BEYOND TRIPTANS: SYSTEMATIC REVIEW FOCUSING ON THE EFFICACY AND SAFETY PROFILE OF CGRP RECEPTOR ANTAGONISTS IN MIGRAINE MANAGEMENT

Mikołaj Szulewski; Gabriela Bajor; Zofia Gniadek; Joanna Kozak; Aleksandra Salagierska; Kacper Melka; Patrycja Machno; Patryk Matuszczak; Agata Pszczółka; Wiktoria Jurczyk-Florkiewicz

doi:10.31435/ijitss.1(49).2026.5037

Authors

Mikołaj Szulewski Medical Doctor, Szpital Powiatowy in Chrzanów, Chrzanów, Poland https://orcid.org/0009-0005-3100-421X
Gabriela Bajor Medical Doctor, The University Hospital in Krakow, Kraków, Poland https://orcid.org/0009-0006-9275-0491
Zofia Gniadek Medical Doctor, The University Hospital in Krakow, Kraków, Poland https://orcid.org/0009-0008-6648-9677
Joanna Kozak Medical Doctor, Stefan Zeromski Specialist Hospital, Krakow, Poland https://orcid.org/0009-0001-9272-334X
Aleksandra Salagierska Medical Doctor, 5th Military Hospital with Polyclinic in Cracow, Cracow, Poland https://orcid.org/0009-0006-8935-5191
Kacper Melka Medical Doctor, SP ZOZ Szpital Powiatowy im. Edmunda Biernackiego w Opocznie, Opoczno, Poland https://orcid.org/0009-0000-4217-3821
Patrycja Machno Medical Doctor, The University Hospital in Krakow, Kraków, Poland https://orcid.org/0009-0000-0973-5968
Patryk Matuszczak Medical Doctor, SPZOZ Myślenice, Myślenice, Poland https://orcid.org/0009-0002-1090-9421
Agata Pszczółka Medical Doctor, SPZOZ Myślenice, Myślenice, Poland https://orcid.org/0009-0000-0008-955X
Wiktoria Jurczyk-Florkiewicz Medical Doctor, The University Hospital in Krakow, Kraków, Poland https://orcid.org/0009-0003-0457-508X

DOI:

https://doi.org/10.31435/ijitss.1(49).2026.5037

Keywords:

Migraine, CGRP Receptor Antagonists, Rimegepant, Gepants, Atogepant, Zavegepant

Abstract

Background: Despite the availability of traditional pharmacotherapies, including triptans and nonsteroidal anti-inflammatory drugs (NSAIDs), clinical value is often limited by suboptimal efficacy, significant cardiovascular contraindications, and the risk of medication-overuse headache (MOH). This study aims to evaluate the clinical efficacy and safety of rapidly developing calcitonin gene-related peptide (CGRP) receptor antagonists named ‘gepants’.

Material and methods: A systematic review of scientific literature was performed to evaluate the efficacy of novel antimigraine agents. A structured search of the PubMed database was conducted using keywords including "migraine", "gepant", and "CGRP receptor antagonists." Emphasis was placed on clinical trials, RCTs, and meta-analyses, supplemented by references to neurological textbooks to provide clinical context.

Results: Analysis of clinical data indicates that daily administered gepants reduce mean monthly migraine days (MMDs) compared to placebo in preventive treatment model. Furthermore, gepants proved their efficacy in acute migraine treatment, providing pain relief and the absence of the most bothersome symptoms (MBS). Multiple studies evaluating novel gepants have reported safety profiles comparable to placebo. In addition, gepants do not exert vasoconstrictive effects, making them a viable candidate for triptan-unsuitable patients or those who had documented adverse events (AEs) of traditional oral preventive medications (OPMs).

Conclusions: Novel CGRP receptor antagonists represent a significant advancement in migraine therapy. By providing high tolerability and efficacy without the risk of MOH, hepatotoxicity or cardiovascular events, gepants emerge as a transformative option for both acute relief and prophylaxis in adult triptan-unsuitable patients suffering from migraine.

