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

Abstract and Introduction


Objective: Millions of patients present to US emergency departments (ED) annually for the treatment of migraine. First-line treatments, including metoclopramide, prochlorperazine, and sumatriptan, fail to provide sufficient relief in up to one-third of treated patients. In this narrative review, we discuss the evidence supporting the use of injectable (intravenous, intramuscular, or subcutaneous) medications for patients in the ED who fail to improve sufficiently after treatment with first-line medication.

Methods: We used the American Headache Society's guideline, "Management of Adults with Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies," published in 2016, to identify first-line medications for migraine. We then conducted a PubMed search to determine whether any evidence supported the use of these medications as second-line therapy and whether any evidence existed to support the use of injectable therapies not discussed in the guideline as second-line therapy.

Results: We identified only scant high-quality randomized data of second-line therapy. Therefore, we based our recommendations on medications that have reliably demonstrated efficacy as first-line treatment of migraine. These medications include injectable non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. Dihydroergotamine and valproic acid have some data supporting efficacy. More recently, greater occipital nerve blocks (GONBs) have been shown to be efficacious. With the exception of meperidine, opioids have been shown to be not efficacious. Most data published to date demonstrate no role for propofol and ketamine.

Conclusions: There are no evidence-based second-line treatments of migraine in the ED setting. For patients with migraine, who fail to improve after treatment with a first-line medication, it is reasonable to use an intravenous NSAID or intravenous acetaminophen. Alternatively, clinicians adept at performing a GONB may offer this treatment.


In 2016, the American Headache Society (AHS) published a guideline statement on the parenteral treatment of migraine in the emergency setting.[1] This guideline, applicable to the millions of patients who use an emergency department (ED) in the United States and internationally for the treatment of migraine, endorsed the use of the antidopaminergic antiemetics prochlorperazine and metoclopramide, in addition to subcutaneous sumatriptan as first-line therapy. The guideline also endorsed dexamethasone to prevent headache recurrence. While many other parenteral medications were reviewed, for no other medication was the accumulated evidence of efficacy reliable enough to recommend routine use, particularly as a first-line medication. However, for some patients and in some circumstances, prochlorperazine, metoclopramide, or sumatriptan are not sufficient. Some patients may receive these medications and fail to respond—it is clear that up to 33% of patients in the ED who receive one of the antidopaminergic antiemetics, and up to 35% of patients who receive sumatriptan will require a second medication to achieve satisfactory relief of their headache (Table 1). Others may have contraindications or poor experiences with these medications. Therefore, we conducted this review to discuss which medication emergency providers, and others who work or consult in an ED, should use in this situation. Specifically, we review which injectable (intravenous, intramuscular, or subcutaneous) medications are most likely to be effective among patients in the ED with migraine refractory to metoclopramide, prochlorperazine, or sumatriptan.