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Comparative Efficacy of Oral Calcitonin-Gene–Related Peptide Antagonists for the Treatment of Acute Migraine: Updated Meta-analysis

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Abstract

Background and Objective

The calcitonin gene-related peptide (CGRP) is a new therapeutic target in migraine—a common disorder resulting in reduced quality of life. The aim of this study was to compare the clinical efficacy of five oral CGRP antagonists with that of a placebo and triptans against acute migraine via meta-analysis.

Methods

Suitable randomized controlled trials (RCTs) were searched in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) to compare the efficacy of oral CGRP antagonists with that of a placebo and triptans against acute migraine. Review Manager 5.4 was used for data analysis.

Results

A total of 17 trials met the eligibility criteria and were studied in detail. The CGRP antagonists were significantly more effective than the placebo with respect to outcomes such as pain freedom at 2 h post-dose (odds ratio = 2.11; 95% confidence intervals [CIs] = 1.90–2.35) and pain relief at 2 h post-dose (odds ratio = 1.94; 95% CIs = 1.70–2.21). Similar results were found in the subgroup analysis conducted to compare the clinical efficacy of the FDA-approved oral CGRP antagonists (ubrogepant and rimegepant) and placebo. However, the CGRP antagonists were less effective than the triptans with respect to outcomes such as pain freedom at 2 h post-dose (odds ratio = 0.66; 95% CIs = 0.55–0.78) and pain relief at 2 h post-dose (odds ratio = 0.78; 95% CIs = 0.66–0.93).

Conclusion

CGRP antagonists are more effective than placebo against acute migraine; however, further studies are required to consider CGRP antagonists as standard first-line treatment for acute migraine instead of triptans, especially in patients with co-existing cardiovascular diseases.

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References

  1. Edvinsson L. Role of CGRP in migraine. Handb Exp Pharmacol. 2019;255:121–30. https://doi.org/10.1007/164_2018_201.

    Article  CAS  PubMed  Google Scholar 

  2. Viana M, Sances G, Linde M, Ghiotto N, Guaschino E, Allena M, et al. Clinical features of migraine aura: results from a prospective diary-aided study. Cephalalgia. 2017;37(10):979–89. https://doi.org/10.1177/0333102416657147.

    Article  PubMed  Google Scholar 

  3. Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174–82. https://doi.org/10.1016/s1474-4422(17)30435-0.

    Article  CAS  PubMed  Google Scholar 

  4. Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia. 1992;12(4):221–8. https://doi.org/10.1046/j.1468-2982.1992.1204221.x ((discussion 186)).

    Article  CAS  PubMed  Google Scholar 

  5. Goadsby PJ, Holland PR. An update: pathophysiology of migraine. Neurol Clin. 2019;37(4):651–71. https://doi.org/10.1016/j.ncl.2019.07.008.

    Article  PubMed  Google Scholar 

  6. Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician. 2011;83(3):271–80.

    PubMed  Google Scholar 

  7. de Vries T, Villalón CM, MaassenVanDenBrink A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacol Ther. 2020;211:107528. https://doi.org/10.1016/j.pharmthera.2020.107528.

    Article  CAS  PubMed  Google Scholar 

  8. Papademetriou V. Cardiovascular risk assessment and triptans. Headache. 2004;44(Suppl 1):S31–9. https://doi.org/10.1111/j.1526-4610.2004.04106.x.

    Article  PubMed  Google Scholar 

  9. Tfelt-Hansen P, Olesen J. Taking the negative view of current migraine treatments: the unmet needs. CNS Drugs. 2012;26(5):375–82. https://doi.org/10.2165/11630590-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  10. van Hoogstraten WS, MaassenVanDenBrink A. The need for new acutely acting antimigraine drugs: moving safely outside acute medication overuse. J Headache Pain. 2019;20(1):54. https://doi.org/10.1186/s10194-019-1007-y.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology. 2015;84(7):688–95. https://doi.org/10.1212/wnl.0000000000001256.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Moreno-Ajona D, Pérez-Rodríguez A, Goadsby PJ. Gepants, calcitonin-gene-related peptide receptor antagonists: what could be their role in migraine treatment? Curr Opin Neurol. 2020;33(3):309–15. https://doi.org/10.1097/wco.0000000000000806.

    Article  CAS  PubMed  Google Scholar 

  13. Agostoni EC, Barbanti P, Calabresi P, Colombo B, Cortelli P, Frediani F, et al. Current and emerging evidence-based treatment options in chronic migraine: a narrative review. J Headache Pain. 2019;20(1):92. https://doi.org/10.1186/s10194-019-1038-4.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Negro A, Martelletti P. Gepants for the treatment of migraine. Expert Opin Investig Drugs. 2019;28(6):555–67. https://doi.org/10.1080/13543784.2019.1618830.