References

Ailani, J., Burch, R. C., & Robbins, M. S. (2021). The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache: The Journal of Head and Face Pain, 61(7), 1021–1039. https://doi.org/10.1111/head.14153

Ailani, J., Lipton, R. B., Goadsby, P. J., Guo, H., Miceli, R., Severt, L., Finnegan, M., & Trugman, J. M. (2021). Atogepant for the Preventive Treatment of Migraine. New England Journal of Medicine, 385(8), 695–706. https://doi.org/10.1056/NEJMoa2035908

Ankrom, W., Bondiskey, P., Li, C., Palcza, J., Liu, W., Dockendorf, M. F., Matthews, C., Panebianco, D., Reynders, T., Wagner, J. A., Jakate, A., Mesens, S., Kraft, W. K., & Marcantonio, E. E. (2020). Ubrogepant Is Not Associated With Clinically Meaningful Elevations of Alanine Aminotransferase in Healthy Adult Males. Clinical and Translational Science, 13(3), 462–472. https://doi.org/10.1111/cts.12728

Ashina, M., McAllister, P., Gaul, C., Leyva-Rendon, A., Ramirez, L. M., Nalpas, C., Thiry, A., Abraham, L., Fountaine, R. J., & Fullerton, T. (2025). Rimegepant for acute treatment of migraine in triptan-unsuitable adults: A randomized, double-blind, placebo-controlled phase 4 trial. Cephalalgia, 45(11). https://doi.org/10.1177/03331024251395298

Bashir, A., Lipton, R. B., Ashina, S., & Ashina, M. (2013). Migraine and structural changes in the brain. Neurology, 81(14), 1260–1268. https://doi.org/10.1212/WNL.0b013e3182a6cb32

Bertz, R., Donohue, M., Madonia, J., Bhardwaj, R., Matschke, K. T., Anderson, M. S., Croop, R., & Liu, J. (2025). Safety, tolerability, and pharmacokinetics of single and multiple ascending doses of zavegepant nasal spray in healthy adults from two phase 1 randomized, placebo‐controlled trials. Headache: The Journal of Head and Face Pain, 65(8), 1331–1343. https://doi.org/10.1111/head.15042

Bhardwaj, R., Donohue, M. K., Madonia, J., Morris, B., Marbury, T. C., Matschke, K. T., Croop, R., Bertz, R., & Liu, J. (2024). Reduced hepatic impairment study to evaluate pharmacokinetics and safety of zavegepant and to inform dosing recommendation for hepatic impairment. Clinical and Translational Science, 17(7). https://doi.org/10.1111/cts.13813

Blair, H. A. (2023). Rimegepant: A Review in the Acute Treatment and Preventive Treatment of Migraine. CNS Drugs, 37(3), 255–265. https://doi.org/10.1007/s40263-023-00988-8

Boinpally, R., Jakate, A., Butler, M., Borbridge, L., & Periclou, A. (2021). Single‐Dose Pharmacokinetics and Safety of Atogepant in Adults With Hepatic Impairment: Results From an Open‐Label, Phase 1 Trial. Clinical Pharmacology in Drug Development, 10(7), 726–733. https://doi.org/10.1002/cpdd.916

Boinpally, R., McNamee, B., Yao, L., Butler, M., McGeeney, D., Borbridge, L., & Periclou, A. (2021). A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single‐Dose, Phase 1 Crossover Trial. Clinical Pharmacology in Drug Development, 10(9), 1099–1107. https://doi.org/10.1002/cpdd.940

Croop, R., Berman, G., Kudrow, D., Mullin, K., Thiry, A., Lovegren, M., L’Italien, G., & Lipton, R. B. (2024). A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine. Cephalalgia, 44(4). https://doi.org/10.1177/03331024241232944

Croop, R., Lipton, R. B., Kudrow, D., Stock, D. A., Kamen, L., Conway, C. M., Stock, E. G., Coric, V., & Goadsby, P. J. (2021). Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. The Lancet, 397(10268), 51–60. https://doi.org/10.1016/S0140-6736(20)32544-7

Croop, R., Madonia, J., Stock, D. A., Thiry, A., Forshaw, M., Murphy, A., Coric, V., & Lipton, R. B. (2022). Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double‐blind, randomized, placebo‐controlled, dose‐ranging trial. Headache: The Journal of Head and Face Pain, 62(9), 1153–1163. https://doi.org/10.1111/head.14389

de Vries, T., Villalón, C. M., & MaassenVanDenBrink, A. (2020). Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacology & Therapeutics, 211, 107528. https://doi.org/10.1016/j.pharmthera.2020.107528

Dodick, D. W., Lipton, R. B., Ailani, J., Lu, K., Finnegan, M., Trugman, J. M., & Szegedi, A. (2019). Ubrogepant for the Treatment of Migraine. New England Journal of Medicine, 381(23), 2230–2241. https://doi.org/10.1056/NEJMoa1813049

Dodick, D. W., Shewale, A. S., Lipton, R. B., Baum, S. J., Marcus, S. C., Silberstein, S. D., Pavlovic, J. M., Bennett, N. L., Young, W. B., Viswanathan, H. N., Doshi, J. A., & Weintraub, H. (2020). Migraine Patients With Cardiovascular Disease and Contraindications: An Analysis of Real-World Claims Data. Journal of Primary Care & Community Health, 11. https://doi.org/10.1177/2150132720963680

