Medicine for Migraine: Moving Closer to Relief

Migraine is a recurrent multiphasic cephalgia characterized by a headache that, if untreated, lasts more than 4 hours and has at least 2 characteristics described in Table 1.¹ Many patients experience aura and postdrome symptoms before and after the headache, respectively. Researchers have developed several therapeutics for acute treatment and prevention of migraine (eg, serotonin 5HT_1B/1D receptor agonists, gepants, calcitonin gene-related peptide [CGRP] antagonists, and ditans [5HT_1F receptor agonists]).² Regardless, migraine is third among all health conditions in years lost to disability.³

Basic Pathophysiology of Migraine

Historically, migraine was considered a vascular disorder characterized by cranial artery dilation; however, it is clear now that vessel dilation is an insignificant factor in migraine.^4.5 It appears that the trigeminocervical complex prompts migraine symptomatology, causing pain sensations that project within the central nervous system.⁶

With older therapies, medication-overuse headache emerged when patients used excessive amounts of some acute therapies for migraine (Table 2).^7,8 An advantage of the newer medications is that they do not seem to induce medication-overuse headache. Among the available medications, only 1 ditan was FDA-approved. As of May 31, 2026, its distribution was ceased in the US. Limited product will be available until remaining supply is exhausted.⁹

Calcitonin Gene-Related Peptide

CGRP is widely expressed in the nervous system and is a potent meningeal vasculature vasodilator.^10-12 Migraine attacks elevate serum CGRP, and CGRP antagonists block the peptide’s activity.^13,14 Gepants competitively inhibit the CGRP receptor, whereas monoclonal antibodies (mAbs) either bind circulating CGRP ligands or the receptor itself to prevent pathway activation. By reducing CGRP-mediated signaling, these agents decrease migraine frequency and/or abort acute migraine attacks without causing the vasoconstriction associated with triptans.^15,16

First-generation gepants demonstrated clinical efficacy but were discontinued due to elevated liver enzymes and potential hepatotoxicity.^17,18 Researchers refined the molecular structure and developed oral second-generation gepants: atogepant (Qulipta; AbbVie), rimegepant (Nurtec ODT; Pfizer), and ubrogepant (Ubrelvy; AbbVie).^19-21 Usually well-tolerated, the most common adverse effects (AEs) are nausea, constipation, somnolence or fatigue, dry mouth, and dyspepsia or abdominal discomfort.

The FDA has approved 4 monoclonal CGRP antagonists: erenumab (Aimovig; Amgen), fremanezumab (AJovy; Teva), galcanezumab (Emgality; Lilly), and eptinezumab (Vyepti; Lundbeck). Erenumab blocks the receptor itself; the other 3 bind circulating CGRP ligand.

CGRP mAbs are generally well-tolerated. Common AEs include nasopharyngitis, constipation, and injection site reactions. These medications could elevate vascular risk since CGRP is cardioprotective, so they are contraindicated in patients with a history of myocardial infarction or ischemic stroke in the previous 6 months.^22,23 No data are available in pregnant individuals.

CGRP monoclonal antibodies provide no relief to roughly one-third of patients.²⁴ Fortunately, researchers are examining several potential targets to explore.

What’s Next?

Pituitary adenylate cyclase activating polypeptide (PACAP) is a new research target with a distinct pathway from that of CGRP.²⁵ Its neuroprotective effect seems to be related to increased neuronal excitability.²⁶ Most closely watched is the PACAP-38 pathway target, with the mAb bocunebart (Lu AG09222) the leading entity.^27,28 It binds directly to the PACAP ligand, rather than the receptor, and has shown positive phase 2b results in patients with migraine who had prior preventive treatment failures.^27,28

Of note, the International Nonproprietary Names system recently changed mAb nomenclature to reduce confusion and medication-error risk associated with so many mAbs ending in -mab. The new -bart suffix designates an artificial or engineered antibody-derived molecule.²⁹

Adrenomedullin is under study as a migraine pathway, but it is much earlier in development than PACAP.³⁰ Adrenomedullin belongs to the same peptide family as CGRP and appears to contribute to vasodilation, trigeminovascular activation, and neurogenic inflammation, making it biologically attractive as a target. Complicating its use is its important systemic physiologic roles, especially in vascular tone and endothelial function. Blocking it therapeutically may carry greater cardiovascular or hemodynamic risk than CGRP blockade.³¹ Current work is still largely exploratory.

Conclusion

Migraine headache remains a disabling condition for many Americans. Often, trials of newer medications don’t provide the magnitude of relief that patients want and need. Fortunately, researchers are exploring new pathways that may provide better relief for people who need better options. Pharmacists can be on the front lines of educating patients about the current and emerging therapies.

About the Author

Jeannette Y. Wick, MBA, RPh, FASCP, is the director of the Office of Pharmacy Professional Development at the University of Connecticut School of Pharmacy in Storrs.

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