Pharmacologic Treatment of Migraine: Current and Emerging Therapies

Migraines or severe headaches affect 15.9% of the population each year and prevalence is approximately twice as high in females than in males. There is a significant burden within marginalized groups, with nearly 40% of those who experience migraine being unemployed and a similar percentage classified as “poor” or “near poor.”¹

In addition, migraine is comorbid with depression and anxiety, and higher headache frequency is associated with a more negative life impact.² Despite high costs posing a barrier to many who wish to seek treatment,² migraines account for at least 1.2 million annual emergency department (ED) visits, making it the fifth leading cause of visits to the ED each year.

Opioids have traditionally been used as an abortive migraine treatment in the ED.³ Studies have demonstrated that patients with migraine who use opioids have increased headache-related burden and worsened quality of life than those who do not.⁴

Further, efforts across all pain management specialties to reduce the amount of opioids prescribed for pain due to a 4-fold increase in prescription opioid overdoses between 1999 and 2018³ reveal a need for migraine-specific medications in order to improve patient outcomes and potentially help decrease the use of opioids.

Migraine medications are typically classified in 2 categories: acute/abortive, which treat migraine symptoms after onset, and preventive, which reduce the frequency and severity of symptoms before their occurrence in those with significant attacks (defined as ≥ 4 migraine attacks per month or very disabling attacks for example).⁵

A relatively new class of drugs to treat migraines are calcitonin gene-related peptide (CGRP) inhibitors. CGRP is found in the trigeminal neurons of the nervous system, and studies have shown elevated levels of CGRP are released into the cranial venous outflow during migraine onset.⁶

Existing CGRP-inhibiting medications are injectable monoclonal antibodies used for the acute treatment of migraines (one is also indicated for the treatment of episodic cluster headaches). They act by either binding to the CGRP receptor and acting as an antagonist (erenumab)⁷ or by binding to CGRP and preventing it from binding to the receptor, as in the cases of eptinezumab, fremanezumab, and galcanezumab.^8-10

Gepants, another type of CGRP inhibitor, were initially abandoned when they were studied in the early 2000s due to concerns of liver toxicity. However, a second generation of gepants shows promise for potential acute and preventive treatment of migraines.

Gepants also serve as antagonists to the CGRP receptors, but unlike the monoclonal antibodies, they are small molecules that can be administered orally.¹¹ Two gepants have already been approved by the FDA for acute treatment of migraine: ubrogepant and rimegepant.

In a March 2020 study, 741 patients were given either a placebo or rimegepant 75 mg every other day. The rimegepant group showed a 6.4-day reduction in monthly migraine days in those who had a baseline of 14 or more monthly migraine days and a 4-day reduction in those who experienced fewer than 14 monthly migraine days, demonstrating the efficacy of rimegepant in the preventive treatment of migraine.¹¹

Now approved as a preventive medication, rimegepant is the first migraine treatment with evidence for both acute and preventive use.¹²

In addition, the FDA accepted the New Drug Application for the first preventive-only CGRP receptor antagonist treatment for episodic migraine, atogepant. Results of the phase 3 ADVANCE clinical trials demonstrated the efficacy of atogepant in the prevention of migraine.

A total of 910 participants who experienced 4 to 14 monthly migraine days were randomly given either 10 mg, 30 mg, or 60 mg of atogepant or placebo. Those receiving 10 mg/30 mg/60 mg atogepant experienced a decrease of 3.69/3.86/4.2 mean migraine days a month over a 12-week period, compared with a decrease of 2.48 days in the placebo group. These results demonstrate a significant difference (P <.0001) in the reduction of monthly migraine days for all dosage groups versus the placebo.¹³

Another drug class that has been developed for the treatment of migraine is serotonin or 5-hydroxytryptamine (5-HT) receptor agonists. Medications of this class are called triptans, and traditionally activate the 5-HT1B and 5-HT1D receptor subtypes.

However, triptans have shown a vasoconstrictive effect and are thus contraindicated in patients who have migraine with comorbid cardiovascular disease.¹⁴ Researchers have developed a new subclass called ditans, which activate the 5-HT1F receptors and do not cause vasoconstriction.

Lasmiditan is the first medication of this class to be approved by the FDA for acute treatment of adult migraine with and without aura. It was approved following 2 clinical trials, SAMURAI and SPARTAN, which each compared the effects of lasmiditan and placebo in adults with migraine with a history of 3 to 8 migraine attacks but fewer than 15 migraine days per month.

The SPARTAN study also included patients with migraine with coexisting heart and vascular disease. In both trials, approximately one-third of patients receiving lasmiditan were pain-free at 2 hours compared with only 15% to 21% who had received placebo. There was no evidence of blood vessel constriction in cardiovascular patients in the SPARTAN study.¹⁵

Pharmacists should assess patient comorbidities, symptoms, and history to ensure the selection of the most appropriate migraine medication. They should also instruct patients on proper dosage to improve medication adherence.

With new therapies constantly being developed to improve on former mechanisms, it is important for pharmacists to stay up to date on the available preventive and treatment options to better manage patients.

References

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2. Malone CD, Bhowmick A, Wachholtz AB. Migraine: treatments, comorbidities, and quality of life, in the USA. J Pain Res. 2015;8:537-547. doi: 10.2147/JPR.S88207
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5. American Migraine Foundation. Understanding migraine medications. Published September 20, 2018. Accessed June 21, 2021. https://americanmigrainefoundation.org/resource-library/migraine-medication/.
6. Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache. 2017;57(suppl 2):47-55. doi: 10.1111/head.13081
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8. Vyepti. Prescribing information. Lundbeck Seattle BioPharmaceuticals, Inc; 2020. Accessed June 21, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf
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10. Emgality. Prescribing Information. Eli Lilly and Company; 2019. Accessed June 21, 2021. https://uspl.lilly.com/emgality/emgality.html#pi
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13. Ailani J, Lipton R, Goadsby P, et al. Atogepant significantly reduces mean monthly migraine days in the phase 3 trial (ADVANCE) for the preventive treatment of migraine. Neurology. 2021;96(15 suppl):1494. https://n.neurology.org/content/96/15_Supplement/1494
14. Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain. 2019;20(1):37. doi: 10.1186/s10194-019-0974-3
15. Tepper D. Lasmiditan for the acute treatment of migraine. Headache. 2020;60(6):1225-1226. doi: 10.1111/head.13798