Clinical use of new targeted drugs for preventive treatment of migraine

Migraine is a common neurological disorder in clinical practice. Its burden is largely determined by the presence of chronic, maladaptive patterns that are often resistant to traditional therapeutic approaches. Migraine progression is associated with many poor health outcomes such as an increasing number of comorbidities, primarily anxiety and depression, potential for abuse of analgesics, as well as worsening of functional impairment and decreased quality of life. Prophylactic treatment of migraine is a key patient management strategy which may modify the maladaptive course of the disease and which is required by approximately 40% of patients. The evolution of preventive approaches has enabled a qualitative shift from empirical methods to the use of targeted therapy strategies. The preventive effect of many drugs that are traditionally used to treat migraine was discovered accidentally, as they were developed for other diseases. In recent years, the landscape of pharmacological approaches used for the preventive treatment of migraine has been expanded to include calcitonin gene-related peptide (CGRP)–targeted drugs, which play a key role in the pathophysiology of migraine. Since 2018, anti-CGRP monoclonal antibodies (mAbs) targeting either the CGRP ligand or its receptor have been used for migraine prevention. Unlike the traditional oral agents, this new class of targeted therapy offers distinct advantages in practical use: high efficacy, rapid onset of prophylactic effect, and high tolerability. Certain advantages are also associated with a long half-life and absence of the need for drug titration. Results of clinical trials of the efficacy and safety of anti-CGRP mAbs demonstrated their high efficacy in treating occasional and chronic migraine in patients with heavy use of analgesics, prior preventive treatment failure, and in patients with comorbid emotional and affective disorders. The preventive effect of anti-CGRP mAbs manifests itself as a beneficial disease-modifying effect during the long-term use.

1. Steinmetz JD, Seeher KM, Schiess N, Nichols E, Cao B, Servili C et al. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024;23(4):344–381. https://doi.org/10.1016/S1474-4422(24)00038-3.

2. Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain. 2020;21(1):137. https://doi.org/10.1186/s10194-020-01208-0.

3. Lampl C, Thomas H, Tassorelli C, Katsarava Z, Laínez JM, Lantéri-Minet M et al. Headache, depression and anxiety: associations in the Eurolight project. J Headache Pain. 2016;17:59. https://doi.org/10.1186/s10194-016-0649-2.

4. Buse DC, Fanning KM, Reed ML, Murray S, Dumas PK, Adams AM, Lipton RB. Life With Migraine: Effects on Relationships, Career, and Finances From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. Headache. 2019;59(8):1286–1299. https://doi.org/10.1111/head.13613.

5. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. https://doi.org/10.1177/0333102417738202.

6. May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12(8):455–464. https://doi.org/10.1038/nrneurol.2016.93.

7. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8):1157–1168. https://doi.org/10.1111/j.1526-4610.2008.01217.x.

8. Buse DC, Muenzel EJ, Zagar AJ, Mehrabadi AS, Shapiro RE, Kim G et al. Rates and risk factors for migraine progression using multiple definitions of progression: Results of the longitudinal OVERCOME (US) study. Headache. 2025;65(4):589–607. https://doi.org/10.1111/head.14925.

9. Buse DC, Reed ML, Fanning KM, Bostic RC, Lipton RB. Demographics, Headache Features, and Comorbidity Profiles in Relation to Headache Frequency in People With Migraine: Results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2020;60(10):2340–2356. https://doi.org/10.1111/head.13966.

10. Serrano D, Lipton RB, Scher AI, Reed ML, Stewart WBF, Adams AM, Buse DC. Fluctuations in episodic and chronic migraine status over the course of 1 year: implications for diagnosis, treatment and clinical trial design. J Headache Pain. 2017;18(1):101. https://doi.org/10.1186/s10194-017-0787-1.

11. Viudez-Martínez A, Torregrosa AB, Navarrete F, García-Gutiérrez MS. Understanding the Biological Relationship between Migraine and Depression. Biomolecules. 2024;14(2):163. https://doi.org/10.3390/biom14020163.