    Article  CAS  PubMed  Google Scholar 

  15. Diao Y, Yang H, Zhou YC, Du B. The efficacy and tolerability of ubrogepant for episodic migraine: a systematic review and meta-analysis. 2020. https://doi.org/10.21203/rs.2.20666/v2

  16. Yang Y, Chen M, Sun Y, Gao B, Chen Z, Wang Z. Safety and efficacy of ubrogepant for the acute treatment of episodic migraine: a meta-analysis of randomized clinical trials. CNS Drugs. 2020;34(5):463–71. https://doi.org/10.1007/s40263-020-00715-7.

    Article  CAS  PubMed  Google Scholar 

  17. Cui XP, Ye JX, Lin H, Mu JS, Lin M. Efficacy, safety, and tolerability of telcagepant in the treatment of acute migraine: a meta-analysis. Pain Pract. 2015;15(2):124–31. https://doi.org/10.1111/papr.12158.

    Article  PubMed  Google Scholar 

  18. Yao G, Yu T, Han X, Mao X, Li B. Therapeutic effects and safety of olcegepant and telcagepant for migraine: a meta-analysis. Neural Regener Res. 2013;8(10):938–47. https://doi.org/10.3969/j.issn.1673-5374.2013.10.009.

    Article  Google Scholar 

  19. Gao B, Yang Y, Wang Z, Sun Y, Chen Z, Zhu Y, et al. Efficacy and safety of rimegepant for the acute treatment of migraine: evidence from randomized controlled trials. Front Pharmacol. 2019;10:1577. https://doi.org/10.3389/fphar.2019.01577.

    Article  CAS  PubMed  Google Scholar 

  20. Hong P, Liu Y. Calcitonin gene-related peptide antagonism for acute treatment of migraine: a meta-analysis. Int J Neurosci. 2017;127(1):20–7. https://doi.org/10.3109/00207454.2015.1137915.

    Article  CAS  PubMed  Google Scholar 

  21. Canlas KM, Macalintal-Canlas RA, Sakai F. Efficacy of calcitonin gene-related peptide antagonists in the treatment of acute migraine: a systematic review and meta-analysis. Acta Medica Philippina. 2019;53(1):44–51.

    Article  Google Scholar 

  22. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84. https://doi.org/10.7326/m14-2385.

    Article  PubMed  Google Scholar 

  23. A pharmacokinetic study of MK-1602 in the treatment of acute migraine (MK-1602-007). https://ClinicalTrials.gov/show/NCT01657370. Accessed 30 July 2020

  24. Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2011;31(5):573–84. https://doi.org/10.1177/0333102410388435.

    Article  PubMed  Google Scholar 

  25. Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman R, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia. 2011;31(6):712–22. https://doi.org/10.1177/0333102411398399.

    Article  PubMed  Google Scholar 

  26. Hewitt DJ, Martin V, Lipton RB, Brandes J, Ceesay P, Gottwald R, et al. Randomized controlled study of telcagepant plus ibuprofen or acetaminophen in migraine. Headache. 2011;51(4):533–43. https://doi.org/10.1111/j.1526-4610.2011.01860.x.

    Article  PubMed  Google Scholar 

  27. Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73(12):970–7. https://doi.org/10.1212/WNL.0b013e3181b87942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ho AP, Dahlöf CG, Silberstein SD, Saper JR, Ashina M, Kost JT, et al. Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia. 2010;30(12):1443–57. https://doi.org/10.1177/0333102410370878.

    Article  PubMed  Google Scholar 

  29. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet. 2008;372(9656):2115–23. https://doi.org/10.1016/s0140-6736(08)61626-8.

    Article  CAS  PubMed  Google Scholar 

  30. Connor KM, Aurora SK, Loeys T, Ashina M, Jones C, Giezek H, et al. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache. 2011;51(1):73–84. https://doi.org/10.1111/j.1526-4610.2010.01799.x.

    Article  PubMed  Google Scholar 

  31. Ho TW, Ho AP, Chaitman BR, Johnson C, Mathew NT, Kost J, et al. Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache. 2012;52(2):224–35. https://doi.org/10.1111/j.1526-4610.2011.02052.x.

    Article  PubMed  Google Scholar 

  32. Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70(16):1304–12. https://doi.org/10.1212/01.Wnl.0000286940.29755.61.

