Grand Rounds: Headache, Part 2—Treatment and the Role of Haloperidol

Grand Rounds is a monthly blog series developed by EMS World and FlightBridgeED that will feature top EMS medical directors exploring the intricacies of critical care in EMS practice. In this installment FlightBridgeED Chief Medical Director Jeffrey Jarvis, MD, concludes his two-part look at headaches. Find Part 1 here.

Benign headache, meaning non-life-threatening, is a relatively common complaint in medicine and EMS calls. Part 1 of this article discussed the differential diagnosis and assessment of headaches with a focus on differentiating benign from dangerous causes. In Part 2 we’ll review the literature on medical management of these headaches and look at a recent study of the use of haloperidol (Haldol) for this purpose.

To start with, we know headaches are prevalent, with 1 in 6 Americans experiencing them at least once every three months.¹ Headaches make up between 1%–3% of ED visits and about the same percentage of EMS calls.^1,2 Despite guidelines against the use of opioids,^3–5 they are the most commonly used analgesics for headaches.⁶ Emergency departments use them as a first-line treatment at a rate ranging from 12% in academic centers to 69% in community EDs.⁷ Almost 40% of those headaches treated by EMS were treated with opioids, by far the most commonly used drug class. Unfortunately, most of the time EMS just didn’t treat them at all.²

Why shouldn’t we use opioids for headaches? Well, we know treating migraines with opioids is associated with less pain relief than antidopaminergics, and with longer ED lengths of stay, more admissions, more return ED visits, worse quality of life, and a higher risk of chronic migraines.^6–9 In head-to-head comparisons in randomized controlled trials, both 10 mg of prochlorperazine (Compazine) and 10 mg of metoclopramide (Reglan) provided better pain relief than 1 mg of hydromorphone (Dilaudid).^10,11 Even parenteral NSAIDs did just as well as meperidine (Demerol).¹²

ACEP, the American Headache Society, and the Canadian Headache Society all recommend against using opioids for the primary treatment of atraumatic headaches.^3–5 Instead they recommend a variety of antidopaminergic agents, including metoclopramide, prochlorperazine, droperidol, and ketorolac. And they have some good evidence for this.

Literature Results

When it comes to how these nonopioids compare with each other, there are mixed results. Emergency physician James Callan and colleagues performed an RCT between a 25-mg dose of promethazine (Phenergan) and a 10-mg dose of prochlorperazine (Compazine). They found Compazine had faster relief, more complete headache resolution, less sedation, and the same low rates of akathisias.¹³ Several papers have compared both prochlorperazine and metoclopramide to placebo and found both to be better.^14–16 Dr. Benjamin Friedman looked at the dosing of metoclopramide and found no difference between 10, 20, and 40 mg.¹⁷  

Military physician Marco Coppolla compared 10 mg of metoclopramide with 10 mg of prochlorperazine and found more relief with prochlorperazine than either metoclopramide or placebo, although metoclopramide also did better than placebo.¹⁸ Another similar study found no difference.¹⁹  

Ketorolac by itself has been compared with Compazine and meperidine (Demerol), showing equal effectiveness vs. Demerol but less relief than Compazine.^12,20

Several studies have looked at droperidol showing benefit vs. placebo. One of my favorites was from emergency doc James Miner in 2001.²¹ He compared 5 mg droperidol vs. 10 mg Compazine and found better pain relief with droperidol! As mentioned in Part 1 of this article, droperidol received a “death sentence” when the FDA placed an unwarranted black box warning against it.^22–26

There have been a couple of studies comparing haloperidol (Haldol) to metoclopramide (equally effective)²⁷ and of Haldol vs. placebo (Haldol was better).²⁸ The Haldol vs. placebo effort was pretty small, with only 40 patients enrolled.

We know droperidol works well, but we can’t get it, at least in the U.S. Since haloperidol is a butyrophenone like droperidol, perhaps we should be using it instead. One study compared it to metoclopramide and found they were equally effective, and one very small study compared it to placebo and found it more effective. A larger RCT would be good, though.

The Larger RCT

Fortunately, that’s what we have in a recent paper, “Treatment of Headache in the Emergency Department: Haloperidol in The Acute Setting (THE-HA Study): A Randomized Clinical Trial.”²⁹ This paper by Dr. Jessica McCoy and colleagues was published in the Journal of Emergency Medicine this year. It was a single-center randomized controlled trial of haloperidol vs. placebo in a convenience sample of ED patients between 13 and 55 with headache or migraine. Patients were enrolled between 2015 and 2016. Patients were excluded if they had any red flags (fever, thunderclap nature, trauma, confusion, abnormal neurologic exam, BP greater than 200/100) or a history of SAH, brain mass, stroke, or aneurysm.

After obtaining informed consent, patients were randomized to receive either 2.5 mg haloperidol in 5 ml of saline or a placebo dose of 5 ml of saline; both were given slowly over 1–2 minutes. Their primary outcome was a change in pain score at 30, 60, and 90 minutes compared to baseline. Secondary outcomes were time to relief, degree of relief, side effects, QTc prolongation, and 24-hour ED return visits. If patients needed rescue medication, they received ketorolac 30 mg IV.

Ultimately the authors screened 287 patients to enroll 118: 60 in the placebo group and 58 in the haloperidol group. The groups were pretty similar, indicating their randomization strategy worked well. They found a more significant reduction in pain with haloperidol than placebo. More important, to me anyway, they found a larger proportion of patients with at least a 50% reduction in pain at 30 minutes (35% vs. 12%). By 60 minutes the difference had become even more significant (65% vs. 22%). They found 59% of patients in the haloperidol group who had complete resolution of symptoms.