12. Lipton RB, Buse DC, Nahas SJ, Tietjen GE, Martin VT, Löf E et al. Risk factors for migraine disease progression: a narrative review for a patient-centered approach. J Neurol. 2023;270(12):5692–5710. https://doi.org/10.1007/s00415-023-11880-2.

13. Lipton RB, Serrano D, Nicholson RA, Buse DC, Runken MC, Reed ML. Impact of NSAID and Triptan use on developing chronic migraine: results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2013;53(10):1548–1563. https://doi.org/10.1111/head.12201.

14. Buse DC, Greisman JD, Baigi K, Lipton RB. Migraine Progression: A Systematic Review. Headache. 2019;59(3):306–338. https://doi.org/10.1111/head.13459.

15. Xu J, Kong F, Buse DC. Predictors of episodic migraine transformation to chronic migraine: A systematic review and meta-analysis of observational cohort studies. Cephalalgia. 2020;40(5):503–516. https://doi.org/10.1177/0333102419883355.

16. Buse DC, Versijpt J, Diener HC. Disrupting Migraine Dynamics: A Narrative Review of the Consequences of Modern Anti-CGRP Monoclonal Antibody Therapies. Neurol Ther. 2025;14(4):1185–1196. https://doi.org/10.1007/s40120-025-00769-z.

17. Spierings ELH, Ning X, Ramirez Campos V, Cohen JM, Barash S, Buse DC. Improvements in quality of life and work productivity with up to 6 months of fremanezumab treatment in patients with episodic and chronic migraine and documented inadequate response to 2 to 4 classes of migraine-preventive medications in the phase 3b FOCUS study. Headache. 2021;61(9):1376–1386. https://doi.org/10.1111/head.14196.

18. Pascual J, Panni T, Dell’Agnello G, Gonderten S, Novick D, Evers S. Preventive treatment patterns and treatment satisfaction in migraine: results of the OVERCOME (EU) study. J Headache Pain. 2023;24(1):88. https://doi.org/10.1186/s10194-023-01623-z.

19. Tabeeva GR, Artemenko AR, Koreshkina MI, Osipova VV, Sergeev AV, Latysheva NV et al. Overcoming obstacles to effective treatment of patients with migraine (Statement of the expert group on optimizing treatment of patients with migraine). Neurology, Neuropsychiatry, Psychosomatics. 2025;17(2):4–14. https://doi.org/10.14412/2074-2711-2025-2-4-14.

20. Lipton RB, Buse DC, Serrano D, Holland S, Reed ML. Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013;53(8):1300–1311. https://doi.org/10.1111/head.12154.

21. Sacco S, Ashina M, Diener HC, Haghdoost F, Lee MJ, Monteith TS et al. Setting higher standards for migraine prevention: A position statement of the International Headache Society. Cephalalgia. 2025;45(2):3331024251320608. https://doi.org/10.1177/03331024251320608.

22. Ailani J, Burch RC, Robbins MS. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021–1039. https://doi.org/10.1111/head.14153.

23. Eigenbrodt AK, Ashina H, Khan S, Diener HC, Mitsikostas DD, Sinclair AJ et al. Diagnosis and management of migraine in ten steps. Nat Rev Neurol. 2021;17(8):501–514. https://doi.org/10.1038/s41582-021-00509-5.

24. Groth M, Katsarava Z, Ehrlich M. Results of the gErman migraine PatIent Survey on medical Care and prOPhylactic treatment Experience (EPISCOPE). Sci Rep. 2022;12:4589. https://doi.org/10.1038/s41598-022-08716-w.

25. Tabeeva GR, Kosivtsova OV, Kovalchuk NA, Orlyuk TA. Refractory migraine. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(2):76–86. (In Russ.) https://doi.org/10.14412/2074-2711-2024-2-76-86.

26. Guziy EA, Sergeev AV, Tabeeva GR. Analyzing the predictors of relapse in drug-induced headache: a prospective clinical and psychological study. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(3):44–51. (In Russ.) https://doi.org/10.14412/2074-2711-2024-3-44-51.

