The history and rationale of the development of new drugs for migraine treatment

Abstract

Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers, flunarizine, valproic acid, topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.

Resumo

A migrânea é uma das doenças mais prevalentes e incapacitantes do mundo. O tratamento da crise de migrânea e o tratamento profilático da doença são essenciais para diminuir o seu impacto individual, social e econômico. Este é um artigo de revisão narrativa. Revisamos as principais drogas usadas para a migrânea e os modelos experimentais e referenciais teóricos que levaram ao seu desenvolvimento. Foram abordados os derivados do ergot, triptanas, anti-inflamatórios não hormonais, antidepressivos tricíclicos, betabloqueadores, flunarizina, ácido valproico, topiramato, toxina onabotulínica do tipo A, os ditans, anticorpos monoclonais contra o CGRP e seu receptor e os gepants. Também foram abordados possíveis alvos terapêuticos para o desenvolvimento de novas drogas e drogas que estão em desenvolvimento para o tratamento da migrânea. Muitas das drogas usadas atualmente foram desenvolvidas para o tratamento de outras doenças e se mostraram efetivas para o tratamento da migrânea. Essas ajudaram a ampliar o conhecimento sobre a doença. Com o melhor entendimento da fisiopatologia da migrânea, novas drogas foram e estão sendo desenvolvidas especificamente para o tratamento dessa doença.

Keywords

Headache - Migraine Disorders - Drug Development - Therapeutics - Pathophysiology

Palavras-chave

Cefaleia - Transtornos de Enxaqueca - Desenvolvimento de Medicamentos - Terapêutica - Fisiopatologia

Authors' Contributions

PAK: conceptualization, data curation, formal analysis, project administration, writing – original draft, writing – review & editing; PASRF: formal analysis, project administration, writing – original draft, writing – review & editing; MFPP, LE: formal analysis, writing – review & editing.

