and it sedates patients quickly and you can really fine-tune behavioral control more appropriately,” Glatter said.
Ironically, within a few years, haloperidol also received its own black box warning, similar to the one given to droperidol; in the case of haloperidol, however, the drug stayed in hospital formularies without any disruption in usage.
Staging a Comeback
Shortly after the FDA issued its black box warning, researchers from Washington University School of Medicine in St. Louis, Missouri, 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.”
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. The conclusion was that:
Droperidol is an effective and safe medication in the treatment of nausea, headache, and agitation.
The literature search did not support mandating an ECG or telemetry monitoring for doses <2.5 mg given either intramuscularly or intravenously.
Intramuscular doses of up to 10 mg of droperidol seem to be as safe and as effective as other medications used for sedation of agitated patients.
Droperidol was reintroduced to the US market in February 2019 by American Regent, still with the black box warning. Several months later, the company was reporting shortages of the drug, although the website currently states that it is available.
“We are working diligently to establish adequate market supply of droperidol,” said a company spokesperson.
Meanwhile, some physicians are applauding the drug’s return, while a younger generation of doctors still need to learn about it.
“It is definitely welcome back when it comes,” said Jeffrey C. Riddell, MD, assistant professor of clinical emergency medicine, Keck School of Medicine, University of Southern California, Los Angeles. “Most ED docs I know who used droperidol prior to 2000 loved it, felt it was perfect for our emergency context, and bemoaned it being taken away.”
But the black box warning may make some younger doctors more cautious, said Christopher B. Colwell, MD, chief of emergency medicine at Zuckerberg San Francisco General Hospital and Trauma Center in California.
“There may be some trepidation,” he said, “although those of us who used it for many years before the black box warning will champion it again. This is a far superior drug than the alternatives, and I don’t think there is a better drug for calming the agitated psychiatric or alcohol-abusing patient.”
Roxanne Nelson, RN, BSN is a freelance writer based out of Seattle.