27. Bentivegna E, Onan D, Martelletti P. Unmet Needs in Preventive Treatment of Migraine. Neurol Ther. 2023;12(2):337–342. https://doi.org/10.1007/s40120-023-00438-z.

28. Sacco S, Braschinsky M, Ducros A, Lampl C, Little P, van den Brink AM et al. European headache federation consensus on the definition of resistant and refractory migraine : Developed with the endorsement of the European Migraine & Headache Alliance (EMHA). J Headache Pain. 2020;21(1):76. https://doi.org/10.1186/s10194-020-01130-5.

29. Özge A, Baykan B, Bıçakçı Ş, Ertaş M, Atalar AÇ, Gümrü S, Karlı N. Revolutionizing migraine management: advances and challenges in CGRP-targeted therapies and their clinical implications. Front Neurol. 2024;15:1402569. https://doi.org/10.3389/fneur.2024.1402569.

30. Silvestro M, Iannone LF, Orologio I, Tessitore A, Tedeschi G, Geppetti P, Russo A. Migraine Treatment: Towards New Pharmacological Targets. Int J Mol Sci. 2023;24(15):12268. https://doi.org/10.3390/ijms241512268.

31. Yuan D, Zhang Y, Li Q, Lv Y, Li X, Yu Y, et al. Factors Affecting Preventive Treatment Outcomes for Patients With Newly Diagnosed Chronic Migraine and Their Compliance With Treatment Recommendations in Chongqing Province, China: An Open-Label Prospective Study With Retrospective Baseline. Front Neurol. 2020;11:227. https://doi.org/10.3389/fneur.2020.00227.

32. Kowacs PA, Sampaio Rocha-Filho PA, Peres MFP, Edvinsson L. The history and rationale of the development of new drugs for migraine treatment. A história e os fundamentos do desenvolvimento de novos medicamentos para o tratamento da migrânea. Arq Neuropsiquiatr. 2023;81(12):1084–1097. https://doi.org/10.1055/s-0043-1777723.

33. Mitsikostas DD, Waeber C, Sanchez-Del-Rio M, Raffaelli B, Ashina H, Maassen van den Brink A et al. The 5-HT1F receptor as the target of ditans in migraine – from bench to bedside. Nat Rev Neurol. 2023;19(8):489–505. https://doi.org/10.1038/s41582-023-00842-x.

34. Tardiolo G, Bramanti P, Mazzon E. Migraine: Experimental Models and Novel Therapeutic Approaches. Int J Mol Sci. 2019;20(12):2932. https://doi.org/10.3390/ijms20122932.

35. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies – successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338–350. https://doi.org/10.1038/s41582-018-0003-1.

36. Greco R, Demartini C, De Icco R, Martinelli D, Putortì A, Tassorelli C. Migraine neuroscience: from experimental models to target therapy. Neurol Sci. 2020;41(Suppl. 2):351–361. https://doi.org/10.1007/s10072-020-04808-5.

37. Yuan H, Lauritsen CG, Kaiser EA, Silberstein SD. CGRP Monoclonal Antibodies for Migraine: Rationale and Progress. BioDrugs. 2017;31(6):487–501. https://doi.org/10.1007/s40259-017-0250-5.

38. Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T et al. Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial. JAMA. 2018;319(19): 1999–2008. https://doi.org/10.1001/jama.2018.4853.

39. Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. 2017;377(22):2113–2122. https://doi.org/10.1056/NEJMoa1709038.

40. Silberstein SD, Cohen JM, Seminerio MJ, Yang R, Ashina S, Katsarava Z. The impact of fremanezumab on medication overuse in patients with chronic migraine: subgroup analysis of the HALO CM study. J Headache Pain. 2020;21(1):114. https://doi.org/10.1186/s10194-020-01173-8.

41. Suzuki S, Suzuki K, Shiina T, Haruyama Y, Hirata K. Real-world experience with monthly and quarterly dosing of fremanezumab for the treatment of patients with migraine in Japan. Front Neurol. 2023;14:1220285. https://doi.org/10.3389/fneur.2023.1220285.

