The 2016 American Headache Society (AHS) released recommendations on managing adults with acute migraine headaches.1 In the November 2017 EM:RAP LIN Sessions podcast episode that I recorded, I realized that I overgeneralized several statements about anti-dopaminergic agents and the use of concurrent diphenhydramine for akathisia risk reduction. So I wanted to clarify things and share a deeper-dive on the topic, thanks to the constructive feedback and help of headache guru Dr. David Vinson and EM pharmacists Dr. Curtis Geier, Dr. Bryan Hayes, and Dr. Zlatan Coralic. Below summarizes the nuanced thought processes in the anti-dopaminergic treatment of migraines.

Initial EM:RAP Teaching Points: Migraine Treatment

  1. Avoid opioids
  2. Administer IV crystalloid fluids and ketorolac 10-15 mg IV
  3. Administer anti-dopaminergic agent such as prochlorperazine (Compazine) or metoclopramide (Reglan)
  4. Avoid diphenhydramine – This may not be entirely true.

Point of Clarification: You May Need to Give Diphenhydramine in Some Cases

Prochlorperazine and metoclopramide have nuanced differences, specifically regarding diphenhydramine to reduce the risk of akathisia. Although the AHS graded diphenhydramine use as Class C (may avoid) for acute migraines, this is not the full story.1

1. Avoid diphenhydramine for metoclopramide 10 mg IV dose, but consider diphenhydramine for 20 mg IV dose

For patients receiving 10 mg IV metoclopramide, diphenhydramine has not been been shown to reduce the incidence of akathisia (7-12%).2,3 For those receiving 20 mg IV metoclopramide, however the incidence of akathisia in one study was 20% as compared to 10% for those patients who received 20 mg IV metoclopramide PLUS 25 mg IV diphenhydramine. This positive trend towards akathisia risk reduction suggests diphenhydramine use if this higher dose of 20 mg IV metoclopramide is used.3

2. Administer diphenhydramine when giving prochlorperazine 10 mg IV

Most of the studies that found no benefit with diphenhydramine for reducing akathisia used metoclopramide. However, 1 randomized controlled trial by Vinson et al. in Annals of Emergency Medicine reported a 22% absolute risk reduction using diphenhydramine in the setting of IV prochlorperazine use. More specifically, the incidence of akathisia was:4

  • Prochlorperazine 10 mg IV = 36% (18 of 50 patients)
  • Prochlorperazine 10 mg IV + diphenhydramine 50 mg IV = 14% (7 of 50 patients)

This convincing study led to the 2017 Annals of Emergency Medicine expert recommendation publication “Managing Migraines” by Dr. Benjamin Friedman to administer diphenhydramine when using prochlorperazine for migraine headaches.5

3. When does akathisia tend to occur?

Most cases of akathisia occur within the first hour of giving prochlorperazine; however, they can occur as late as 48 hours later.6 Be sure to give anticipatory guidance to patients and potentially a prescription for diphenhydramine for home.

4. So should I give metoclopramide instead of prochlorperazine to avoid using diphenhydramine?

The downside of IV diphenhydramine use includes excessive patient drowsiness, an opioid-like “high”, and anticholinergic symptoms. Why give this medication when it can be avoided?

Based on 2 head-to-head comparisons, 10 mg IV prochlorperazine seems to outperform 10 mg IV metoclopramide for treating patients with acute migraine headaches. Clinical success was achieved with the following medications:

Coppola et al. (1995)7Jones et al.  (1996)8
Prochlorperazine 10 mg IV82%67%
Metoclopramide 10 mg IV46%34%

Of note, 1 randomized controlled trial compared 10 mg IV prochlorperazine to 20 mg IV metoclopramide (twice the standard dose and may be associated with more akathisia). Both were equally efficacious in treating acute migraines.9

Bottom line: Prochlorperazine is more effective than metoclopramide in treating acute migraines.


For the treatment of acute migraines:

  1. Administer prochlorperazine 10 mg IV plus diphenhydramine as the first line anti-dopaminergic agent over 10 mg IV metoclopramide. Note that a 2008 randomized controlled trial concluded that either (prochlorperazine 10 mg IV plus diphenhydramine) or (higher-dose metoclopramide 20 mg IV plus diphenhydramine) were similarly effective in treating migraine headaches.9
  2. Warn your patients that akathisia may develop as late as 48 hours afterwards.
Prochlorperazine (Compazine)Metoclopramide (Reglan)
* 2 studies showed no difference in a 2-minute bolus versus 15-minute infusion; however, 1 of the studies demonstrated a positive trend favoring a slower 15 minute infusion (akathisia rates of 36.9% and 23.7% for 2-minute versus 15-minute prochlorperazine infusion; p=0.07).10

