Skip to main content
SpringerLink
Log in

Emerging Targets in Migraine

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Migraine is a common and highly disabling neurological disorder. Despite the complexity of its pathophysiology, substantial advances have been achieved over the past 20 years in its understanding, as well as the development of pharmacological treatment options. The development of serotonin 5-HT1B/1D receptor agonists (“triptans”) substantially improved the acute treatment of migraine attacks. However, many migraineurs do not respond satisfactorily to triptans and cardiovascular co-morbidities limit their use in a significant number of patients. As migraine is increasingly considered to be a disorder of the brain, and preclinical and clinical data indicate that the observed vasodilation is merely an epiphenomenon, research has recently focused on the development of neurally acting compounds that lack vasoconstrictor properties. This review highlights the most important pharmacological targets for which compounds have been developed that are highly likely to enter or have already advanced into clinical trials for the acute and preventive treatment of migraine. In this context, preclinical and clinical data on compounds acting on calcitonin gene-related peptide or its receptor, the 5-HT1F receptor, nitric oxide synthase, and acid-sensing ion channel blockers are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Stewart WF, Ricci JA, Chee E, Morganstein D. Lost productive work time costs from health conditions in the United States: results from the American Productivity Audit. J Occup Environ Med. 2003;45(12):1234–46.

    Article  PubMed  Google Scholar 

  2. Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol. 2005;12(Suppl 1):1–27.

    Article  PubMed  Google Scholar 

  3. Menken M, Munsat TL, Toole JF. The global burden of disease study: implications for neurology. Arch Neurol. 2000;57(3):418–20.

    Article  CAS  PubMed  Google Scholar 

  4. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193–210.

    Article  PubMed  Google Scholar 

  5. Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30(2):107–19.

    Article  PubMed  Google Scholar 

  6. Goadsby PJ, Zagami AS, Anthony M, Lance JW, Donnan GA, Bladin PF, et al. Oral sumatriptan in acute migraine. Lancet. 1991;338(8770):782–3.

    Article  CAS  PubMed  Google Scholar 

  7. Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965–73.

    Article  CAS  PubMed  Google Scholar 

  8. Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJ, Sandrini G, Wang SJ, et al. Topiramate in migraine prophylaxis—results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004;251(8):943–50.

    Article  CAS  PubMed  Google Scholar 

  9. Silberstein SD, Neto W, Schmitt J, Jacobs D. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004;61(4):490–5.

    Article  PubMed  Google Scholar 

  10. Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793–803.

    Article  CAS  PubMed  Google Scholar 

  11. Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804–14.

    Article  CAS  PubMed  Google Scholar 

  12. Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921–36.

    Article  PubMed  Google Scholar 

  13. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343–9.

    Article  CAS  PubMed  Google Scholar 

  14. Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst. 1999;76(2–3):176–83.

    Article  CAS  PubMed  Google Scholar 

  15. Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169(2):683–96.

    Article  CAS  PubMed  Google Scholar 

  16. Edvinsson L, Gulbenkian S, Barroso CP, Cunha e Sa M, Polak JM, Mortensen A, et al. Innervation of the human middle meningeal artery: immunohistochemistry, ultrastructure, and role of endothelium for vasomotility. Peptides. 1998;19(7):1213–25.

    Article  CAS  PubMed  Google Scholar 

  17. Hokfelt T, Arvidsson U, Ceccatelli S, Cortes R, Cullheim S, Dagerlind A, et al. Calcitonin gene-related peptide in the brain, spinal cord, and some peripheral systems. Ann N Y Acad Sci. 1992;30(657):119–34.

    Article  Google Scholar 

  18. van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997;21(5):649–78.

    Article  PubMed  Google Scholar 

  19. Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev. 2004;84(3):903–34.

    Article  CAS  PubMed  Google Scholar 

  20. Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol. 1984;16(2):157–68.

    Article  CAS  PubMed  Google Scholar 

  21. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12(10):570–84.

    Article  CAS  PubMed  Google Scholar 

  22. Goadsby PJ. The vascular theory of migraine—a great story wrecked by the facts. Brain. 2009;132(Pt 1):6–7.

    PubMed  Google Scholar 

  23. Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med. 2007;13(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  24. Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol. 2004;142(7):1171–81.

    Article  CAS  PubMed  Google Scholar 

  25. 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(2):193–6.

    Article  CAS  PubMed  Google Scholar 

  26. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33(1):48–56.

    Article  CAS  PubMed  Google Scholar 

  27. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183–7.

    Article  CAS  PubMed  Google Scholar 

  28. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  29. Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104–10.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  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.

    Article  CAS  PubMed  Google Scholar 

  33. Diener HC, Barbanti P, Dahlof 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.

    Article  PubMed  Google Scholar 

  34. Merck. Merck updates status of clinical development programs for investigational CGRP receptor antagonist treatments for acute migraine; MK-3207 clinical development discontinued. Sept. 10, 2009. http://www.merck.com/newsroom/news-release-archive/research-and-development/2009_0910.html. Accessed 10 May 2011.

  35. Salvatore CA, Moore EL, Hershey JC, Lynch CC, Regan CP, Bell IM, et al. Pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist [abstract no. PO333]. Cephalalgia. 2009;29(Suppl 1):139.

    Google Scholar 

  36. 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.

