2025 Highlights in acute migraine treatment

In 2025, the Italian Society for the Study of Headaches and the International Headache Society jointly released a landmark evidence-based guideline that consolidated the expanding treatment landscape for both acute and preventive migraine treatment (1). Medications with high quality of evidence and strong recommendations included paracetamol, several triptans, the combination of acetylsalicylic acid/paracetamol/caffeine, lasmiditan, and the calcitonin gene-related peptide (CGRP) receptor antagonists rimegepant, ubrogepant and zavegepant. This monumental work offered clinicians a structured framework for acute migraine management, synthesizing the best available evidence and setting a high bar for clinical practice moving forward.

Against this backdrop, the most novel scientific contributions of 2025 for acute migraine revolved around gepants, with new data from clinical trials, long-term extension studies and real-world analyses. These investigations not only demonstrated efficacy, but also provided reassurance regarding durability, safety across clinically relevant subgroups and the practical realities of patient adherence.

A key question in clinical practice is whether gepants are effective in patients who do not respond to triptans. Given their higher cost, gepants may be particularly relevant for this subgroup. Ailani et al. (2) directly addressed this issue in a large subgroup analysis of rimegepant use in triptan-naïve, triptan-using, and triptan-failure participants. Across all groups, rimegepant was safe and well tolerated, with adverse events reported in fewer than one quarter of participants. More than 75% of patients across all subgroups preferred rimegepant to their previous acute treatment, including those who had failed two or more triptans. These findings strongly support the role of gepants as effective acute options, as well as for patients with inadequate response to triptans.

Concerns have also been raised about possible sex-specific differences in gepant efficacy, with preliminary data suggesting stronger effects in women. In a pooled secondary analysis of ubrogepant and atogepant trials, Goadsby et al. (3) found no significant sex differences: males and females achieved comparable rates of two-hour pain freedom and most bothersome symptom resolution. Given the underrepresentation of men in migraine trials, these results provide much-needed reassurance that gepants are equally effective regardless of sex.

Depression and anxiety are common comorbidities with migraine, and the literature addressing the response to treatment in this population has been scarce. An important step forward in 2025, was the analysis by Kudrow et al. (4), who specifically examined rimegepant use in participants with comorbid anxiety or depression, including those taking selective serotonin reuptake inhibitors, over a 52-week period. Adverse event rates and discontinuations were similar regardless of psychiatric comorbidity or antidepressant use, providing reassurance for this patient group.

The question of combining acute and preventive CGRP-targeted therapies was addressed by the Phase 4 TANDEM trial, which evaluated ubrogepant as needed in patients receiving daily atogepant (5). The study showed favorable safety and tolerability, with fewer than 10% of participants discontinuing treatment due to adverse events and no new safety signals identified. These results support the pragmatic use of gepants for both prevention and acute treatment in the same patient, reflecting a strategy already increasingly adopted in real-world practice.

The zavegepant nasal program provided complementary insights. Berman et al. reported results from a long-term safety study of zavegepant nasal spray, including a subgroup of patients receiving preventive treatment with CGRP monoclonal antibodies (6). Adverse event rates were comparable between those with and without antibodies, and no new tolerability issues emerged.

In parallel, Zhu et al. (7) performed a network meta-analysis showing that zavegepant nasal provides higher rates of pain freedom and freedom from most bothersome symptom compared with placebo, but with efficacy similar to that of oral gepants. The tolerability profile was also similar between the nasal and the oral formulations.

After demonstrating the efficacy of ubrogepant administered during the prodromal phase in reducing the development of headache within the following 24 hours, Goadsby et al. (8) published an exploratory analysis of pre-specified secondary endpoints focusing on prodromal symptoms. The study showed a significant reduction in the presence of photophobia, fatigue, neck pain, phonophobia and dizziness in the ubrogepant group compared to placebo. Although limited by its exploratory nature, the study suggests that early treatment may reverse or alleviate symptoms likely associated with the early migraine phase, supporting the hypothesis of central nervous system dysfunction involvement.

Clinical trial results were complemented by real-world evidence that sheds light on treatment persistence and effectiveness in everyday practice. In a large US claims analysis, Tepper et al. (9) compared treatment persistence between patients initiating rimegepant and those starting a triptan. At 12 months, 75.8% of rimegepant users remained on therapy compared to 53.5% of triptan users (odds ratio = 2.72). This advantage was consistent across subgroups, including patients with chronic migraine. Persistence is an integrated outcome reflecting efficacy, tolerability, recurrence and patient satisfaction, suggesting that gepants may offer a more sustainable option for long-term acute management.

Finally, the prospective Italian GAINER study further illustrated real-world effectiveness. Iannone et al. (10) followed 103 patients using rimegepant and found that approximately 45% achieved two-hour pain freedom. Importantly, patients who took rimegepant earlier in the attack were significantly more likely to respond. These findings reinforce the principle that early intervention is key for acute treatment success, now demonstrated with gepants in daily clinical practice.

Taken together, the studies of 2025, consolidate gepants as a central pillar of acute migraine management. They are effective across difficult-to-treat subgroups, including triptan-failure patients, equally efficacious in men and women, safe and effective in patients with psychiatric comorbidities, and compatible with concomitant preventive use of CGRP-targeted treatments. Long-term extension data and real-world studies add confidence that efficacy and tolerability are durable and that persistence is higher than with triptans.

Looking ahead, several questions remain. An atogepant trial for acute treatment is ongoing, which could bring a new player into the acute landscape. Special populations such as the elderly and pediatric patients are still underrepresented in trials and warrant focused investigation. Additional safety data in pregnancy and breastfeeding will be essential to guide treatment in these sensitive groups. Furthermore, comparative effectiveness studies between gepants, ditans, triptans and device-based therapies will be needed to refine treatment algorithms.