** 1 study demonstrated no difference in akathisia with slower infusion rates but they used metoclopramide 20 mg IV dose.11

Effectiveness in treating acute migraine headaches+++++
Risk of akathisia36% (14% with concurrent diphenhydramine)7-12%
Diphenhydramine co-administrationYesNo
Starting IV dose10 mg10 mg
Rate of IV infusion2 minutes (no faster than 5 mg/min)* 10,12Slow IV push** 13–15

Additional Reading on Migraine Management

Orr S, Friedman B, 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(6):911-940. [PubMed]
Friedman B, Cabral L, Adewunmi V, et al. Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department-Based Randomized Clinical Trial. Ann Emerg Med. 2016;67(1):32-39.e3. [PubMed]
Friedman B, Bender B, Davitt M, et al. A randomized trial of diphenhydramine as prophylaxis against metoclopramide-induced akathisia in nauseated emergency department patients. Ann Emerg Med. 2009;53(3):379-385. [PubMed]
Vinson D, Drotts D. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med. 2001;37(2):125-131. [PubMed]
Friedman B. Managing Migraine. Ann Emerg Med. 2017;69(2):202-207. [PubMed]
Drotts D, Vinson D. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med. 1999;34(4 Pt 1):469-475. [PubMed]
Coppola M, Yealy D, Leibold R. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med. 1995;26(5):541-546. [PubMed]
Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med. 1996;14(3):262-264. [PubMed]
Friedman B, Esses D, Solorzano C, et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med. 2008;52(4):399-406. [PubMed]
Vinson D, Migala A, Quesenberry C. Slow infusion for the prevention of akathisia induced by prochlorperazine: a randomized controlled trial. J Emerg Med. 2001;20(2):113-119. [PubMed]
Egerton-Warburton D, Povey K. Administration of metoclopramide by infusion or bolus does not affect the incidence of drug-induced akathisia. Emerg Med Australas. 2013;25(3):207-212. [PubMed]
Collins R, Jones J, Walthall J, et al. Intravenous administration of prochlorperazine by 15-minute infusion versus 2-minute bolus does not affect the incidence of akathisia: a prospective, randomized, controlled trial. Ann Emerg Med. 2001;38(5):491-496. [PubMed]
Tura P, Erdur B, Aydin B, Turkcuer I, Parlak I. Slow infusion metoclopramide does not affect the improvement rate of nausea while reducing akathisia and sedation incidence. Emerg Med J. 2012;29(2):108-112. [PubMed]
Regan L, Hoffman R, Nelson L. Slower infusion of metoclopramide decreases the rate of akathisia. Am J Emerg Med. 2009;27(4):475-480. [PubMed]
Parlak I, Atilla R, Cicek M, et al. Rate of metoclopramide infusion affects the severity and incidence of akathisia. Emerg Med J. 2005;22(9):621-624. [PubMed]
David R Vinson, MD

David R Vinson, MD

Senior physician, The Permanente Medical Group (Oakland)
Co-chair, KP CREST Network
Adjunct investigator, Kaiser Permanente Division of Research (Oakland)
Volunteer clinical faculty, UC Davis Department of EM
Curtis Geier, PharmD BCCCP

Curtis Geier, PharmD BCCCP

Clinical Pharmacist, Emergency Medicine
Assistant Clinical Professor, UCSF
San Francisco General Hospital and Trauma Center
Zlatan Coralic, PharmD

Zlatan Coralic, PharmD

Assistant Clinical Professor
Emergency Department Clinical Pharmacist
University of California, San Francisco (UCSF)
Zlatan Coralic, PharmD


Emergency Medicine Clinical Pharmacist. Views expressed here are my own. #FOAMed
Bryan D. Hayes, PharmD, DABAT, FAACT, FASHP

Bryan D. Hayes, PharmD, DABAT, FAACT, FASHP

Leadership Team, ALiEM
Creator and Lead Editor, Capsules and EM Pharm Pearls Series
Attending Pharmacist, EM and Toxicology, MGH
Associate Professor of EM, Division of Medical Toxicology, Harvard Medical School
Bryan D. Hayes, PharmD, DABAT, FAACT, FASHP


EM Pharmacist & Toxicologist @MassGeneralEM | Asst Prof @HarvardMed/@EMRES_MGHBWH | @ALiEMteam leadership | Capsules creator, ALiEMU | President, ABAT | #FOAMed