BenadrylProchlorperazine is a commonly used medication in EM. In certain patients prochlorperazine does wonders for migraines, and remains a great antiemetic choice for undifferentiated nausea/vomiting when ondansetron is ineffective. However, prochlorperazine has antidopinamergic activity increasing the chances of extrapyramidal symptoms (EPS), such as akathisia, dystonia, parkinsonism, and rarely tardive dyskinesia. A common practice in the ED is to give diphenhydramine with prochlorperazine to attenuate EPS.  Does this really work? What is the evidence?

What is the risk of EPS from prochlorperazine?

One study1 looked at 229 adult patients receiving IM/IV prochlorperazine in the ED for nausea/vomiting for migraines. Adverse reactions (dystonia or akathisia) were assessed in the ED and two weeks after discharge:

  • Akathisia: 25 (11%) in the ED and 11 (6%) after discharge
  • Dystonia: 4 (1.7%) in the ED and 5 (2.6%) after discharge

Overall, there was a 1 in 5 chance of an unpleasant reaction from prochlorperazine. In another study2, 44/100 ED patients developed akathisia within 1 hour of intravenous prochlorperazine administration and there was no mention of dystonia.

Although the definitions of akathisia are debatable, these studies show that prochlorperazine adverse reactions may be common when administered parenterally as a one time dose in the ED.

What is the evidence for giving concomitant diphenhydramine?

Design / PopulationInterventionOutcomesComments
Double-blind, randomized, placebo3

18-65 yrs old (n=100)

PCZ 10 mg IV + DPH 50 mg, or placeboAKATHISIA
DPH: 14%
Placebo: 36%
SEDATION using 100 mm visual analog:
DPH: +33 mm
Placebo: +12 mm
DPH reduces risk for akasthisia with NNT 5, but with added sedation
Prospective, open-label, uncontrolled trial4

(includes some pts from above study3)

16-65 yrs old (n=87)

PCZ 10 mg IV +
DPH 25-50 mg IV at 1 hour post-PCZ administration, if akathisia present
Pre DPH 9.8 ±3.6
Post DPH 1.2 ±2.6
DPH may work as an abortive agent for PCZ induced akathisia

What about giving prochlorperazine slower instead of an IV push?

Prochlorperazine IV Push vs Infusion

Design / PopulationInverventionOutcomesComments
Double-blind, randomized / 18-65 yrs old (n=160)52-minute push


15-minute infusion


Push: 36.9%

Infusion: 23.7%


Non significant but trend towards more akathisia if given slower
Double blind, randomized / ≥18 yrs old (n=99)62-minute push


15-minute infusion


Push: 26%

Infusion: 32.7%



Prochlorperazine’s most common adverse reaction is akathisia and may occur in the ED even after a single parenteral 10 mg dose.

In small, one-center ED studies, diphenhydramine has been shown to prevent and treat prochlorperazine associated akathisia at the cost of increased sedation. The authors do not mention any clinically significant sedation that may have resulted in apnea or intubation. Further, the diphenhydramine dose given most often in the above studies was 50 mg. Whether smaller doses (i.e. 12.5-25 mg) or oral administration have the same EPS-attenuating benefit with a decreased risk of sedation remains unknown. It has also been suggested that smaller doses of prochlorperazine (i.e., 5 mg) may cause less akathisia.

Although prochlorperazine 15-minute infusion has not been shown to reduce akathisia compared to a 2-minute injection, we should always exercise caution and follow medication administration instructions as rapid boluses of some commonly administered drugs in EM can have significant adverse effects (i.e., labetalol).7 Prochlorperazine should be given no faster than 5 mg per minute.8

Should I always give diphenhydramine with prochlorperazine?

It depends. The mentioned studies had strict exclusion criteria: no designated driver after discharge, pregnancy, pre-existing motor disorders, glaucoma, bowel obstruction, and if patients had taken certain medications (i.e., benzodiazepines, opioids) which are commonly co-administered in everyday practice.

The author’s recommendations 4

A good candidate for diphenhydramine co-administration is “an ED migraneur who will be treated with [prochlorperazine 10 mg IV] who intends to go home with a driver upon discharge and sleep.” In patients receiving smaller doses of prochlorperazine or in those “in whom anticholinergic effects should be avoided, one may consider foregoing adjudicative diphenhydramine and reserving it as a therapeutic agent if needed.

A special thanks to UCSF pharmacy resident Raymond Chao, PharmD for assistance with this post!

Olsen J, Keng J, Clark J. Frequency of adverse reactions to prochlorperazine in the ED. Am J Emerg Med. 2000;18(5):609-611. [PubMed]
Drotts D, Vinson D. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med. 1999;34(4 Pt 1):469-475. [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]
Vinson D. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270. [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]
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]
How Fast Is Too Fast For IV Push Medications. Institute For Safe Medication Practices. Published May 15, 2003. Accessed February 19, 2019.
Lexi-Comp Online (TM), Pediatric & Neonatal Lexi-Drugs Online (TM), Hudson, Ohio: Lexi-Comp, Inc.; January 29, 2011.
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