Publikationsverlauf

Eingereicht: 03. Oktober 2023

Angenommen: 21. November 2023

Artikel online veröffentlicht:
29. Dezember 2023

• References

• 1 Stovner LJ, Hagen K, Linde M, Steiner TJ. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain 2022; 23 (01) 34
• 2 Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z. Lifting The Burden: the Global Campaign against Headache. Migraine remains second among the world's causes of disability, and first among young women: findings from GBD2019. J Headache Pain 2020; 21 (01) 137
• 3 Peres MFP, Queiroz LP, Rocha-Filho PS, Sarmento EM, Katsarava Z, Steiner TJ. Migraine: a major debilitating chronic non-communicable disease in Brazil, evidence from two national surveys. J Headache Pain 2019; 20 (01) 85
• 4 Foxhall K. The “Beating of Hammers”: Classical and medieval approaches to hemicrania. In: Foxhall K. ed. Migraine: a history. . Baltimore: Johns Hopkins University Press; 2019
• 5 Graham JR, Wolff HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neur Psych 1938; 39: 737-763
• 6 Leao AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7: 359-390
• 7 Lashley KS. Patterns of cerebral integration indicated by the scotomas of migraine. Arch NeurPsych 1941; 46: 331-339
• 8 Lauritzen M, Jørgensen MB, Diemer NH, Gjedde A, Hansen AJ. Persistent oligemia of rat cerebral cortex in the wake of spreading depression. Ann Neurol 1982; 12 (05) 469-474
• 9 Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981; 9 (04) 344-352
• 10 Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8 (02) 136-142
• 11 Weiller C, May A, Limmroth V. et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1 (07) 658-660
• 12 Mehnert J, Fischer-Schulte L, May A. Aura phenomena do not initiate migraine attacks-Findings from neuroimaging. Headache 2023; 63 (08) 1040-1044 ; Epub ahead of print
• 13 Charles A. Aura is a symptom of a migraine attack, not its cause. Headache 2023; 63 (08) 1029-1030 ; Epub ahead of print
• 14 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 (06) 338-350
• 15 Sampaio Rocha-Filho PA, Gherpelli JLD. Premonitory and Accompanying Symptoms in Childhood Migraine. Curr Pain Headache Rep 2022; 26 (02) 151-163
• 16 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. 02) 351-361
• 17 Tardiolo G, Bramanti P, Mazzon E. Migraine: Experimental models and novel therapeutic approaches. Int J Mol Sci 2019; 20 (12) 2932
• 18 Buzzi MG, Carter WB, Shimizu T, Heath III H, Moskowitz MA. Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology 1991; 30 (11) 1193-1200
• 19 Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23 (02) 193-196
• 20 Hoskin KL, Kaube H, Goadsby PJ. Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-Fos and electrophysiological study. Brain 1996; 119 (Pt 1): 249-256
• 21 Eulenburg A. Lehrbuch der Funktionellen Nervenkrankheiten. . Berlin: August Hirschwald; 1871
• 22 Tzanck MAp. Bull Soc Méd Hosp Paris 1928; 52: 513
• 23 Friedman AP, Brenner C. Treatment of the migraine attack. Am Pract Dig Treat 1948; 2 (07) 467-470
• 24 Doepfner W, Cerletti A. Comparison of lysergic acid derivatives and antihistamines as inhibitors of the edema provoked in the rat's paw by serotonin. Int Arch Allergy Appl Immunol 1958; 12 (1-2): 89-97
• 25 Sicuteri F. Prophylactic and therapeutic properties of 1-methyl-lysergic acid butanolamide in migraine. Int Arch Allergy Appl Immunol 1959; 15: 300-307
• 26 Müller-Schweinitzer E. Ergot alkaloids in migraine: Is the effect via 5-HT receptors?. In: Olesen J, Saxena PR. eds. 5-Hydroxytryptamine Mechanisms in Primary Headaches. . New York: Raven; 1992: 297-304
• 27 Hakkarainen H, Vapaatalo H, Gothoni G, Parantainen J. Tolfenamic acid is as effective as ergotamine during migraine attacks. Lancet 1979; 2 (8138) 326-328
• 28 Migraine AM. N Engl J Med 2020; 383: 1866-1876
• 29 Yuill GM, Swinburn WR, Liversedge LA. A double-blind crossover trial of isometheptene mucate compound and ergotamine in migraine. Br J Clin Pract 1972; 26 (02) 76-79
• 30 Tulunay FC, Ergün H, Gülmez SE. et al. The efficacy and safety of dipyrone (Novalgin) tablets in the treatment of acute migraine attacks: a double-blind, cross-over, randomized, placebo-controlled, multi-center study. Funct Neurol 2004; 19 (03) 197-202
• 31 Goldstein J, Silberstein SD, Saper JR, Ryan Jr RE, Lipton RB. Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study. Headache 2006; 46 (03) 444-453
• 32 Humphrey PPA, Feniuk W, Perren MJ. et al. GR43175, a selective agonist for the 5-HT1-like receptor in dog isolated saphenous vein. Br J Pharmacol 1988; 94 (04) 1123-1132
