Second-line Interventions for Migraine in the Emergency Department

A Narrative Review

Farnam Kazi MD; Mallika Manyapu MD; Maha Fakherddine MD; Kumelachew Mekuria MD; Benjamin W. Friedman MD, MS


Headache. 2021;61(10):1467-1474. 

In This Article


In our literature review, we were only able to identify scant data on this topic—there were very few randomized studies of second-line therapy. One small study was conducted among patients who had failed first-line therapy in the ED.[13] This study randomized 28 patients with migraine refractory to metoclopramide to treatment with greater occipital nerve block (GONB) or sham nerve block and is discussed in more detail below. An outpatient study randomized patients who had not improved after one dose of subcutaneous sumatriptan to a second dose of subcutaneous sumatriptan or to placebo.[14] It also is discussed below. Of the dozens of randomized studies conducted in the ED setting, no other study addressed migraine refractory to first-line medication. Most published data on migraine refractory to first-line parenteral medication are not controlled, randomized, or blinded. Therefore, we are left to suggest strategies for treatment based on efficacy in first-line situations.

One simple strategy to use among patients who fail to improve after one dose of injectable medication is to re-dose the initial medication—if one dose of the medication was not effective, perhaps a second dose would be. This hypothesis was formally tested for sumatriptan. In a randomized study, 216 patients who had insufficient relief after receiving sumatriptan 6 mg SQ were randomized to a subsequent 6 mg dose or placebo. There was no difference between groups in the number of patients who reported improvement in headache severity.[14] For the antidopaminergic antiemetics, we could not identify any randomized studies that evaluated the efficacy of the second dose of either metoclopramide or prochlorperazine. A re-dosing strategy was used in one small study, in which patients who presented to an ED with migraine were treated with sequential doses of metoclopramide 20 mg IV, up to a total of 80 mg, until their headache had improved sufficiently.[2] This was not a randomized assessment of dosing efficacy, but the large cumulative dose of metoclopramide (80 mg) was well-tolerated. Another study randomized patients in the ED with migraine to initial doses of 10, 20, or 40 mg of metoclopramide.[5] There were no differences in efficacy or side effects between these groups but this study did not test a re-dosing strategy—it just tested a range of different initial doses. Therefore, we concluded that subcutaneous sumatriptan should not be re-dosed because it is unlikely to be efficacious. With regard to metoclopramide, it is uncertain whether or not a subsequent dose would be efficacious for patients who do not improve after an initial dose but, based on these two studies, it is unlikely to result in an increased rate of adverse events.

A second simple strategy to use among patients who fail to improve after one dose of injectable medications is a cross-over strategy, in which patients who do not improve after being administered one of these two antidopaminergic antiemetics are administered sumatriptan, or patients who do not improve after receiving sumatriptan are given one of the antidopaminergic antiemetics. This strategy also has not been formally evaluated.