A Randomized Trial of Diphenhydramine as Prophylaxis Against Metoclopramide-Induced Akathisia in Nauseated Emergency Department Patients

Study objectiveAkathisia, an adverse effect observed at times after administration of parenteral metoclopramide, is an unpleasant symptom complex characterized by restlessness and agitation. Some try to limit the development of akathisia by coadministering diphenhydramine when using parenteral metoclopramide. The goal of this investigation is to determine whether concomitant administration of diphenhydramine 25 mg decreased the rate of development of akathisia after administration of 10 mg or 20 mg of intravenous metoclopramide.MethodsThis was a randomized, double-blind, factorial design trial. Patients who presented to our emergency department with a primary or secondary chief complaint of nausea were randomized to one of the following 4 groups: (1) metoclopramide 10 mg+diphenhydramine 25 mg; (2) metoclopramide 10 mg+placebo; (3) metoclopramide 20 mg+diphenhydramine 25 mg; (4) metoclopramide 20 mg+placebo. The medications were inserted into a 50-mL bag of normal saline solution and administered as an intravenous drip during 15 minutes. Primary outcome was development of akathisia within 60 minutes of medication administration, as measured by blinded assessors using a short akathisia instrument, or use of rescue medication for treatment of akathisia by blinded clinical staff. Patients were also asked at baseline and 30 minutes later whether they felt restless.ResultsTwo hundred eighty-nine patients were randomized and 286 patients were included in the final analysis. Within 1 hour of medication administration, 17 of 143 patients randomized to diphenhydramine (12%; 95% confidence interval [CI] 8% to 18%) and 17 of 143 (12%; 95% CI 8% to 18%) randomized to placebo developed akathisia (95% CI for difference of 0%: –8% to 8%). Thirteen of 143 patients randomized to metoclopramide 10 mg (9%; 95% CI 5% to 15%) and 21 of 143 randomized to metoclopramide 20 mg (15%; 95% CI 10% to 22%) developed akathisia (95% CI for difference of 6%: –2% to 14%). In those administered prophylactic diphenhydramine, odds of akathisia relative to placebo were 1.0 (95% CI 0.5 to 2.0). Odds of akathisia in those administered 20 mg of metoclopramide relative to the 10-mg dose were 1.7 (95% CI 0.8 to 3.6). Among patients who received 20 mg of metoclopramide, subjective restlessness was reported by 7 of 72 (9.7%) patients who received diphenhydramine and 14 of 71 (19.7%) patients who received placebo (95% CI for difference of 10%: –2% to 22%).ConclusionRoutine prophylaxis with diphenhydramine to prevent akathisia is unwarranted when intravenous metoclopramide is administered over 15 minutes. For patients administered 20 mg of metoclopramide, prophylactic diphenhydramine may decrease subjective restlessness.