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

Other Medication Strategies

Nonspecific Analgesics

Acetaminophen. In the AHS guideline, intravenous (IV) acetaminophen was rated "possibly effective" based on efficacy versus active comparators in two randomized controlled trials (RCTs) although it failed to beat placebo in one RCT. We identified two RCTs of acetaminophen published after the guideline. In the first study, 52 patients with migraine received either IV metoclopramide 10 mg or IV acetaminophen 1 g.[15] Pain severity was measured at 15-, 30-, 60-, and 120-min intervals. Acetaminophen was far superior to metoclopramide at 15 min and maintained a modest lead at later times. No side effects were reported in this study. The second study was a randomized double-blind trial of 90 patients comparing IV acetaminophen as an adjunct to prochlorperazine+diphenhydramine versus prochlorperazine+diphenhydramine alone.[16] Pain scores were lower in the acetaminophen arm. Rescue medication was given to 38% of the acetaminophen group as opposed to 53% of the placebo group. The average length of stay was not changed.

Acetylsalicylic Acid. Based on four randomized studies, the AHS guideline endorsed the use of IV acetylsalicylic acid with a rating of "likely effective." We did not identify any additional studies of acetylsalicylic acid.

Nonsteroidal Anti-inflammatory Drugs

Dexketoprofen. Based on two randomized studies, the AHS guideline endorsed the use of IV dexketoprofen with a rating of "likely effective." Since the guideline was published, three randomized studies of dexketoprofen have been published. In one unblinded study of 154 patients, IV dexketoprofen was not as effective as subcutaneous injections of tenoxicam/lidocaine/thiocolchicoside.[17] In a 150-patient study of dexketoprofen versus metoclopramide versus the combination of the two, the combination was superior at 30 min, though there were no differences in short-term outcomes between dexketoprofen and metoclopramide.[7] In a randomized, placebo-controlled study of 224 patients, dexketoprofen was more efficacious than placebo within an hour of treatment.[18]

Diclofenac. Based on three randomized studies, the AHS guideline endorsed the use of parenteral diclofenac with a rating of "may offer." There have been no studies of parenteral diclofenac published since.

Ketorolac. Based on four randomized studies, the AHS guideline endorsed the use of parenteral ketorolac with a rating of "may offer." We identified two additional studies of ketorolac. One four-arm study randomized 128 patients to dexamethasone 8 mg, ketorolac 30 mg, metoclopramide 10 mg, or chlorpromazine 25 mg.[19] There were no substantial differences between the groups. A small study randomized 23 patients to intramuscular ketorolac or oral diclofenac and found no differences between the groups.[20]


Haloperidol. IV haloperidol was considered "likely effective" in the AHS guideline. Readers were cautioned that patients should be warned about extrapyramidal side effects. This recommendation was based on one comparative effectiveness study in which patients who received haloperidol had outcomes at least as good as metoclopramide and another small placebo-controlled study in which haloperidol outperformed placebo. We identified one new RCT published subsequently.[21] The study randomized 118 patients to 2.5 mg of haloperidol or normal saline. Haloperidol demonstrated a superior reduction of pain severity at 30 and at 60 min.

Chlorpromazine. Parenteral chlorpromazine was rated as "possibly effective" in the AHS guideline. This was based on three randomized studies that compared chlorpromazine to placebo, metoclopramide, and ketorolac. We identified one new double-blind RCT trial published after the guideline.[19] The study randomized 128 patients to one of four groups; each participant received one of the following drugs intravenously: dexamethasone 8 mg, ketorolac 30 mg, metoclopramide 10 mg, or chlorpromazine 25 mg. The severity of headache was assessed at the starting point, 1 h after treatment, and 24 h after treatment. No significant difference was found in the severity of symptoms among the four study arms. Side effects were more common in the chlorpromazine arm and less common among the dexamethasone-treated patients.

Anti-seizure Drugs

Valproic Acid. IV valproic acid was rated as "likely effective" in the AHS guideline based on four studies. It was outperformed by metoclopramide, prochlorperazine, and ketorolac while having no difference in efficacy when compared with dexamethasone or acetylsalicylic acid. We identified two randomized control trials published after the guideline. The first study enrolled 37 patients and compared 15 mg/kg of IV valproic acid with 6 mg of subcutaneous sumatriptan.[22] Overall pain scale reduction and medication response time were superior in the valproate arm. No significant side effects were noted. The second study enrolled 72 patients and compared 400 mg IV valproic acid with 16 mg IV dexamethasone.[23] There was no difference reported among patients without an aura, but valproic acid was superior to dexamethasone in those with an aura. No side effects were reported.


In the AHS guidelines, based on limited data supporting efficacy, IV opioids were rated as "possibly effective" (meperidine), "possibly ineffective" (morphine), or "insufficient evidence" (nalbuphine, hydromorphone). Because of no evidence supporting efficacy and mounting evidence of long-term harm, clinicians were encouraged to avoid hydromorphone and morphine. Limited data supporting efficacy and mounting evidence of long-term harm resulted in neither a positive nor a negative recommendation for meperidine and nalbuphine. In the intervening years, one additional study was published in which hydromorphone was compared with prochlorperazine+diphenhydramine.[24] This study, which reported outcomes on 126 patients, demonstrated a substantial benefit of prochlorperazine over hydromorphone, both in the ED and at 48 h.


