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

Recommendations and Discussion

We were unable to identify sufficient data that directly addressed the question of which injectable (intravenous, intramuscular, or subcutaneous) medication to use as second-line therapy if initial medication provides inadequate relief. Instead, we found numerous comparative effectiveness studies, and some placebo-controlled studies, which, when taken together, paint a complicated picture of the efficacy of a variety of medications for acute treatment of migraine, and result in a fair amount of uncertainty about what medication to use as second-line therapy. We present a flow diagram in Table 2, which represents the authors' opinion about how to treat patients in the ED with migraine who do not respond sufficiently to first-line medication.

Antidopaminergic medications were recommended as primary treatment of migraine in the AHS guideline and evidence has continued to emerge demonstrating the efficacy of multiple different medications from this class. If a different type of medication is used as first-line medication, then it is appropriate to use an antidopaminergic medication as a rescue medication. For patients who report insufficient relief after one dose of an antidopaminergic medication, it is unclear if a second dose will afford additional relief. We believe this may be a reasonable strategy, particularly if the antidopaminergic is combined with another type of medication such as DHE. However, it must be noted that this strategy of re-dosing or switching to a different antidopaminergic medication has not been studied—it is not known whether or not this strategy is efficacious, and whether the risk of medication-induced adverse events is cumulative. Clinicians should be attuned to the risks of extrapyramidal symptomatology and the theoretical possibility of dysrhythmias. Please see Table 3 for a list of antidopaminergic medications with proven efficacy in migraine.

Unlike with the antidopaminergics, a strategy of retreatment with subcutaneous sumatriptan has been studied and determined to be not effective. Some ED-based studies also suggest that sumatriptan is most likely to be effective earlier in the headache course.[3] However, for patients who do not improve after treatment with a different type of medication, it is reasonable to use subcutaneous sumatriptan in this role.

Three different parenteral NSAIDs were evaluated in the AHS guideline—dexketoprofen, diclofenac, and ketorolac. Each of these received a favorable rating from the AHS guideline authors, though the evidence was insufficient for these medications to be considered first-line therapy. Since the AHS guideline was published, more data have been published supporting the efficacy of this class of medication. Therefore, these medications may be considered for patients with treatment refractory headache. It also seems reasonable to combine these medications with other classes of medications, such as the antidopaminergics or triptans.

Similarly, IV acetaminophen received a favorable rating in the initial guideline statement but ultimately was not endorsed as a first-line medication because of inconsistent results. Since the guideline was published, more data have emerged supporting the use of IV acetaminophen for acute treatment of migraine. Therefore, IV acetaminophen may also be considered for the second-line treatment of migraine and, as with the NSAIDs, may be combined with other classes of medication when used in this role.

The sedative/hypnotics are an appealing class of medications to use as second-line therapy because of the increasing frequency of their use in the ED for management of acute general pain (ketamine) and seizures (propofol). However, neither ketamine nor propofol consistently demonstrated benefit for migraine and reliably cause serious or unpleasant side effects. Therefore, these medications should not be used routinely as second-line therapy for migraine.

Similarly, anti-seizure drugs are intuitively appealing for the treatment of migraine and do play an important role in migraine prevention. However, the benefit of injectable anti-seizure drugs has not been well established. To our knowledge, the only anti-seizure drug studied in this manner is valproic acid, which received a favorable rating in the AHS guideline, but did not consistently demonstrate efficacy and so was not promoted as a first-line medication. Subsequent to the publication of the guideline, a small study was published in which IV valproic acid seemed superior to sumatriptan, as first-line therapy.[22] Therefore, valproic acid may be considered for patients who require additional treatment.

Opioids were not recommended in the original guideline. During the intervening years, additional data have emerged demonstrating poor acute outcomes among patients treated with hydromorphone. Therefore, even though it is possible that meperidine is efficacious for migraine, we believe that accumulating evidence of long-term harm associated with opioids means that, in most cases, opioids should not be offered to patients as a second-line medication unless no other class of medication can be used.

Dexamethasone was not previously recommended for acute efficacy[1] but more recently published data suggest that dexamethasone may have a benefit acutely as well.[31] Particularly because dexamethasone should be used anyway for the prevention of headache recurrence, it is reasonable to administer it as a second-line medication with the goal of improving in-ED outcomes. The optimal dose of dexamethasone in this role has not been well established, with some investigators using doses as high as 16 mg.[23]

Injectable DHE is a medication in need of more data. It is commonly used for patients with migraine refractory to other treatment, though no high-quality data are available to support its use in this role. Most data come from non-randomized studies, in which DHE is often combined with antidopaminergics.[36–39] Decisions on use of injectable DHE can also be informed by the efficacy of non-injectable forms of DHE.[40] If DHE is used, we recommend it be combined with an antidopaminergic antiemetic with the goal of suppressing common upper gastrointestinal side effects and increasing efficacy.

The GONB with a local anesthetic has emerged as the injectable treatment with the most reliably efficacious data since the publication of the AHS guideline. This procedure is now an important tool in the armamentarium of clinicians who treat migraine in the emergency setting and may be considered for patients with migraine refractory to first-line treatments.

While the focus of this review is injectable medications, oral medications may occasionally play a role in the second-line treatment of migraine in the ED and will be discussed briefly. A variety of oral medications are available and can be considered for patients with migraine refractory to first-line injectable therapy, particularly for those patients whose nausea or vomiting resolved after treatment with first-line medication. Oral triptans have been studied extensively in the outpatient setting and have demonstrated safety and efficacy in this setting, though no ED-based data are available.[41] Similarly, outpatient data indicate that second-generation oral CGRP receptor antagonists and serotonin 1F agonists are efficacious.[42] The role of these medications vis-à-vis injectable medications for patients in the ED with migraine refractory to injectable medication is still to be determined.