Abstract
BACKGROUND: Triptans have long served as the primary acute migraine treatment, while gepants represent a newer, non-vasoconstrictive alternative. Although clinical trials have explored efficacy within each class, head-to-head studies are lacking, and real-world data on optimal treatment response and patient-level predictors of outcomes remain limited. We leverage baseline data from the HeAD-US study to conduct real-world comparisons of triptans and gepants for 2-hour pain freedom (2hPF) and 24-hour pain relief (24hPR), and to identify demographic, clinical, and treatment-related predictors of these outcomes. METHODS: Head-US is a survey conducted among users of the Migraine Buddy application. Eligible participants completed the survey, met ICHD-3 criteria for migraine and reported using acute monotherapy with a gepants (n = 570) or triptan (n = 1018). Primary outcomes, 2hPF and 24hPR post-treatment, were assessed using the Migraine Treatment Optimization Questionnaire (mTOQ-6). Potential predictors included demographic factors, clinical measures, and treatment-related factors. Logistic regression models were applied to complete-case data, with pairwise comparisons estimated via marginal-means. RESULTS: Among 1,588 eligible respondents 570 used gepants and 1,018 used a triptan. Mean age was 43.35 years (SD = 13.04), and 94.8% were female. Gepant users demonstrated 39% higher odds of achieving 24hPR compared to triptan users (OR = 1.39, 95% CI: 1.11-1.74) though there were no significant differences the the 2hPF outcome. Reduced odds of adequate 2hPF were associated with higher migraine symptom severity, high-frequency episodic migraine, chronic migraine, severe pain intensity, and severe migraine disability. Odds of achieving 24hPR were reduced in those with higher migraine symptom severity, higher attack frequency, severe migraine disability, and preventive medication use. Predictors of treatment response were similar in the pooled sample and in those using gepants and in those using triptans. CONCLUSION: In this large, real-world cohort, triptans and gepants showed comparable effectiveness for 2hPF, but gepants demonstrated a significant advantage for 24hPR. Clinical features such as symptom severity, headache frequency, disability, and comorbid treatment burden were important predictors of treatment response. These findings support the need for larger, head-to-head clinical trials definitively comparing these medication classes for migraine management and may inform personalized selection of acute migraine therapies in clinical practice.