Innovative treatments for migraine: a new era

Migraine therapy has been revolutionized in recent years by the development of drugs whose mechanisms of action specifically target the biological events underlying migraine pain. These agents, including both acute and preventive treatments, primarily act on calcitonin gene–related peptide (CGRP), a key mediator in the migraine pathophysiological cascade. ¹ These are complemented by ditans, which represent an evolution of triptans, as they are 5-hydroxytryptamine 1F receptor agonists with a more favorable tolerability profile compared with triptans. ² In this context, rimegepant, ubrogepant, zavegepant, and lasmiditan have expanded acute treatment options beyond nonsteroidal anti-inflammatory drugs and triptans, while rimegepant, atogepant, erenumab, galcanezumab, fremanezumab, and eptinezumab have broadened preventive strategies alongside established therapies such as tricyclic antidepressants, antiepileptic drugs, and beta-blockers. The transition from nonspecific drugs, or agents repurposed for migraine, to mechanism-based targeted therapies is enabling the development of precision medicine that is increasingly tailored to individual patient needs. Moreover, the scientific evidence supporting the efficacy and tolerability of these agents is substantially stronger than that available for earlier therapies, consistent with an increasingly evidence-based approach to migraine care. ³ The introduction of these therapies is leading to meaningful improvements in quality of life, reducing migraine-related disability and the overall disease burden, which has long been recognized as high.^4,5 This has consequently led to a shift in migraine management from a reactive, attack-focused approach to early, proactive, and individualized strategies aimed at preventing disease progression with safe and effective therapies. ⁶

The scope of this Special Collection (https://journals.sagepub.com/topic/collections-tan/tan-1-special_collection_innovative_treatments/tana) is to provide new insights into the diagnostic and therapeutic approach to patients with migraine, including pathways to diagnosis, healthcare utilization, and patterns of acute and preventive treatment. Recently introduced acute and preventive migraine therapies are discussed, with particular emphasis on migraine pathophysiology, multidisciplinary management, and diagnostic approaches across the headache continuum from childhood to adulthood.

Waliszewska-Prosół et al. ⁷ provided valuable insights into key stages of the migraine patient journey, including symptom onset, pathways to diagnosis, healthcare utilization, and patterns of acute and preventive treatment. This paper represents a valuable starting point, as it captures the real-world situation of patients with migraine in Europe, and particularly in Poland, during the 2021–2022 period, just before the widespread adoption of anti-CGRP monoclonal antibodies following EMA approval and the definition of reimbursement criteria in that country. The authors showed that, despite high consultation and diagnosis rates, most Polish patients were receiving suboptimal treatment at the time of the survey. Acute management relied predominantly on nonsteroidal anti-inflammatory drugs and acetaminophen, often combined with codeine, while triptans were used by just over half of patients, contributing to high rates of medication overuse. Preventive therapies were markedly underutilized, with few patients receiving prophylaxis and most prescribed agents being older, non-migraine-specific drugs. This reflects the marked heterogeneity that has characterized the therapeutic transition across Europe, where real-world access in clinical practice—driven by reimbursement policies and prescribing criteria—has varied widely between countries, with the effective introduction of new therapies depending on national healthcare systems.

With respect to acute care, the special collection includes studies investigating the real-world use, safety, and effectiveness of lasmiditan.^8,9 Vaghi et al., in a prospective, multicenter, real-world study, evaluated the effectiveness and tolerability of two oral doses of lasmiditan (50 and 100 mg) for the acute treatment of migraine. They found that both doses were clinically effective, with effectiveness independent of prior triptan failure, supporting lasmiditan as a valuable therapeutic option for patients not responders or have contraindications to triptans. ⁸ The other study on lasmiditan, by Katsuki et al., ⁹ extended the perspective beyond Europe by examining 2-year lasmiditan prescription patterns using time-series clustering analysis. The study showed that lasmiditan prescriptions generally declined over 2 years, most commonly evolving into combination therapy with analgesics or triptans. Three distinct prescribing trajectories—continuous use, gradual tapering, and early discontinuation—were identified, highlighting heterogeneity in real-world practice and the need for further research on optimal use and medication overuse risk. These findings support a view that can likely be generalized to other novel migraine therapies: innovative treatments are not intended to fully replace traditional options but rather represent effective alternatives that meaningfully expand the range of available therapeutic options.

The special collection also includes papers that focus on pathophysiological aspects of migraine that remain poorly understood. This is exemplified by the study by Cesareo et al., ¹⁰ which showed that patients with migraine exhibit significant quadrant-specific retinal nerve fiber layer structural changes compared with healthy controls, despite preserved vascular networks. Short-term treatment with anti-CGRP monoclonal antibodies was associated with increased vascular perfusion in the superficial and radial peripapillary capillary plexuses, potentially contributing to the prevention of irreversible ocular damage. These findings suggest that retinal changes in migraine, detected through optical coherence tomography, can serve as a rapid measure for monitoring migraine progression and treatment response. ¹⁰ As suggested by the authors, the effects of anti-CGRP monoclonal antibody therapy may be monitored sequentially using optical coherence tomography in a noninvasive manner and may confer short-term benefits, potentially reducing the development of irreversible vascular damage. ¹⁰

The other paper focusing on pathophysiology, authored by Silalahi and Hariyanto, ¹¹ addresses a highly controversial issue: the association between migraine and patent foramen ovale (PFO). Whether a causal relationship exists between migraine and PFO, or whether PFO should be regarded merely as an epiphenomenon, remains a matter of debate. Assessing whether percutaneous PFO closure may contribute to a reduction in migraine-related disability could help clarify the presence of a causal association between the two conditions. The authors performed a systematic review and meta-analysis of randomized clinical trials and observational studies addressing this issue. ¹¹ The meta-analysis showed that PFO closure was associated with a modest but significant reduction in both monthly migraine attacks and migraine days compared with control interventions. However, no significant differences were observed between groups in terms of complete migraine resolution or improvements in disability and impact measures, investigated through the headache impact test-6 and the migraine disability assessment test. Moreover, in terms of safety, PFO closure demonstrated a favorable safety profile, with adverse events reported in only a small proportion of patients. The authors conclude that even larger trials are still needed to clarify this issue, screening for PFO may be considered as part of the comprehensive evaluation of patients with migraine, and in selected cases, PFO closure could be contemplated as a potential therapeutic option. ¹¹

Within the framework of a multiparametric assessment of migraine, Ruban et al., ¹² also contributing to this special collection, hypothesized that liver enzymes, which regulate blood glutamate levels, may serve as an indirect marker of glutamatergic imbalance associated with migraine. They concluded that higher aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase levels may be associated with a lower prevalence of migraine, suggesting that inefficient plasma glutamate regulation could play a role in migraine pathology. ¹² This evidence further paves the way for a multiparametric assessment of patients with migraine, with attention paid not only to vascular risk factors but also to metabolic dysfunctions. Finally, the paper by Salfi et al. ¹³ investigated the clinical characteristics of headache in a large school-based population. This study addresses an equally relevant issue, namely, the age at migraine onset and how migraine clinical features evolve across different stages of life. This issue is particularly important considering the previously discussed observations highlighting the need for early intervention, as recommended by the International Headache Society. ⁵ As reported by the authors, headaches change differently for boys and girls as they grow, becoming more frequent, more intense, and easier to diagnose from childhood to adolescence. ¹³ Additionally, the impact of headaches, especially in older students, highlights the importance of recognizing them early and providing treatments that are suitable for their age. Another key issue highlighted by this paper is that, with increasing age, the prevalence of so-called undifferentiated headache decreases in favor of more definitive migraine diagnoses. ¹³ This observation reflects the fact that diagnostic criteria developed for adults cannot be directly applied to children and adolescents but require age-specific adaptations to preserve diagnostic sensitivity and specificity. This is essential to improve diagnostic sensitivity and enable timely migraine diagnosis and multidisciplinary care.

In summary, our special collection gathers valued contributions from many leading authors working in the field of migraine. Many additional mechanisms and factors can be discussed within the pathophysiology of migraine, several of which are likely to pave the way for further innovative therapies, including those targeting the pituitary adenylate cyclase-activating polypeptide pathway.^14,15 These advances clearly signal that migraine treatment has entered a new era, characterized by mechanism-based therapies and a rapidly expanding landscape of promising therapeutic targets.