New Developments in Migraine Treatment
Several touted “migraine-specific” agents have been recently developed, including CGRP receptor antagonists (for abortive use) and monoclonal antibodies targeting CGRP receptors or the protein itself (preventive use). These medications represent a great advancement in current treatment of migraine to a more specific, tailored therapy based on known pathophysiologic mechanisms. Several oral CGRP receptor antagonists in development have shown promising efficacy in treating migraine with superiority to placebo and comparability to triptans, but many of the trials have been discontinued due to concerns of hepatotoxicity after taking the drug for multiple consecutive days. A phase IIRCT published in 2016 found that ubrogepant, a CGRP receptor antagonist, yielded modest results as an abortive agent in the indicator single migraine freedom at two hours after medication administration when compared to placebo; there were no signs of hepatotoxicity within 1 week of drug administration.30 These agents are on track for possible FDA approval.
In recent years, four monoclonal antibodies targeting CGRP or the CGRP receptor have been tested in humans for the prevention of migraine: galcanezumab, eptinezumab, erenumab, and fremanezumab.31 High-quality RCTs have demonstrated the efficacy of these antibodies in decreasing migraine days in episodic migraine as well as chronic migraine. Fremanezumab showed efficacy in reducing monthly migraines in a phase III trial of 1130 patients with chronic migraine.32 Erenumab—the only monoclonal antibody that targets the CGRP receptor—demonstrated similar efficacy for episodic migraine in addition to chronic migraine.33 The reported reduction in monthly migraine has been approximately three to six episodes per month and significantly greater than placebo. Of note, patients with chronic migraine were excluded from the previously cited studies if they had failed preventative treatment with two to three prophylactic medications. Despite the promising results of these positive trials, additional studies are needed to determine the long-term efficacy, safety, and cost-effectiveness of monoclonal antibodies. An analysis of a 5-year study of erenumab revealed sustained treatment effect and safety at week 64, with 25% of patients reporting 100% reduction in monthly migraine days.34 Erenumab, galcanezumab, and fremanezumab are all currently FDA-approved for migraine prevention. The long-term safety is still questioned, as well as the role of these agents as first-line treatments or only after multiple medications failures. As CGRP is an essential vasodilatory protein for cerebral and coronary arteries, its potential contraindication in patients with coronary artery disease, past stroke, or uncontrolled hypertension for example has not been well-studied but should be taken into consideration when there is a thought of prescribing these agents.
Another breakthrough in the treatment of migraine is the development of 5-HT1F receptor antagonists Particularly, this drug class binds more specifically to the serotonin IF receptor than triptans which bind to the 5HTlb/d receptors with the potential for vasoconstriction.35 This new drug class called ditans may be highly valuable for an aging population that is no longer eligible for triptan therapy because of cardiovascular and cerebrovascular risk factors or in those with known coronary artery disease.
Role of Opiates in Migraine Treatment
A crisis exists in the United States and other countries around the world with the inordinate amount of opioids being used for non-cancer-related pain syndromes. One of the largest culprits is the use of opioids for migraine, especially in the ED. Although consensus guidelines have advised against the use of opioids for migraine, a recent publication noted a 70% increase in the use of hydromorphone, morphine, and oxycodone in U.S. emergency departments from 2001 to 2010.36 Looking at the data, opioids are typically less effective or, at most, equally effective as multiple non-opioid acute migraine treatments, including ketorolac,37 DHE,38 corticosteroids,39 and dopamine receptor antagonists.40 In addition, opioids have the distinction of being associated with abuse and habituation. Opioids drain medical resources, as they have been shown to lead to an increase in headache relapse and need for a return to the ED for further treatment.41 A recent study has shown that if patients in the ED are administered opioids, it results in longer ED stays than if non-opioid compounds are utilized.42 Opioids should only be used on infrequent occasions for migraine therapy, including pregnancy, in patients with multiple risk factors to non-opioid medications, and in the rare patient who presents to the ED with no history of abuse (opioid or other drugs or alcohol) and has multiple documented medical contraindications to almost every other class of acute migraine medication that can be delivered in the ED for status migrainosus; thus on very rare occasions. All opioids for home use as an acute headache treatment should be limited at maximum to 2 days a week and with a limited number of pill amounts being given on the prescription which automatically limits abuse and medication overuse potential.