    Article  PubMed  Google Scholar 

  37. 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. Epub 2013 Aug 21.

  38. Zeller J, Poulsen KT, Sutton JE, Abdiche YN, Collier S, Chopra R, et al. CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat. Br J Pharmacol. 2008;155(7):1093–103.

    Article  CAS  PubMed  Google Scholar 

  39. Zhu DXD, Zhang J, Zhou L, Smith B, Salyers K, Yu S, et al. A human CGRP receptor antagonist antibody, AA95, is effective in inhibiting capsaicin-induced increase in dermal blood flow in cynomolgus monkeys. Headache. 2012;52(5):871–2.

    Google Scholar 

  40. Bergerot A, Holland PR, Akerman S, Bartsch T, Ahn AH, MaassenVanDenBrink A, et al. Animal models of migraine: looking at the component parts of a complex disorder. Eur J Neurosci. 2006;24(6):1517–34.

    Article  CAS  PubMed  Google Scholar 

  41. Silberstein SD. Emerging target-based paradigms to prevent and treat migraine. Clin Pharmacol Ther. 2013;93(1):78–85.

    Article  CAS  PubMed  Google Scholar 

  42. Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257–70.

    Article  CAS  PubMed  Google Scholar 

  43. Mitsikostas DD, Sanchez del Rio M, Moskowitz MA, Waeber C. Both 5-HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis. Eur J Pharmacol. 1999;369(3):271–7.

    Article  CAS  PubMed  Google Scholar 

  44. Diener HC. Efficacy and safety of intravenous acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine. A double-blind, double-dummy, randomized, multicenter, parallel group study. The ASASUMAMIG Study Group. Cephalalgia. 1999;19(6):581–8.

    Article  CAS  PubMed  Google Scholar 

  45. Limmroth V, May A, Diener H. Lysine-acetylsalicylic acid in acute migraine attacks. Eur Neurol. 1999;41(2):88–93.

    Article  CAS  PubMed  Google Scholar 

  46. Weatherall MW, Telzerow AJ, Cittadini E, Kaube H, Goadsby PJ. Intravenous aspirin (lysine acetylsalicylate) in the inpatient management of headache. Neurology. 2010;75(12):1098–103.

    Article  CAS  PubMed  Google Scholar 

  47. Limmroth V, May A, Auerbach P, Wosnitza G, Eppe T, Diener HC. Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine. J Neurol Sci. 1996;138(1–2):60–5.

    Article  CAS  PubMed  Google Scholar 

  48. Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 2003;126(Pt 1):241–7.

    Article  PubMed  Google Scholar 

  49. Goldstein DJ, Roon KI, Offen WW, Ramadan NM, Phebus LA, Johnson KW, et al. Selective serotonin 1F (5-HT1F) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet. 2001;358(9289):1230–4.

    Article  CAS  PubMed  Google Scholar 

  50. Ferrari MD, Farkkila M, Reuter U, Pilgrim A, Davis C, Krauss M, et al. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan—a randomised proof-of-concept trial. Cephalalgia. 2010;30(10):1170–8.

    Article  PubMed  Google Scholar 

  51. Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia. 2010;30(10):1159–69.

    Article  PubMed  Google Scholar 

  52. Farkkila M, Diener HC, Geraud G, Lainez M, Schoenen J, Harner N, et al. 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;11:405–13.

    Article  PubMed  Google Scholar 

  53. Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 1995;682(1–2):167–81.

    Article  CAS  PubMed  Google Scholar 

  54. De Col R, Koulchitsky SV, Messlinger KB. Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport. 2003;14(2):229–32.

    Article  PubMed  Google Scholar 

  55. Lin Q, Palecek J, Paleckova V, Peng YB, Wu J, Cui M, et al. Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol. 1999;81(3):1075–85.

    CAS  PubMed  Google Scholar 

  56. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47(5):614–24.

    Article  CAS  PubMed  Google Scholar 

  57. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123(Pt 8):1703–9.

    Article  PubMed  Google Scholar 

  58. Hoskin KL, Bulmer DC, Goadsby PJ. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by L-NAME. Neurosci Lett. 1999;266(3):173–6.

    Article  CAS  PubMed  Google Scholar 

  59. Lambert GA, Hoskin KL, Zagami AS. Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. Neuropharmacology. 2004;47(1):92–105.

    Article  CAS  PubMed  Google Scholar 

  60. Olesen J, Thomsen LL, Iversen H. Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci. 1994;15(5):149–53.

    Article  CAS  PubMed  Google Scholar 

  61. Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport. 1993;4(8):1027–30.

    Article  CAS  PubMed  Google Scholar 

  62. Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain. 2004;110(3):675–80.

    Article  CAS  PubMed  Google Scholar 

  63. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, Olesen J, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology. 2003;60(6):935–40.

    Article  CAS  PubMed  Google Scholar 

  64. Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J. Nitric oxide synthase inhibition in migraine. Lancet. 1997;349(9049):401–2.

    Article  CAS  PubMed  Google Scholar 

  65. Hoffmann J, Goadsby PJ. New agents for acute treatment of migraine: CGRP receptor antagonists, iNOS inhibitors. Curr Treat Options Neurol. 2011;14:50–9.

    Article  Google Scholar 

  66. Olesen J. Nitric oxide-related drug targets in headache. