Acute treatment landscape has many options

Acute migraine therapy with a drug approved for migraine prevention may warrant further study amid the landscape of available acute therapies, a meta-analysis and phase III trial published simultaneously in JAMA suggested.

“There are several acute treatments for migraine, with varying degrees of supporting evidence. Use of triptans, NSAIDs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function,” wrote Zhen Wang, PhD, of Mayo Clinic in Rochester, Minnesota, and co-authors wrote about their meta-analysis of acute migraine therapies. “The evidence for many other interventions, including opioids, was limited.”

Among patients who had a moderate to severe migraine attack, treatment with intravenous eptinezumab, an anti-calcitonin gene-related peptide (CGRP) antibody approved for migraine prevention, led to faster headache and symptom resolution than placebo, reported Roger Cady, MD, of the Lundbeck La Jolla Research Center in San Diego, and co-authors, in a report of their phase III trial.

In an editorial accompanying the studies, Rebecca Burch, MD, of Harvard University and Melissa Rayhill, MD, of the State University of New York in Buffalo, wrote that taken together, the reports “communicate a message of optimism. Many effective acute treatment options are available for patients with migraine, and CGRP-targeted medications may transform the approach to migraine treatment.”

Meta-analysis of acute treatments

The systematic review and meta-analysis included evidence about triptans and non-steroidal anti-inflammatory drugs from 15 systematic reviews. For other interventions, Wang and colleagues looked at 115 randomized clinical trials with 28,803 patients.

Triptans and non-steroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day and increased risk of mild and transient adverse events versus placebo. Compared with placebo, anti-CGRP receptor antagonists, lasmiditan (5-HT1F receptor agonist), dihydroergotamine, ergotamine plus caffeine acetaminophen, antiemetics, butorphanol, and tramadol in combination with acetaminophen were significantly associated with pain reduction and increase in mild adverse events.

Several non-pharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation, transcranial magnetic stimulation, external trigeminal nerve stimulation, and noninvasive vagus nerve stimulation.

Eptinezumab trial

The phase III RELIEF trial of eptinezumab for acute migraine was conducted from November 2019 to July 2020 and included adults with a one year or more history of migraine who had attacks 4-15 days per month. Participants were randomized to either eptinezumab injection (100 mg) within 6 hours of a qualifying moderate to severe migraine (n=238) or placebo injection (n=242).

Compared with placebo, patients treated with eptinezumab had faster headache pain freedom (median 4 hours versus 9 hours, HR 1.54; P<0.001) and absence of the most bothersome symptom (median 2 hours versus 3 hours, HR 1.75; P<0 .001).

“Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution,” Cady and colleagues wrote. “Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established.”

“This is the first study to report rapid, acute benefits of a CGRP monoclonal antibody started for prevention, thereby serving as a possible inflection point for how clinicians conceptualize the role of CGRP monoclonal antibodies as migraine therapies,” the editorialists observed.

This trial, and a recent phase 2/3 trial of rimegepant, a small-molecule CGRP receptor antagonist FDA approved for the acute treatment of migraine, “both evaluated treatments targeted at CGRP or its receptor and indicate that this class of therapies may transcend the traditional dividing line between acute and preventive migraine medications,” Burch and Rayhill added. “The possibility of an entirely new approach to migraine treatment, whereby acute therapies may have preventive benefit and preventive treatments have immediate effects, is an intriguing step forward for the field.”

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In the eptinezumab trial, the mean participant age was 44 and 84% were women. Other results included less rescue medication use within 24 hours for the eptinezumab versus placebo group (31.5% versus 59.9%, respectively, OR 0.31, 95% CI, 0.21-0.45; P< 0.001).

Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group. The most common event was hypersensitivity, which occurred only with eptinezumab (2.1%; n=5, all within 40 minutes of infusion). No treatment-emergent serious adverse events were reported.

Burch and Rayhill pointed out that translating these and other findings into meaningful improvements in clinical practice and patient care require comparative effectiveness and safety studies among different migraine acute treatments, simplified acute treatment decision-making, an assessment of cost and access barriers, and continuous safety monitoring.

“Furthermore, clinicians and researchers cannot be complacent with recent breakthroughs because many patients are still left with disabling symptoms,” they wrote. “Unrelenting and bold research is required to continue development of new acute therapies. Effective, reliable, and safe acute treatment for migraine is within reach, and patients deserve nothing less.”

Limitations of eptinezumab for acute migraine include logistical barriers which may prevent it from being used the way it was in the trial.

“Eptinezumab is currently only available after insurance approval, which can take several days to obtain, and administration requires access to an infusion center,” the editorialists wrote.” It is unlikely that these barriers will be traversed within 6 hours of headache onset.”

  1. Acute migraine therapy with a drug approved for migraine prevention may warrant further study amid the landscape of available acute therapies, a meta-analysis and phase III trial published simultaneously in JAMA suggested.

  2. Compared with placebo, patients with acute migraine treated with eptinezumab had shorter time to headache and symptom resolution.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The meta-analysis was funded by the Agency for Healthcare Research and Quality (AHRQ). Wang reported no disclosures.

The phase III trial was sponsored and funded by H. Lundbeck. Cady is an employee and stockholder of Lundbeck.

Burch is a member of the board of the American Headache Society and the Headache Cooperative of New England. She receives a stipend for work as an associate editor for the journal Neurology. Rayhill had no disclosures.

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