The Comeback Of The Not So Underdog
December 2001 was a sad day in the medical community. The FDA mandated a “black box warning for Droperidol A widely used, and effective anti-anxiety, sedative, and anti-emetic. So why are we talking about it today? Glad you asked!
Per the norm in medicine, things are changing constantly. Due to the amazing amount of research that is done on a daily basis, we are finding that things that we once though were good (MAST Trousers (I may have dated myself there)), are in fact actually bad. And the same for the other way around. Things that we once thought were bad, actually aren’t as bad as we thought, or not even bad at all! That’s the beauty of evidence based medicine!
So lets take a look at what Droperidol is, how it works, what it’s good for, and what changes you can expect to possibly see over the next few years with this drug coming back into the limelight.
Now, don’t get me wrong. I’ve been in EMS for a little while (19 years actually). But when our service did our most recent protocol updates and added Droperidol to our box of tricks, I had NO idea what it was. It was taken off the market due to the above mentioned “black box” warning about a year before I started in EMS. So I have never seen the drug, done a flash card on the drug, Nadda. I’m sure most of ya’ll are in the same boat, right? So I decided to dig into this “new” (to-me) drug and find out exactly what it’s all about.
Ups-Downs-Ins- and kinda outs of Droperidool
Droperidol (less commonly known under it’s trade name Inapsine) is a butyrophenone with anti-emetic, anti-anxiety, and sedative properties. It is closely related to Haloperidol, which most of ya’ll are pretty familiar with. If you were to take Haloperidol and remove the hydroxy group and replace it with a double bond in the peptide ring as well as replace the 4-chloroprene’s group with a benzimidazol-2-on-1-Lynn group, you have Droperidol .
So how does it work? Well, that part seems to be a little up in the air. Some scientists say that it may block the dopamine receptions in the chemoreceptor trigger zone (CTZ), which lends to the anti-emetic effect, It may also bind to postsynaptic GABA receptors in the central nervous system, which increases the inhibitory effect of GABA and leads to the sedative and anti-anxiety properties. 
Droperidol has been shown to be not only a sedative for actually agitated psychiatric patients, but it does well at controlling intractable migraine headaches as well as single medicinal solution to cannabinoid hyperemesis syndrome, which we are seeing a lot more of an emergence of here in our region. More specifically, K2 is making a comeback. If I can avoid the extended amounts of time cleaning puke from the back of my truck by skipping over the Zofran/Benadryl combo and straight to one medicine. I’ll take it!
Let’s get to the research
There have been several studies done over the last decade that show that Droperidol is actually superior to midazolam or olanzapine for the sedation of actually agitated patients. One randomized control trial showed that Droperidol at a dose of 5mg IV, was better than when midazolam is given on it’s own.  When Droperidol and midazolam are combined (5-10mg IV), the combination is show to be even more effective in controlling severe agitation and combativeness secondary to acute psychosis. In a recently published 2020 retrospective, observant, cohort study; Droperidol was shown to be safe ad effective when dosed correctly as an analgesic, anti-emetic, or sedative . In that study alone, there were 5,784 patients given Droperidol at a single center United States emergency room between 01•01•2012 and 04•18•2018. Median age for these patients was 38 years old. Droperidol was given as an analgesic in 21.8% of those patients, for headache in 57.0%, as a sedative in 8.7%, and as an anti-emetic in 12.5% of the patients respectively. Within this study they looked at chart reviews to find patients that had complete symptom resolution with Droperidol as the only medication. Of the headache cohort, 79.5% had complete resolution. Pain other than headaches showed a 50% complete resolution. Nausea and vomiting showed an astounding 56.5% complete resolution, and the sedation cohort was 48.3% complete resolution. Throughout this study, patients were give a median dose of only 0.625mg. The authors also compared Droperidol to Haloperidol. While haloperidol does have a longer duration of action at 6-20 hrs vs droperidol at 2-4 hours; the onset of action is significantly quicker with droperidol at 5-10 minutes vs haloperidol at 20-30 minutes . I don’t know anyone who wouldn’t want 15-20 minutes less time with an agitated psychiatric patient having the risk of hurting themselves or someone else.