    Article  CAS  PubMed  Google Scholar 

  33. 60(th) Annual Scientific Meeting American Headache Society. Headache. 2018;58(S2):61-215. https://doi.org/10.1111/head.13306.

  34. Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med. 2019;381(2):142–9. https://doi.org/10.1056/NEJMoa1811090.

    Article  CAS  PubMed  Google Scholar 

  35. Croop R, Goadsby PJ, Stock DA, Conway CM, Forshaw M, Stock EG, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394(10200):737–45. https://doi.org/10.1016/s0140-6736(19)31606-x.

    Article  CAS  PubMed  Google Scholar 

  36. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34(2):114–25. https://doi.org/10.1177/0333102413500727.

    Article  PubMed  Google Scholar 

  37. Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36(9):887–98. https://doi.org/10.1177/0333102416653233.

    Article  PubMed  Google Scholar 

  38. Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381(23):2230–41. https://doi.org/10.1056/NEJMoa1813049.

    Article  CAS  PubMed  Google Scholar 

  39. Lipton RB, Dodick DW, Ailani J, Lu K, Finnegan M, Szegedi A, et al. Effect of ubrogepant vs placebo on pain and the most bothersome associated symptom in the acute treatment of migraine: the ACHIEVE II randomized clinical trial. JAMA. 2019;322(19):1887–98. https://doi.org/10.1001/jama.2019.16711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cameron C, Kelly S, Hsieh SC, Murphy M, Chen L, Kotb A, et al. Triptans in the acute treatment of migraine: a systematic review and network meta-analysis. Headache J Head Face Pain. 2015;55:221–35.

    Article  Google Scholar 

  41. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358(9294):1668–75.

    Article  CAS  Google Scholar 

  42. US Food & Drug Administration. Migraine: developing drugs for acute treatment. Center for Drug Evaluation and Research. 2018. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/migraine-developing-drugs-acute-treatment. Accessed 17 July 2020

  43. Curto M, Capi M, Cipolla F, Cisale GY, Martelletti P, Lionetto L. Ubrogepant for the treatment of migraine. Expert Opin Pharmacother. 2020;21(7):755–9. https://doi.org/10.1080/14656566.2020.1721462.

    Article  CAS  PubMed  Google Scholar 

  44. Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain. 2019;20(1):37. https://doi.org/10.1186/s10194-019-0974-3.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Viana M, Genazzani AA, Terrazzino S, Nappi G, Goadsby PJ. Triptan nonresponders: do they exist and who are they? Cephalalgia. 2013;33(11):891–6.

    Article  Google Scholar 

  46. De Matteis E, Guglielmetti M, Ornello R, Spuntarelli V, Martelletti P, Sacco S. Targeting CGRP for migraine treatment: mechanisms, antibodies, small molecules, perspectives. Expert Rev Neurother. 2020;20(6):627–41. https://doi.org/10.1080/14737175.2020.1772758.

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Jae-Hwan Kwak and In-hwan Baek contributed equally to this study.

Authors and Affiliations

  1. College of Pharmacy, Kyungsung University, 309, Suyeong-ro, Nam-gu, Busan, 48434, Republic of Korea

    Dong Kyoung Ha, Min Ji Kim, Jae-Hwan Kwak & In-hwan Baek

  2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

    Nayoung Han

  3. Functional Food and Drug Convergence Research Center, Industry-Academic Cooperation Foundation, Kyungsung University, 309, Suyeong-ro, Nam-gu, Busan, 48434, Republic of Korea

    Jae-Hwan Kwak & In-hwan Baek

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  1. Dong Kyoung Ha
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Contributions

DKH: methodology, formal analysis, software, writing. MJK: methodology, formal analysis. NH: formal analysis, supervision, writing—review and editing. J-HK: conceptualization, investigation, resources, supervision. IB: conceptualization, methodology, software, supervision, writing.

Corresponding authors

Correspondence to Jae-Hwan Kwak or In-hwan Baek.

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The authors declare that there are no conflicts of interest.

Funding

This work was supported by the BB21+ Project in 2020. This research was supported by Kyungsung University Research Grants in 2020.

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Because this is a secondary literature-based study, ethic approval is not necessary.

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Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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Ha, D.K., Kim, M.J., Han, N. et al. Comparative Efficacy of Oral Calcitonin-Gene–Related Peptide Antagonists for the Treatment of Acute Migraine: Updated Meta-analysis. Clin Drug Investig 41, 119–132 (2021). https://doi.org/10.1007/s40261-020-00997-1

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