A New Aura of Relief: Emerging Treatments for Migraines

Migraines occur in more than 30 million people in the United States alone.¹ According to the International Headache Society, a migraine is a specific type of headache characterized by having at least 2 of the following symptoms: moderate to severe pain intensity, unilateral pain, throbbing or pulsating sensation, and/or increased symptoms with routine physical activity.

Additionally, the headache must also be accompanied by nausea and/or vomiting or photophobia/phonophobia.¹ The development of migraines may be secondary to factors that include, but are not limited to, disease states such as hypertension, dyslipidemia, coronary artery disease, stroke, and diabetes mellitus.¹

Migraines may also present with or without aura. An aura may serve as a precursor to a migraine or may present simultaneously. Those that present without aura experience pain as the primary indication of a migraine.

The pain from a migraine can be debilitating and limit otherwise normal daily activities. Walking the dog or simply getting out of bed in the morning may be strenuous for those experiencing a migraine.

There are pharmacological options for those who experience migraines in the form of abortive or preventative therapy. Abortive therapy is taken at the first sign of a migraine and preventative therapy may be beneficial to those who experience frequent migraines to help reduce migraine occurrence.

The pathophysiology of migraines remains largely unknown; however, it may be theorized that intracranial vasoconstriction and rebound vasodilation may contribute to migraines with aura. However, migraines that occur without aura do not show signs of insufficient blood supply.¹

There are several medications available for both abortive and preventative therapy. Several of these medications have been used for migraines for several years and are effective, however come with some patient-specific limitations. There have also been several agents that have been FDA-approved in recent years that may be more favorable for many patients and providers.

For patients with migraines, non-drug treatment options can include keeping a headache diary to assist with identifying triggers, such as stress, foods, and sleep environment. In addition to this, stress management, massage therapy, or applying cold compresses with or without ice to the head may also be helpful. However, for many patients, nonpharmacological therapy is not sufficient.

Abortive therapy is a mainstay of pharmacological migraine treatment.² OTC options for abortive therapy includes acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs). These options may be effective for some patients whose migraines are mild to moderate.

Caffeine in combination with acetaminophen or aspirin may also be effective to treat some migraine headaches.³ Prescription therapies include serotonin receptor agonists—commonly referred to as triptans.

Opioids, butalbital-containing products, and tramadol are typically not recommended due to the risk for abuse, dependence, as well as limited efficacy in migraine relief.³ While antiemetics don’t treat pain, they can be useful in patients with nausea and vomiting associated with migraines.⁴

Preventative therapy may be considered in patients who experience frequent migraines and are using abortive treatment 2 or more days a week or 3 or more times per month, have an overall decreased quality of life, or if abortive therapy is ineffective or contraindicated.¹ Oral preventative therapies that are commonly used include beta-blockers, anti-epileptics, antidepressants, and monophasic contraceptives in patients who have migraine without aura.

Although medications such as triptans, beta-blockers, and anti-epileptics have long been commonly used as mainstays of therapy for migraine treatment or prevention, they are also associated with several adverse effects (AEs) and contraindications for use. Triptans are contraindicated in patients with several cardiac conditions, including hypertension and coronary artery disease, and are associated with a phenomenon of “chest pressure syndrome,” which is typically not a medical emergency, but still an intolerable AE for many.⁵

Beta-blockers and anti-epileptic medications also have extensive AE profiles that many patients may not favor or be able to tolerate. Although these medications may be effective for migraines, their contraindications, precautions, and AE profiles limit their use for many individuals.

In the past few years, several new emerging therapies have been FDA-approved for migraine treatment and prevention. These medications have shown favorable outcomes with more tolerable AEs compared to the other therapies that have been used for migraines.

These medications vary in mechanism of action, but are different from the other commonly used therapies on the market. The mechanisms of action of these new emerging medications include calcitonin gene-related peptide (CGRP) antagonists, a novel 5-HT_1F receptor agonist, and monoclonal antibodies. These differing mechanisms of action account for better tolerability as well as more options for patients who may have contraindications to other therapies.

Atogepant (Qulipta) is a CGRP antagonist approved by the FDA for prevention of migraines in adults. This once daily oral tablet is supplied in 3 different strengths for patients who suffer debilitating migraines and have responded poorly to other preventative therapies.⁶

Phase 3 studies showed a significant reduction in days with migraines per month compared to placebo.^7,8 Providers should consider patients' liver and kidney function, pregnancy status or plans to become pregnant, and concurrent use of CYP3A4 inhibitors or organic anion transport inhibitors before prescribing atogepant.⁹

Rimegepant (Nurtec ODT) is another oral CGRP antagonist that is supplied as a 75 mg orally disintegrating tablet (ODT). Rimegepant can be considered for abortive treatment of moderate to severe migraines in patients for whom standard therapy with triptans is ineffective or contraindicated due to cardiovascular risks.¹⁰

Rimegepant is also indicated for migraine prevention in patients with frequent and debilitating migraines who have not found relief with adequate trials with other therapies and is taken as a 75 mg dose once every other day.⁶ Prescribers should collect a detailed patient history and review patients’ current medications for CYP3A4 inhibitors/inducers and P-gp inhibitors before prescribing rimegepant.⁶