• 33 Edvinsson L, Villalón CM, MaassenVanDenBrink A. Basic mechanisms of migraine and its acute treatment. Pharmacol Ther 2012; 136 (03) 319-333
• 34 González-Hernández A, Marichal-Cancino BA, MaassenVanDenBrink A, Villalón CM. Serotonergic modulation of neurovascular transmission: A focus on prejunctional 5-HT receptors/mechanisms. Biomedicines 2023; 11 (07) 1864
• 35 Cameron C, Kelly S, Hsieh SC. et al. Triptans in the acute treatment of migraine: A systematic review and network meta-analysis. Headache 2015; 55 (Suppl. 04) 221-235
• 36 Vikelis M, Mitsikostas DD, Rapoport AM. Sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Pain Manag (Lond) 2014; 4 (02) 123-128
• 37 Loder EW, Rayhill M, Burch RC. Safety problems with a transdermal patch for migraine: lessons from the development, approval, and marketing process. Headache 2018; 58 (10) 1639-1657
• 38 Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 2000; 60 (06) 1259-1287
• 39 Nelson DL, Phebus LA, Johnson KW. et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia 2010; 30 (10) 1159-1169
• 40 Edvinsson JCA, Maddahi A, Christiansen IM. et al. Lasmiditan and 5-Hydroxytryptamine in the rat trigeminal system; expression, release and interactions with 5-HT₁ receptors. J Headache Pain 2022; 23 (01) 26
• 41 Färkkilä M, Diener HC, Géraud G. et al; COL MIG-202 study group. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol 2012; 11 (05) 405-413
• 42 Ashina M, Reuter U, Smith T. et al. Randomized, controlled trial of lasmiditan over four migraine attacks: Findings from the CENTURION study. Cephalalgia 2021; 41 (03) 294-304
• 43 Goadsby PJ, Wietecha LA, Dennehy EB. et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain 2019; 142 (07) 1894-1904
• 44 Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB. COL MIG-301 Study Group. Lasmiditan is an effective acute treatment for migraine: A phase 3 randomized study. Neurology 2018; 91 (24) e2222-e2232
• 45 Martin VT, Ahmed Z, Hochstetler HM. et al. Tolerability and safety of lasmiditan treatment in elderly patients with migraine: Post hoc analyses from randomized studies. Clin Ther 2021; 43 (06) 1066-1078
• 46 Shapiro RE, Hochstetler HM, Dennehy EB. et al. Lasmiditan for acute treatment of migraine in patients with cardiovascular risk factors: post-hoc analysis of pooled results from 2 randomized, double-blind, placebo-controlled, phase 3 trials. J Headache Pain 2019; 20 (01) 90
• 47 Edvinsson L. Novel migraine therapy with calcitonin gene-regulated peptide receptor antagonists. Expert Opin Ther Targets 2007; 11 (09) 1179-1188
• 48 González-Hernández A, Marichal-Cancino BA, MaassenVanDenBrink A, Villalón CM. Side effects associated with current and prospective antimigraine pharmacotherapies. Expert Opin Drug Metab Toxicol 2018; 14 (01) 25-41
• 49 Edvinsson L, Linde M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet 2010; 376 (9741) 645-655
• 50 Croop R, Madonia J, Stock DA. et al. Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial. Headache 2022; 62 (09) 1153-1163
• 51 Lipton RB, Croop R, Stock DA. et al. 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. Lancet Neurol 2023; 22 (03) 209-217
• 52 Dodick DW, Lipton RB, Ailani J. et al. Ubrogepant for the treatment of migraine. N Engl J Med 2019; 381 (23) 2230-2241
• 53 Friedman AP. The migraine syndrome. Bull N Y Acad Med 1968; 44 (01) 45-62
• 54 Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol 1979; 36 (11) 695-699
• 55 Lampl C, Huber G, Adl J. et al. Two different doses of amitriptyline ER in the prophylaxis of migraine: long-term results and predictive factors. Eur J Neurol 2009; 16 (08) 943-948
• 56 https://go.drugbank.com/drugs/
• 57 Rabkin R, Stables DP, Levin NW, Suzman MM. The prophylactic value of propranolol in angina pectoris. Am J Cardiol 1966; 18 (03) 370-383
• 58 Weber RB, Reinmuth OM. The treatment of migraine with propranolol. Neurology 1972; 22 (04) 366-369
• 59 Hedman C, Winther K, Knudsen JB. The difference between non-selective and beta 1-selective beta-blockers in their effect on platelet function in migraine patients. Acta Neurol Scand 1986; 74 (06) 475-478
• 60 Kaniecki RG. A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 1997; 54 (09) 1141-1145
• 61 Drillisch C, Girke W. [Results of treatment of migraine patients with cinnarizine and flunarizine]. Med Welt 1980; 31 (51-52): 1870-1872
• 62 Louis P. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 1981; 21 (06) 235-239
• 63 Sørensen KV. Valproate: a new drug in migraine prophylaxis. Acta Neurol Scand 1988; 78 (04) 346-348
• 64 Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 1992; 12 (02) 81-84
• 65 Silberstein SD, Lipton RB, Dodick DW. et al; Topiramate Chronic Migraine Study Group. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 2007; 47 (02) 170-180
• 66 Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. TOPMAT-MIG-201(TOP-CHROME) Study Group. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 2007; 27 (07) 814-823
• 67 Diener H-C, Tfelt-Hansen P, Dahlöf C. et al; MIGR-003 Study Group. Topiramate in migraine prophylaxis–results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004; 251 (08) 943-950
• 68 Lipton RB, Silberstein S, Dodick D. et al. Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study. Cephalalgia 2011; 31 (01) 18-30
• 69 Hu C, Zhang Y, Tan G. Advances in topiramate as prophylactic treatment for migraine. Brain Behav 2021; 11 (10) e2290
• 70 Jankovic J, Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology 1990; 40 (02) 277-280
• 71 Aurora S. Botulinum toxin type A for the treatment of migraine. Expert Opin Pharmacother 2006; 7 (08) 1085-1095
• 72 Dodick DW, Turkel CC, DeGryse RE. et al; PREEMPT Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache 2010; 50 (06) 921-936
• 73 Aoki KR, Francis J. Updates on the antinociceptive mechanism hypothesis of botulinum toxin A. Parkinsonism Relat Disord 2011; 17 (Suppl. 01) S28-S33
• 74 Melhado EM, Santos PSF, Kaup AO. et al. Consensus of the Brazilian Headache Society (SBCe) for the prophylactic treatment of episodic migraine: Part I. Arq Neuropsiquiatr 2022; 80 (08) 845-861
• 75 Santos PSF, Melhado EM, Kaup AO. et al. Consensus of the Brazilian Headache Society (SBCe) for prophylactic treatment of episodic migraine: part II. Arq Neuropsiquiatr 2022; 80 (09) 953-969
• 76 Yuan H, Lauritsen CG, Kaiser EA, Silberstein SD. CGRP monoclonal antibodies for migraine: Rationale and progress. BioDrugs 2017; 31 (06) 487-501
• 77 Scheffler A, Messel O, Wurthmann S. et al. Erenumab in highly therapy-refractory migraine patients: First German real-world evidence. J Headache Pain 2020; 21 (01) 84
• 78 Dodick DW, Ashina M, Brandes JL. et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 2018; 38 (06) 1026-1037
• 79 Goadsby PJ, Reuter U, Hallström Y. et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 2017; 377 (22) 2123-2132
• 80 Tepper S, Ashina M, Reuter U. et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017; 16 (06) 425-434
• 81 Tepper SJ, Diener HC, Ashina M. et al. Erenumab in chronic migraine with medication overuse: Subgroup analysis of a randomized trial. Neurology 2019; 92 (20) e2309-e2320
• 82 Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: The randomized, double-blind, placebo-controlled REGAIN study. Neurology 2018; 91 (24) e2211-e2221
• 83 Mulleners WM, Kim BK, Láinez MJA. et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol 2020; 19 (10) 814-825
• 84 Dodick DW, Doty EG, Aurora SK. et al. Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine. Cephalalgia 2021; 41 (03) 340-352
• 85 Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia 2018; 38 (08) 1442-1454
• 86 Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: The EVOLVE-1 randomized clinical trial. JAMA Neurol 2018; 75 (09) 1080-1088
• 87 Dodick DW, Goadsby PJ, Silberstein SD. et al; ALD403 study investigators. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014; 13 (11) 1100-1107
• 88 Dodick DW, Silberstein SD, Bigal ME. et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: A randomized clinical trial. JAMA 2018; 319 (19) 1999-2008
• 89 Ferrari MD, Diener HC, Ning X. et al. Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. Lancet 2019; 394 (10203): 1030-1040
• 90 Silberstein SD, Dodick DW, Bigal ME. et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017; 377 (22) 2113-2122
• 91 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 (01) 114
• 92 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
• 93 Ashina M, Saper J, Cady R. et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia 2020; 40 (03) 241-254
• 94 Ashina M, Lanteri-Minet M, Pozo-Rosich P. et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): a multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol 2022; 21 (07) 597-607
• 95 Diener HC, Marmura MJ, Tepper SJ. et al. Efficacy, tolerability, and safety of eptinezumab in patients with a dual diagnosis of chronic migraine and medication-overuse headache: Subgroup analysis of PROMISE-2. Headache 2021; 61 (01) 125-136