Haloperidol had more side effects than placebo at 30 minutes (mostly akathisia), but oddly enough fewer side effects at 60 minutes.

The haloperidol group had fewer return ED visits at 24 hours and more patients who would want the same drug in the future. Notably, there was no more QTc prolongation with haloperidol than with placebo, suggesting we don’t need the 12-lead before giving Haldol, at least at this dose.

So the bottom line in this RCT is that Haldol 2.5 mg IV is safe and effective for benign headaches. I’m not ready to use this instead of my go-tos, metoclopramide (Reglan) or prochlorperazine (Compazine), depending on which I can get at the moment. Still, I think this is a very reasonable treatment for those who failed Reglan or Compazine or have some reason not to receive them.

References

1. Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache, 2018; 58: 496–505.

2. Jarvis JL, Johnson B, Crowe RP. Out-of-hospital assessment and treatment of adults with atraumatic headache. JACEP Open, 2020; 1: 17–23.

3. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Acute Headache; Godwin SA, Cherkas DS, Panagos PD, et al. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Acute Headache. Ann Emerg Med, 2019 Oct; 74(4): e41–e74.

4. Orr SL, Friedman BW, Christie S et al. Management of Adults With Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache, 2016; 56: 911–40.

5. Orr SL, Aube M, Becker WJ et al. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. Cephalalgia, 2015; 35: 271–84.

6. McCarthy LH, Cowan RP. Comparison of parenteral treatments of acute primary headache in a large academic emergency department cohort. Cephalalgia, 2015; 35: 807–15.

7. Young N, Silverman D, Bradford H, Finkelstein J. Multicenter prevalence of opioid medication use as abortive therapy in the ED treatment of migraine headaches. Am J Emerg Med, 2017; 35: 1,845–9.

8. Bigal ME, Lipton RB. Excessive opioid use and the development of chronic migraine. Pain, 2009; 142: 179–82.

9. Buse DC, Pearlman SH, Reed ML, Serrano D, Ng-Mak DS, Lipton RB. Opioid use and dependence among persons with migraine: results of the AMPP study. Headache, 2012; 52: 18–36.

10. Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs. IV hydromorphone for migraine. Neurology, 2017; 89: 2,075–82.

11. Griffith JD, Mycyk MB, Kyriacou DN. Metoclopramide versus hydromorphone for the emergency department treatment of migraine headache. J Pain, 2008; 9: 88–94.

12. Davis CP, Torre PR, Williams C et al. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: evaluations by patients. Am J Emerg Med, 1995; 13: 146–50.

13. Callan JE, Kostic MA, Bachrach EA, Rieg TS. Prochlorperazine vs. promethazine for headache treatment in the emergency department: a randomized controlled trial. J Emerg Med, 2008; 35: 247–53.

14. Ellis G, Delaney J, DeHart DA, Owens A. The efficacy of metoclopramide in the treatment of migraine headache. Ann Emerg Med, 1993; 22: 191–95.

15. Jones J, Sklar D, Dougherty JM, White W. Randomized Double-blind Trial of Intravenous Prochlorperazine for the Treatment of Acute Headache. JAMA, 1989; 261: 1,174–6.

16. Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A Prospective, Double-Blind Study of Metoclopramide Hydrochloride for the Control of Migraine in the Emergency Department. Ann Emerg Med, 1990; 19: 1,083–7.

17. Friedman BW, Mulvey L, Esses D et al. Metoclopramide for Acute Migraine: A Dose-Finding Randomized Clinical Trial. Ann Emerg Med, 2011; 57: 475–82.

18. Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med, 1995; 26: 541–6.

19. Friedman BW, Esses D, Solorzano C, et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med, 2008; 52: 399–406.

20. Seim MB, March JA, Dunn AK. Intravenous ketorolac vs. intravenous prochlorperazine for the treatment of migraine headaches. Acad Emerg Med, 1998; 5: 573–6.

21. Miner JR, Fish SJ, Smith SW, Biros MH. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med, 2001; 8: 873–9.

22. 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: 230–8.

23. Colwell CB. Managing the acutely agitated patient: Why Denver brought back the forgotten agent droperidol. EMS Magazine, 2010; 39: 18–9.

24. Horowitz BZ, Bizovi K, Moreno R. Droperidol—behind the black box warning. Acad Emerg Med, 2002 Jun; 9(6): 615–8.

25. Macht M, Mull AC, McVaney KE, et al. Comparison of droperidol and haloperidol for use by paramedics: assessment of safety and effectiveness. Prehosp Emerg Care, 2014; 18: 375–80.

26. Newman DH. Training the Mind, and the Food and Drug Administration, on Droperidol. Ann Emerg Med, 2015; 66: 243–45.

27. Gaffigan ME, Bruner DI, Wason C, Pritchard A, Frumkin K. A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department. J Emerg Med, 2015; 49: 326–34.

28. Honkaniemi J, Liimatainen S, Rainesalo S, Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache, 2006; 46: 781–7.

29. McCoy JJ, Aldy K, Arnall E, Petersen J. Treatment of Headache in the Emergency Department: Haloperidol in the Acute Setting (THE-HA Study): A Randomized Clinical Trial. J Emerg Med, 2020 Jul; 59(1): 12–20.

Jeffrey L. Jarvis, MD, MS, EMT-P, FACEP, FAEMS, is the chief medical director for FlightBridgeED, LLC, and cohost of the FlightBridgeED EMS Lighthouse Project Podcast. He also serves as an EMS medical director for the Williamson County EMS system and Marble Falls Area EMS and is an emergency physician at Baylor Scott & White Hospital in Round Rock, Tex. He is board certified in emergency medicine and EMS. He began his career as a paramedic with Williamson County EMS in 1988 and continues to maintain his paramedic license.