Dong, L., Dong, W., Jin, Y., Jiang, Y., Li, Z., & Yu, D. (2025). The Global Burden of Migraine: A 30-Year Trend Review and Future Projections by Age, Sex, Country, and Region. Pain and Therapy, 14(1), 297–315. https://doi.org/10.1007/s40122-024-00690-7

Gibbins, I. L., Furness, J. B., Costa, M., MacIntyre, I., Hillyard, C. J., & Girgis, S. (1985). Co-localization of calcitonin gene-related peptide-like immunoreactivity with substance P in cutaneous, vascular and visceral sensory neurons of guinea pigs. Neuroscience Letters, 57(2), 125–130. https://doi.org/10.1016/0304-3940(85)90050-3

Goadsby, P. J., Dodick, D. W., Ailani, J., Trugman, J. M., Finnegan, M., Lu, K., & Szegedi, A. (2020). Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. The Lancet Neurology, 19(9), 727–737. https://doi.org/10.1016/S1474-4422(20)30234-9

Goadsby, P. J., Tepper, S. J., Watkins, P. B., Ayele, G., Miceli, R., Butler, M., Severt, L., Finnegan, M., Szegedi, A., Trugman, J. M., & Jakate, A. (2019). Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults. Cephalalgia, 39(14), 1753–1761. https://doi.org/10.1177/0333102419869918

Ho, T. W., Connor, K. M., Zhang, Y., Pearlman, E., Koppenhaver, J., Fan, X., Lines, C., Edvinsson, L., Goadsby, P. J., & Michelson, D. (2014). Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology, 83(11), 958–966. https://doi.org/10.1212/WNL.0000000000000771

Lipton, R. B., Croop, R., Stock, D. A., Madonia, J., Forshaw, M., Lovegren, M., Mosher, L., Coric, V., & Goadsby, P. J. (2023). Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. The Lancet Neurology, 22(3), 209–217. https://doi.org/10.1016/S1474-4422(22)00517-8

Lucas, C. (2021). Migraine with aura. Revue Neurologique, 177(7), 779–784. https://doi.org/10.1016/j.neurol.2021.07.010

Lundberg, J. M., Franco-Cereceda, A., Hua, X., Hökfelt, T., & Fischer, J. A. (1985). Co-existence of substance P and calcitonin gene-related peptide-like immunoreactivities in sensory nerves in relation to cardiovascular and bronchoconstrictor effects of capsaicin. European Journal of Pharmacology, 108(3), 315–319. https://doi.org/10.1016/0014-2999(85)90456-X

Messlinger, K. (2018). The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system. The Journal of Headache and Pain, 19(1), 22. https://doi.org/10.1186/s10194-018-0848-0

Min, K. C., Kraft, W. K., Bondiskey, P., Colón‐González, F., Liu, W., Xu, J., Panebianco, D., Mixson, L., Dockendorf, M. F., Matthews, C. Z., & Boinpally, R. (2021). Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults. Clinical and Translational Science, 14(2), 599–605. https://doi.org/10.1111/cts.12917

Pozo-Rosich, P., López, J. A. G., Lisewski, P., Aslan, A. N., Seehra, H., Thiry, A., Abraham, L., Ramirez, L. M., Fountaine, R., & Fullerton, T. (2025). A phase 4, randomized, double-blind, placebo-controlled trial evaluating the efficacy and tolerability of rimegepant for the prevention of episodic migraine in adults with a history of inadequate response to traditional oral preventive medications. Cephalalgia, 45(11). https://doi.org/10.1177/03331024251391378

Russell, F. A., King, R., Smillie, S.-J., Kodji, X., & Brain, S. D. (2014). Calcitonin Gene-Related Peptide: Physiology and Pathophysiology. Physiological Reviews, 94(4), 1099–1142. https://doi.org/10.1152/physrev.00034.2013

Vandenbussche, N., Laterza, D., Lisicki, M., Lloyd, J., Lupi, C., Tischler, H., Toom, K., Vandervorst, F., Quintana, S., Paemeleire, K., & Katsarava, Z. (2018). Medication-overuse headache: a widely recognized entity amidst ongoing debate. The Journal of Headache and Pain, 19(1), 50. https://doi.org/10.1186/s10194-018-0875-x

Yang, Y., Chen, M., Sun, Y., Gao, B., Chen, Z., & Wang, Z. (2020). Safety and Efficacy of Ubrogepant for the Acute Treatment of Episodic Migraine: A Meta-Analysis of Randomized Clinical Trials. CNS Drugs, 34(5), 463–471. https://doi.org/10.1007/s40263-020-00715-7