• 96 Lipton RB, Goadsby PJ, Smith J. et al. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology 2020; 94 (13) e1365-e1377
• 97 Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13 (09) 885-892
• 98 Lipton RB, Tepper SJ, Silberstein SD. et al. Reversion from chronic migraine to episodic migraine following treatment with erenumab: Results of a post-hoc analysis of a randomized, 12-week, double-blind study and a 52-week, open-label extension. Cephalalgia 2021; 41 (01) 6-16
• 99 Lipton RB, Cohen JM, Bibeau K. et al. Reversion from chronic migraine to episodic migraine in patients treated with fremanezumab: Post hoc analysis from HALO CM Study. Headache 2020; 60 (10) 2444-2453
• 100 Drellia K, Kokoti L, Deligianni CI, Papadopoulos D, Mitsikostas DD. Anti-CGRP monoclonal antibodies for migraine prevention: A systematic review and likelihood to help or harm analysis. Cephalalgia 2021; 41 (07) 851-864
• 101 Ailani J, Lipton RB, Goadsby PJ. et al; ADVANCE Study Group. Atogepant for the preventive treatment of migraine. N Engl J Med 2021; 385 (08) 695-706
• 102 Croop R, Goadsby PJ, Stock DA. 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): 737-745
• 103 Powell LC, L'Italien G, Popoff E. et al. Health state utility mapping of rimegepant for the preventive treatment of migraine: Double-blind treatment phase and open label extension (BHV3000-305). Adv Ther 2023; 40 (02) 585-600
• 104 Blumenfeld AM, Boinpally R, De Abreu Ferreira R. et al. Phase Ib, open-label, fixed-sequence, drug-drug interaction, safety, and tolerability study between atogepant and ubrogepant in participants with a history of migraine. Headache 2023; 63 (03) 322-332
• 105 Ashina M, Tepper SJ, Reuter U. et al. Once-daily oral atogepant for the long-term preventive treatment of migraine: Findings from a multicenter, randomized, open-label, phase 3 trial. Headache 2023; 63 (01) 79-88
• 106 Boinpally R, Jakate A, Butler M, Periclou A. Atogepant and sumatriptan: no clinically relevant drug-drug interactions in a randomized, open-label, crossover trial. Pain Manag (Lond) 2022; 12 (04) 499-508
• 107 Lipton RB, Pozo-Rosich P, Blumenfeld AM. et al. Rates of response to atogepant for migraine prophylaxis among adults: A secondary analysis of a randomized clinical trial. JAMA Netw Open 2022; 5 (06) e2215499
• 108 Lipton RB, Pozo-Rosich P, Blumenfeld AM. et al. Effect of atogepant for preventive migraine treatment on patient-reported outcomes in the randomized, double-blind, phase 3 ADVANCE Trial. Neurology 2023; 100 (08) e764-e777
• 109 Schwedt TJ, Lipton RB, Ailani J. et al. Time course of efficacy of atogepant for the preventive treatment of migraine: Results from the randomized, double-blind ADVANCE trial. Cephalalgia 2022; 42 (01) 3-11
• 110 Pozo-Rosich P, Ailani J, Ashina M. et al. Atogepant for the preventive treatment of chronic migraine (PROGRESS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023; 402 (10404): 775-785
• 111 Al-Hassany L, Boucherie DM, Creeney H. et al; European Headache Federation School of Advanced Studies (EHF-SAS). Future targets for migraine treatment beyond CGRP. J Headache Pain 2023; 24 (01) 76
• 112 Mikhailov N, Leskinen J, Fagerlund I. et al. Mechanosensitive meningeal nociception via Piezo channels: Implications for pulsatile pain in migraine?. Neuropharmacology 2019; 149: 113-123
• 113 Barbanti P, Egeo G, Aurilia C, Fofi L, Della-Morte D. Drugs targeting nitric oxide synthase for migraine treatment. Expert Opin Investig Drugs 2014; 23 (08) 1141-1148
• 114 Ashina M, Doležil D, Bonner JH. et al. A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia 2021; 41 (01) 33-44
• 115 Edvinsson L, Tajti J, Szalárdy L, Vécsei L. PACAP and its role in primary headaches. J Headache Pain 2018; 19 (01) 21
• 116 Frederiksen SD, Warfvinge K, Ohlsson L, Edvinsson L. Expression of pituitary adenylate cyclase-activating peptide, calcitonin gene-related peptide and headache targets in the trigeminal ganglia of rats and humans. Neuroscience 2018; 393: 319-332
• 117 Edvinsson JCA, Grell AS, Warfvinge K, Sheykhzade M, Edvinsson L, Haanes KA. Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system. Cephalalgia 2020; 40 (12) 1296-1309
• 118 Warfvinge K, Edvinsson L. Cellular distribution of PACAP-38 and PACAP receptors in the rat brain: Relation to migraine activated regions. Cephalalgia 2020; 40 (06) 527-542
• 119 Sarrouilhe D, Dejean C, Mesnil M. Involvement of gap junction channels in the pathophysiology of migraine with aura. Front Physiol 2014; 5: 78