42. Spierings ELH, Kärppä M, Ning X, Cohen JM, Campos VR, Yang R, Reuter U. Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized, placebo-controlled trial. J Headache Pain. 2021;22(1):26. https://doi.org/10.1186/s10194-021-01232-8.

43. Drellia K, Kokoti L, Deligianni CI, Papadopoulos D, Mitsikostas DD. AntiCGRP monoclonal antibodies for migraine prevention: A systematic review and likelihood to help or harm analysis. Cephalalgia. 2021;41(7):851–864. https://doi.org/10.1177/0333102421989601.

44. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298(5871):240–244. https://doi.org/10.1038/298240a0.

45. Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol Rev. 2023;103(2):1565–1644. https://doi.org/10.1152/physrev.00059.2021.

46. Juhasz G, Zsombok T, Modos EA, Olajos S, Jakab B, Nemeth J et al. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain. 2003;106(3):461–470. https://doi.org/10.1016/j.pain.2003.09.008.

47. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183–187. https://doi.org/10.1002/ana.410280213.

48. Labastida-Ramírez A, Caronna E, Gollion C, Stanyer E, Dapkute A, Braniste D et al. Mode and site of action of therapies targeting CGRP signaling. J Headache Pain. 2023;24(1):125. https://doi.org/10.1186/s10194-023-01644-8.

49. Ohlsson L, Kronvall E, Stratton J, Edvinsson L. Fremanezumab blocks CGRP induced dilatation in human cerebral, middle meningeal and abdominal arteries. J Headache Pain. 2018;19(1):66. https://doi.org/10.1186/s10194-018-0905-8.

50. Melo-Carrillo A, Strassman AM, Nir RR, Schain AJ, Noseda R, Stratton J, Burstein R. Fremanezumab-A Humanized Monoclonal Anti-CGRP AntibodyInhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors. J Neurosci. 2017;37(44):10587–10596. https://doi.org/10.1523/JNEUROSCI.2211-17.2017.

51. Melo-Carrillo A, Noseda R, Nir RR, Schain AJ, Stratton J, Strassman AM, Burstein R. Selective Inhibition of Trigeminovascular Neurons by Fremanezumab: A Humanized Monoclonal Anti-CGRP Antibody. J Neurosci. 2017;37(30):7149–7163. https://doi.org/10.1523/JNEUROSCI.0576-17.2017.

52. Noseda R, Schain AJ, Melo-Carrillo A, Tien J, Stratton J, Mai F et al. Fluorescently-labeled fremanezumab is distributed to sensory and autonomic ganglia and the dura but not to the brain of rats with uncompromised blood brain barrier. Cephalalgia. 2020;40(3):229–240. https://doi.org/10.1177/0333102419896.

53. Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system – 40 years and counting. Lancet Neurol. 2019;18(8):795–804. https://doi.org/10.1016/S1474-4422(19)30185-1.

54. Friedman DI, Cohen JM. Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine. Emerg Top Life Sci. 2020;4(2):179–190. https://doi.org/10.1042/ETLS20200018.

55. Fiedler-Kelly JB, Cohen-Barak O, Morris DN, Ludwig E, Rasamoelisolo M, Shen H, Levi M. Population pharmacokinetic modelling and simulation of fremanezumab in healthy subjects and patients with migraine. Br J Clin Pharmacol. 2019;85(12):2721–2733. https://doi.org/10.1111/bcp.14096.

56. Goadsby PJ, Silberstein SD, Yeung PP, Cohen JM, Ning X, Yang R, Dodick DW. Long-term safety, tolerability, and efficacy of fremanezumab in migraine: A randomized study. Neurology. 2020;95(18):e2487–e2499. https://doi.org/10.1212/WNL.0000000000010600.

