Black Boxed? Droperidol as an Anti-emetic

The Gist:  Droperidol is a safe and effective anti-emetic at low doses (0.625-2.5 mg) and, as of September 2013, its use is supported in the ED with recommendations against routine EKG/telemetry monitoring by this AAEM Clinical Practice Statement (evidence based review of droperidol safety).

The background:  From EMCrit's podcast on chemical restraints to EM Lit of Note reviews of ondansetron, FOAM teams with support for droperidol.  My experience in the ED, however, has varied widely.  Over the past six months, I've rotated through seven emergency departments in the Eastern US.  I've discovered that people have very strong feelings about droperidol.  In some places, droperidol flowed freely yet judiciously and in others, the drug was a dirty word.  As part of a recent rotation, I gave a presentation on the use of droperidol as an anti-emetic so I figured I'd share my slide set.

Why do we care?  There are so many anti-emetics!

• Drug shortages.  Hospitals across the nation are experiencing shortages of many drugs, including anti-emetics such as ondansetron, promethazine, prochlorperazine, and metoclopramide.  Nausea and vomiting is a "bread and butter" issue in the ED and it's vital that we're equipped to take care of patients, even when we don't have our favorite drugs. 
• This database review found a statistically significant increase in adverse events after switching from droperidol to promethazine after the black box warning, when a shortage of prochlorperazine existed as well.  
• Intolerance to other medications. The charts of many patients with migraines list allergies to promethazine, prochlorperazine, and metachlopramide.  
• I recently had a patient with an intractable migraine who typically received relief from meperidine from his neurologist.  Unfortunately, on a long weekend, the neurologist's office was closed and the hospital didn't stock meperidine.  Opioid analgesics didn't mitigate the pain but droperidol did the trick (at 2.5 mg). 
• Cost.  Droperidol has been around for decades and is cheap.  Ondansetron became generic in the US a few years ago, but remains more expensive than droperidol.  
• Effective.  Droperidol 0.625 mg is as  effective as 4mg of ondansetron as demonstrated by Kriesler et al (this looked at post-operative nausea and vomiting).  Braude et al demonstrated that this effectiveness translates into the ED setting in a double-blind RCT comparing droperidol 1.25 mg, metoclopramide 10 mg, prochlorperazine 10 mg, and saline placebo.
• These drugs often end up in our "migraine cocktails" and low-dose droperidol appears to work in migraines as well, representing a cheap intervention for ill patients (1)

The basics:

• Butryophenone (like haloperidol)
• D2 agonist, anti-emetic effect is likely secondary to effects in the chemoreceptor trigger zone.
• Short-acting, works in 3-10 minutes

Safety

• Side Effects:  Drowsiness, dysphoria, dystonia, akasthisia but these effects are easily fixed with diphenhydramine and aren't the reason that hospitals and physicians are sometimes reticent to embrace droperidol...The Prolonged the QT interval
• Mechanism:  It's thought that droperidol blocks the rapid component of the delayed K+ and current depolarizing targets: L-type Ca2+ current, Na+-Ca2+ exchanger, and the Na+-K+ adenosine triphosphatase.  This mechanism may explain the susceptibility of individuals with Type I Long QT syndrome (2).

2001 Black Box Warning

Based on two studies (Lischke and White) and MedWatch reports.  I won't rehash all of the data here, but it's found in my slideset and in this summary.  Applies to FDA approved doses (2.5 mg and above).

MedWatch Reports

• 271 unique, spontaneous adverse cardiovascular events from 93 individuals
• Most cases were reported to the FDA between 1999-2001 (events dated 1970-2001)
• 71 cases reported on July 9, 2001 by an unknown number of sources that occurred on a variety of dates.  This is a bizarre smattering of cases and trends that have led many to conclude that the FDA black box made room for ondansetron (then on-patent) to gain a larger portion of the nausea/vomiting market share.  I won't comment on this since it's more speculation than evidence based.
• 10 of these cases were associated with doses of droperidol 2.5 mg or less.  Is this really a significant number of cases given the thousands of doses of droperidol administered each year in the decades it's been on the market?
• Individuals in these cases were not your typical healthy individuals (see Table below from Habib et al). There are some individuals for whom droperidol is probably not the safest drug.  Think arrythmias or predisposing cardiac conditions.

More recent evidence  Studies fail to demonstrate that inidviduals receiving droperidol have adverse clinical events secondary to the QTc prolongation.  Thus, is the minimal, transient QTc prolongation a clinically relevant marker?

• Charbit et al (2005) prospective, single blind study where patients (n=85) received 0.75 mg droperidol OR 4 mg ondansetron. Demonstrated no difference in QTc prolongation and demonstrated zero adverse effects
• QTc prolonged before administration in 21% of subjects 
• Maximum Increases in QTc: Droperidol 17 +/- 9 ms, Ondansetron  20 +/- 13 ms
• In 2008, Rappaport of the FDA stated that the FDA warning for droperidol did not apply to doses below 2.5 mg, as they had not evaluated that data (3).  
• Ondansetron has been found to prolong the QTc for up to 120 minutes and has been associated with torsades de pointes, as in this paper by Hafermann et al.  In fact, this month, the 32 mg dose of ondansetron was pulled from the market. 

• Treating primary headaches in the ED: can droperidol regain its role?

Experts' take on the droperidol black box warning

• Droperidol: A Cost-Effective Antiemetic for Over Thirty Years
• Journal Watch
• Droperidol - Behind the Black Box Warning