This study shows us that Droperidol is effective in the sedation, analgesia, and antiemetic area, and usually doesn’t require addition medications. It also proves one major thing I haven’t brought up yet. Remember how I mentioned earlier that in 2001 the FDA slapped a black box warning on Droperidol? That warning was due to QTc prolongation and Torsades de Pointes. The FDA recommended that EKG monitoring take place not only after administration of Droperidol, but before as well. Now In my years I’ve learned a few tricks, but I have yet to learn how to lasso an acutely agitated psych patient with my EKG cables, let alone get them to stick to said patient and then hope the patient stays still long enough for me to make sure that the QTc is not longer than 440 Msec in males or >450 msec in females . If any of ya’ll have, please share the secret with the world. Don’t be greedy.
Onto The “Bad” news (That ended up not really being bad)
TThe FDA’s warning was based on 273 case reports that were recorded over a 4 year time period of the 89 deaths that occurred within those case reviews, the doses of droperidol ranged significantly from 25mg to 250mg .
Let’s circle back to the study we talked about just briefly and the median dose range of 0.625mg. Ya’ll, that’s quite the difference. That study also showed ZERO deaths within 24 hours as well as ZERO fatal arrhythmias. None. Out of almost 6,000 patients, not a single one died or showed clinically significant arrhythmias. Combining 4 different retrospective studies and averaging the percentage of Torsades occurrences in relation to Droperidol since 2015, showed a result of 1/29,084. That’s an instance of only 0.0034%  and even when QTc prolongation emerged, it was short lived. Peaking at 10 minutes and disappearing 15 minutes. 
So not only do we have a drug that has about a 50% rate at treating acute psychosis, nausea/vomiting, and headaches. But we’ve also determined (over several studies over I might add), that when dosed correctly - There is little concern for cardiac events as the FDA had lead us to believe in the past.
Considerations and Mindfulness Points
Just like any other medication it has it’s downfalls. The most common side effects are extra-pyramidal such as dystopia or akisthesia. Which we should be used to looking for if Haloperidol is in our toolbox. These are easily reminded with the administration of Benadryl . Be mindful and very selective in your use with Droperidol in the pediatric and geriatric populations. Just like Haloperidol it is metabolized within the liver and excreted mainly through urine, so also be mindful of renal and hepatic impaired patient populations. Droperidol is also a pregnancy Class C medication and does crossover into breast milk. Once again, be mindful of pregnant and breastfeeding mommas.
When the FDA handed out it’s warning on droperidol, a lot of the medical community fought back. Almost the entire first page of google when you type in “Droperidol” are studies showing the FDA how the warning was unfounded when the drug is properly dosed. When used properly, Droperidol can help you control an agitated patient much quicker than haloperidol and without needing secondary rescue medications. It is also another great addition to the lineup for severe hyperemesis and intractable migraines.
I would expect to see this medication slowly bringing itself back in the pre-hospital world over the next several years and is probably already back in the pyxsis of most EC’s around the country!
References 1 - Isbister, G., Calver, L., Page, C., Stokes, B., Bryant, J. and Downes, M., 2010. Randomized Controlled Trial of Intramuscular Droperidol Versus Midazolam for Violence and Acute Behavioral Disturbance: The DORM Study. Annals of Emergency Medicine, 56(4), pp.392-401.e1. 2 - Jeffery Hill, M. and Jeffery Hill, M., 2022. The Return of Droperidol... — Taming the SRU. [online] Taming the SRU. Available at: <https://www.tamingthesru.com/blog/2019/4/20/the- return-of-droperidol> [Accessed 17 January 2022]. 3 - Nuttall, G., Malone, A., Michels, C., Trudell, L., Renk, T., Marienau, M., Oliver, W. and Ackerman, M., 2013. Does Low-dose Droperidol Increase the Risk of Polymorphic Ventricular Tachycardia or Death in the Surgical Patient?. ASA Publiations. 4 - Perkins, J., Ho, J., Heller, M., Mills, L., Singh, A. and Soucy, Z., 2013. Safety of Droperidol Use in the Emergency Department.
[ebook] AAEM. Available at: <https://www.aaem.org/UserFiles/file/ Safety-of-Droperidol-Use-in-the-ED.pdf> [Accessed 17 January 2022]. 5 - Rezaie, S., 2021. Droperidol: Making a Comeback. [Blog] REBEL EM, Available at: <https://rebelem.com/droperidol-making-a- comeback/> [Accessed 17 January 2022]. 6 - U.S. National Library of Medicine. (2005, March 25). Droperidol. National Center for Biotechnology Information. PubChem Compound Database. Retrieved January 12, 2022, from https:// pubchem.ncbi.nlm.nih.gov/compound/Droperidol