Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department–Based Randomized Clinical Trial

Abstract

Background More than one million patients present to US emergency departments (ED) annually seeking care for acute migraine. Parenteral anti-histamines have long been used in combination with anti-dopaminergics such as metoclopramide to treat acute migraine in the ED. High quality data supporting this practice do not exist. We determined whether administration of diphenhydramine 50mg IV + metoclopramide 10mg IV resulted in greater rates of sustained headache relief than placebo+ metoclopramide 10mg IV. Methods This was a randomized, double-blind clinical trial comparing two active treatments for acute migraine in an ED. Eligible patients were adults younger than 65 years presenting with an acute moderate or severe headache meeting International Classification of Headache Disorders-2 migraine criteria. Patients were stratified based on presence or absence of allergic symptoms. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within two hours of medication administration, and maintaining this level of relief without use of any additional headache medication for 48 hours. Secondary efficacy outcomes include mean improvement on a 0 to 10 verbal scale between baseline and one hour, the frequency with which subjects indicated they would want the same medication the next time they present to the ED with migraine, and the ED throughput time. Sample size calculation using a 2-sided alpha of 0.05, a beta of 0.20 and a 15% difference between study arms determined the need for 374 patients. An interim analysis was conducted when data were available for 200 subjects. Results 420 patients were approached for participation. 208 eligible patients consented to participate and were randomized. At the planned interim analysis, the data safety monitoring committee recommended that the study be halted for futility. Baseline characteristics were comparable between the groups. 14% (29/208) of the sample reported allergic symptoms. Of patients randomized to diphenhydramine, 40% (40/100) reported sustained relief at 48 hours, as did 37% (38/103) of patients randomized to placebo (95%CI for difference of 3%: −10, 16%). One hour after medication administration, those randomized to diphenhydramine improved by a mean of 5.1 on the 0 to 10 scale versus 4.8 for those randomized to placebo (95%CI for difference of 0.3: −0.6, 1.1). 85% (84/99) of the patients in the diphenhydramine arm reported they would want the same medication combination during a subsequent ED visit, as did 76% (77/102) of those who received placebo (95%CI for difference of 9%: −2, 20%). Median ED length of stay was 122 minutes (IQR: 84, 180) in the diphenhydramine group and 139 minutes (IQR: 90, 235) in the placebo arm. Rates of side effects, including akathisia, were comparable between the groups. Conclusions Intravenous diphenhydramine, when administered as adjuvant therapy with metoclopramide, does not improve migraine outcomes.

Management of Adults With Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies

“…We identified one study of diphenhydramine for migraine . In a class 1 study, there were no differences in outcomes or adverse events among 208 adults randomized to diphenhydramine 50 mg IV or placebo.…”

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

“…Literature has shown that a drop-out rate of less than 5% is minor,26 27 and the calculated ratios of dropped participants to total events (3/34 and 7/15, respectively) were not significant to influence intervention effect. High risk for bias was noted for the ‘Other bias’ category in the Friedman et al (2016) study as the trial was halted slightly past the halfway point due to enforcement of a stopping rule 24. This stopping rule was established prior to initiation of the trial and stated that the study was to be stopped if the absolute risk reduction of headache was less than 7.5% in the cohort receiving diphenhydramine and metoclopramide.…”

“…Only four RCTs satisfied eligibility criteria and sample sizes were small. One study was halted near the halfway point due to enforcement of a stopping rule, introducing the possibility that results may not reflect the actual outcome if the study was completed 24. In addition, a no-intention-to-treat analysis was performed for drop-outs.…”

Migraine Care Challenges and Strategies in US Uninsured and Underinsured Adults: A Narrative Review, Part 2

“…Hydroxyzine possesses anxiolytic qualities and has been studied for use in pain alone and with DHE in migraine . Diphenhydramine is frequently used as a parenteral adjunct for migraine treatment in the ED, though study results have been mixed . Neither drug is listed in the AHS guidelines or the 2000 AAN practice parameter.…”

“…18,19 Diphenhydramine is frequently used as a parenteral adjunct for migraine treatment in the ED, though study results have been mixed. 11,[20][21][22][23][24] Neither drug is listed in the AHS guidelines or the 2000 AAN practice parameter.…”