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.

Objective We compared metoclopramide 20 mg IV, combined with diphenhydramine 25 mg IV, to ketorolac 30 mg IV in adults with tension-type headache and all non-migraine, non-cluster recurrent headaches. Methods In this ED-based randomized, double-blind study, we enrolled adults with non-migraine, non-cluster recurrent headaches. Patients with tension-type headache were a subgroup of special interest. Our primary outcome was a comparison of the improvement in pain score between baseline and one hour later, assessed on a 0 to 10 verbal scale. We defined a between-group difference of 2.0 as the minimum clinically significant difference. Secondary endpoints included: 1) need for rescue medication in the ED; 2) achieving headache freedom in the ED and sustaining it for 24 hours; and 3) patient’s desire to receive the same medication again. Results We included 120 patients in the analysis. The metoclopramide/diphenhydramine arm improved by a median of 5 (IQR 3,7) scale units while the ketorolac arm improved by a median of 3 (IQR 2,6) (95%CI for difference: 0, 3). Metoclopramide + diphenhydramine were superior to ketorolac for all three secondary outcomes: the number needed to treat for not requiring ED rescue medication was 3 (95%CI: 2, 6), for sustained headache freedom 6 (95%CI: 3, 20), and for wish to receive the same medication again 7 (95%CI: 4, 65). Tension-type headache subgroup results were similar. Conclusions For adults who presented to an ED with tension-type headache or with non-migraine, non-cluster recurrent headache, IV metoclopramide + diphenhydramine provided more headache relief than IV ketorolac.

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