Eptinezumab (Vyepti) is an injectable CGRP antagonist used for the prevention of migraines in adults. Eptinezumab is administered as a 30-minute intravenous (IV) infusion once every 3 months and is recommended for patients who have failed trials of at least 2 other preventative therapies.¹¹

Because eptinezumab is administered as a quarterly IV infusion, it can be a convenient choice for patients who do not wish to self-administer injections at home. Phase 3 trials showed a significant reduction in days with migraine per month in comparison to placebo.¹² There are currently no dosage adjustments for eptinezumab, although patients should be monitored for hypersensitivity reactions.¹³

Lasmiditan (Reyvow) is a novel 5-HT_1F receptor agonist and is used as abortive treatment for moderate to severe migraines.¹⁴ Unlike other serotonin agonists that target 5HT_1B and 5HT_1D receptors, lasmiditan’s novel mechanism may allow for migraine relief in patients resistant to other medications, or who have contraindications to these medications due to the effects on the cardiovascular system.¹⁵

Lasmiditan comes in 3 different dosages and should not be taken more than once in a 24-hour period, and physicians should review patients’ medication regimen for P-gp substrates, other central nervous system depressants, serotonergic drugs, and drugs that may lower heart rate.¹⁴ Patients should be educated on the potential for medication overuse headaches and sedation that may be caused when using lasmiditan.¹⁴

The chart below provides more information about these newer medications, as well as several other new medications that have been FDA-approved for migraine treatment and/or prevention in recent years.

Recent FDA-Approved Therapies^{6,9,13,14,16-19}

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As evidenced by this article, there are a multitude of medications available for migraine prevention and treatment. However, there are also several limitations associated with migraine therapies, specifically some of the traditional gold standard therapies, including AE profile, contraindications, and other comorbidities.

Some of the newest FDA-approved drugs for migraines may have better tolerability and efficacy for both migraine treatment and prevention compared to other agents on the market due to their differing mechanisms of action. New drug therapies for migraines have been developed to improve the quality of life and give those who suffer from migraines the ability to perform day-to-day activities that would otherwise be near impossible.

The more medication options developed for migraines, the more inclusive migraine therapy can become. By having more medication therapy options, patients who are limited by certain comorbidities or tolerability will have a broader selection to choose from instead of having to endure the pain from migraines without hope for relief.

References

1. Chawla J. Migraine Headache. Medscape. Accessed November 18, 2022. https://emedicine.medscape.com/article/1142556-overview.
2. VA/DoD Clinical Practice Guideline for the Primary Care Management of Headache. Department of Veterans Affairs/Department of Defense. Accessed November 18, 2022. https://www.healthquality.va.gov/guidelines/pain/headache/VADoDHeadacheCPGFinal508.pdf.
3. VanderPluym JH, Halker Singh RB, Urtecho M, et al. Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis. JAMA. 2021;325(23):2357–2369. doi:10.1001/jama.2021.7939
4. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based Guideline update: Pharmacologic Treatment for Episodic Migraine Prevention in adults: Table 1. Neurology. 2012;78(17):1337-1345. doi:10.1212/wnl.0b013e3182535d20
5. Jamieson DG. The safety of triptans in the treatment of patients with migraine. Am J Med. February 1, 2002;112:135-40.
6. Nurtec ODT. Package insert. Biohaven Pharmaceuticals; 2020.
7. Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the Preventive Treatment of Migraine. New England Journal of Medicine. 2021;385(8):695-706. doi:10.1056/nejmoa2035908
8. U.S. FDA Accepts AbbVie’s New Drug Application for Atogepant for the Preventive Treatment of Migraine. AbbVie News Center. Accessed November 18, 2022. https://news.abbvie.com/news/press-releases/us-fda-accepts-abbvies-new-drug-application-for-atogepant-for-preventive-treatment-migraine.htm
9. Quilipta. Package insert. AbbVie Pharmaceuticals; 2021.
10. Ailani J, Burch RC, Robbins MS. The American Headache Society Consensus Statement: Update on Integrating New Migraine Treatments into Clinical Practice. Headache: the Journal of Head and Face Pain. 2021;61(7):1021-1039. doi:10.1111/head.14153
11. Loder EW, Burch RC. Who Should Try New Antibody Treatments for Migraine? JAMA Neurology. 2018;75(9):1039. doi:10.1001/jamaneurol.2018.1268
12. Ashina M, Saper J, Cady R, et al. Eptinezumab in Episodic migraine: a randomized, double-blind, placebo-controlled Study (PROMISE-1). Cephalalgia. 2020;40(3):241-254. doi:10.1177/0333102420905132
13. Vyepti. Package insert. Lundbeck Seattle BioPharmaceuticals; 2020.
14. Reyvow. Package insert. Eli Lilly and Company; 2020.
15. Neeb L, Meents J, Reuter U. 5-HT1F Receptor agonists: A New Treatment Option for Migraine attacks? Neurotherapeutics. 2010;7(2):176-182. doi:10.1016/j.nurt.2010.03.003
16. Emgality. Package insert. Eli Lilly and Company; 2021.
17. Ajovy. Package insert. Teva Pharmaceuticals; 2018.
18. Aimovig. Package insert. Amgen, Novartis Pharmaceuticals; 2018.
19. Ubrelvy. Package insert. Allergan; 2019.