Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis

Emerg Med J. 2018 May;35(5):325-331. doi: 10.1136/emermed-2017-206944. Epub 2018 Feb 3.


Objectives: To determine the effectiveness of prophylactic anticholinergic medications in reducing extrapyramidal symptoms in patients taking acute antiemetics with a dopamine D2 receptor antagonist effect.

Methods: Systematic searches of all published studies through March 2017 were identified from PubMed, Cochrane library, Embase, Web of Science and Scopus. Only randomised controlled trials of patients receiving dopamine D2 antagonist antiemetic therapy for acute migraine in which an anticholinergic or placebo was compared were included. Pooled ORs were calculated for incidence of extrapyramidal symptoms and sedation.

Results: Four placebo-controlled randomised controlled trials consisting of 737 patients met the inclusion criteria for our meta-analysis. The effect of diphenhydramine differed depending on the method of administration of the antiemetic. When the antiemetic was delivered as a 2 min antiemetic bolus, the odds of extrapyramidal symptoms were significantly reduced in the diphenhydramine group compared with placebo (OR 0.42; 95% CI 0.22 to 0.81; P=0.01). However, when the antiemetic was given as a 15 min infusion, there was no significant difference in extrapyramidal symptoms with or without diphenhydramine (OR 1.06; 95% CI 0.58 to 1.91; P=0.85). The lowest incidence of extrapyramidal symptoms was observed in patients receiving a 15 min antiemetic infusion without diphenhydramine prophylaxis (9.8%). In two trials including 351 patients that dichotomously reported sedation scales, diphenhydramine had significantly higher rates of sedation (31.6%vs19.2%, OR 2.01, 95% CI 1.21 to 3.33; P=0.007).

Conclusion: Prophylactic diphenhydramine reduces extrapyramidal symptoms in patients receiving bolus antiemetic therapy with a dopamine D2 antagonist effect, but not when it is given as an infusion. Because of significantly greater sedation with diphenhydramine, the most effective strategy is to administer the D2 antagonist antiemetic as a 15 min infusion without prophylaxis.

Keywords: admission avoidance; clincial management; emergency care system; emergency care systems; emergency departments; headache; treatment.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antiemetics / adverse effects*
  • Antiemetics / therapeutic use
  • Basal Ganglia Diseases / drug therapy*
  • Basal Ganglia Diseases / prevention & control*
  • Cholinergic Antagonists / pharmacology*
  • Cholinergic Antagonists / therapeutic use
  • Diphenhydramine / adverse effects
  • Diphenhydramine / therapeutic use
  • Humans


  • Antiemetics
  • Cholinergic Antagonists
  • Diphenhydramine