Propofol. The AHS guideline identified two randomized studies of propofol. In the first, propofol was dosed in 30–40 mg boluses with subsequent 10–20 mg boluses every 3–5 min up to 120 mg.[25] In the second, propofol was dosed at 10 mg every 5–10 min up to 80 mg.[26] In the first study, propofol demonstrated greater efficacy than sumatriptan at 30 min. In the second, propofol demonstrated greater efficacy than dexamethasone. The AHS guideline deemed propofol as "possibly effective" up to 45 min. However, based on high-risk adverse events (oxygen desaturation), the guideline authors made no recommendation. Subsequently, two studies of propofol for migraine have been published. The first was a small, randomized, unblinded study of propofol versus standard care.[27] Propofol was dosed at 1 mg/kg. In this study, pain scores between the groups were comparable, though patients who received propofol were able to be discharged sooner. The second was a randomized, double-blind, placebo-controlled study.[28] Propofol failed to outperform placebo with regard to headache freedom, use of rescue medication, or desire to receive the same medication again, though a greater percentage of participants who received propofol reported a reduction in pain scores.

Ketamine. In the AHS guideline, IV ketamine was not recommended due to insufficient evidence from only one class 3 study. We identified one additional RCT published subsequently. In this double-blind RCT, prochlorperazine/diphenhydramine was compared with ketamine/ondansetron.[29] A total of 54 patients were enrolled, randomized to receive either prochlorperazine 10 mg intravenously along with diphenhydramine 25 mg intravenously, or intravenous ketamine at 0.3 mg/kg along with intravenous ondansetron at 4 mg. The prochlorperazine group substantially outperformed the ketamine group at 60 min. Two patients in the ketamine arm had severe dysphoria while one patient in the prochlorperazine arm had akathisia. Patients who received ketamine had higher rates of vomiting and rescue medication administration.

Other Medications

Magnesium. In the AHS guidelines, magnesium was not given a recommendation because in five randomized studies with varying methodology, magnesium failed to demonstrate a benefit versus placebo reliably. However, based on one placebo-controlled study, the guideline authors felt magnesium may have a benefit for patients with migraine with aura. We identified one additional randomized study published after the guideline.[30] In this study, patients were randomized to magnesium 2 g, prochlorperazine 10 mg, or metoclopramide 10 mg, each infused over 20 min. There were no substantial differences in pain scores among the groups or in the frequency of use of rescue medication. However, this study was limited by the concomitant use of off-protocol analgesic medication or dexamethasone in more than 50% of study participants.

Dexamethasone. In the AHS guideline, dexamethasone was not given a recommendation for acute treatment, though it was recommended for the prevention of headache recurrence. This rating was based on data from four studies with conflicting results. We identified three additional studies published in the interim. One four-arm study randomized 128 patients to dexamethasone 8 mg, ketorolac 30 mg, metoclopramide 10 mg, or chlorpromazine 25 mg.[19] There were no substantial differences between the groups. A second study randomized 90 patients to dexamethasone 8 mg or valproate 400 mg.[23] Both medications were highly effective, with dexamethasone outperforming valproate on some outcomes. A final study randomized 220 patients to metoclopramide + dexamethasone 10 mg IM or metoclopramide + methylprednisolone acetate 160 mg IM.[31] Fewer patients who received the dexamethasone required rescue medication in the ED.

Dihydroergotamine. Based on two lower quality studies, dihydroergotamine (DHE) was determined to be "possibly effective" in the AHS guideline. In these studies, DHE resulted in similar pain outcomes as diclofenac and sumatriptan. We were unable to identify any randomized studies published subsequently.

Granisetron. We identified two studies of the serotonin 5HT3 antagonist granisetron for migraine, which were not included in the AHS guideline. These studies, one of which compared granisetron with placebo and one granisetron with metoclopramide,[32] were of lower quality and came to different conclusions regarding granisetron's efficacy for migraine. Therefore, the available evidence does not indicate a role for intravenous 5HT3 antagonists for migraine pain.[33]

Greater Occipital Nerve Block

The GONB was not formally evaluated in the AHS guideline. The guideline authors identified one study that incorporated a GONB. This study tested whether triamcinolone, a corticosteroid, provided benefit when added to local anesthetics in a GONB and found no benefit.

We identified three RCTs of GONBs published subsequent to the guideline. In the first, 28 patients with persistent pain despite first-line treatment with IV metoclopramide were randomized to a true GONB with bupivacaine or an intradermal injection of bupivacaine.[13] Among this group, the true block resulted in greater rates of headache freedom and sustained headache relief than the sham control. In the second RCT, 60 patients were randomized into three groups: GONB with bupivacaine, sham block with normal saline, or medical management with dexketoprofen and metoclopramide.[34] By 45 min, the true nerve block and medical management groups had improved comparably and resulted in more pain relief than the sham block group. The third RCT used a double-dummy design and randomized 99 patients to IV metoclopramide or GONB with bupivacaine.[35] The results of this study favored IV metoclopramide, although these study authors reported that in experienced hands, the GONB was at least as effective as IV metoclopramide.