57. Silberstein SD, Cohen JM, Seminerio MJ, Yang R, Ning X, Ashina M. Longterm efficacy of fremanezumab in chronic and episodic migraine patients with acute medication overuse at baseline: results of a 1-year study [Presentation]. In: International Headache Congress (IHC), Dublin, Ireland, 5–8 September 2019. Available at: https://ihs-headache.org/wp-content/uploads/2020/06/3798_tgt-66220-ihc19-poster-ihc-po-168-final.pdf.

58. Goadsby PJ, Dodick D, Cohen JM, Yang R, Ning X, Silberstein SD. Long-term response rates in chronic and episodic migraine patients with concomitant preventive medication use: results of a 1-year study [Presentation]. In: International Headache Congress (IHC), Dublin, Ireland, 5–8 September 2019. Available at: https://ihs-headache.org/wp-content/uploads/2020/06/3812_tgt-66216-ihc19-poster-ihc-dp-035-final.pdf.

59. Hajjaj I, Baraldi C, Pellesi L. Fremanezumab for the Treatment of Migraine Complicated by Medication Overuse: A Systematic Review. Clin Drug Investig. 2025;45(5):247–254. https://doi.org/10.1007/s40261-025-01433-y.

60. Vikelis M, Rikos D, Argyriou AA, Dermitzakis EV, Andreou AP, Russo A. Switching between anti-CGRP monoclonal antibodies in migraine prophylaxis. Expert Rev Neurother. 2025;25(3):359–374. https://doi.org/10.1080/14737175.2025.2461766.

61. Overeem LH, Peikert A, Hofacker MD, Kamm K, Ruscheweyh R, Gendolla A et al. Effect of antibody switch in non-responders to a CGRP receptor antibody treatment in migraine: A multi-center retrospective cohort study. Cephalalgia. 2022;42(4-5):291–301. https://doi.org/10.1177/03331024211048765.

62. Pellesi L, Garcia-Azorin D, Rubio-Beltrán E, Ha WS, Messina R, Ornello R et al. Combining treatments for migraine prophylaxis: the state-of-the-art. J Headache Pain. 2024;25(1):214. https://doi.org/10.1186/s10194-024-01925-w.

63. Pellesi L, Do TP, Ashina H, Ashina M, Burstein R. Dual Therapy With AntiCGRP Monoclonal Antibodies and Botulinum Toxin for Migraine Prevention: Is There a Rationale? Headache. 2020;60(6):1056–1065. https://doi.org/10.1111/head.13843.

64. Scuteri D, Tonin P, Nicotera P, Vulnera M, Altieri GC, Tarsitano A et al. Pooled Analysis of Real-World Evidence Supports Anti-CGRP mAbs and OnabotulinumtoxinA Combined Trial in Chronic Migraine. Toxins. 2022;14(8):529. https://doi.org/10.3390/toxins14080529.

65. Szkutnik-Fiedler D. Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of New Anti-Migraine Drugs-Lasmiditan, Gepants, and CalcitoninGene-Related Peptide (CGRP) Receptor Monoclonal Antibodies. Pharmaceutics. 2020;12(12):1180. https://doi.org/10.3390/pharmaceutics12121180.

66. Martelletti P, Edvinsson L, Ashina M. Shaping the future of migraine targeting Calcitonin-Gene-Related-Peptide with the Disease-Modifying Migraine Drugs (DMMDs). J Headache Pain. 2019;20(1):60. https://doi.org/10.1186/s10194-019-1009-9.

67. Barbanti P, Aurilia C, Egeo G, Proietti S, Torelli P, d’Onofrio F et al. Impact of multiple treatment cycles with anti-CGRP monoclonal antibodies on migraine course: focus on discontinuation periods. Insights from the multicenter, prospective, I-GRAINE study. J Neurol. 2024;271(5):2605–2614. https://doi.org/10.1007/s00415-024-12192-9.

68. Barbanti P, Aurilia C, Torelli P, Egeo G, d’Onofrio F, Finocchi C et al. Threeyear treatment with anti-CGRP monoclonal antibodies modifies migraine course: the prospective, multicenter I-GRAINE study. J Neurol. 2025;272(2):170. https://doi.org/10.1007/s00415-025-12911-w.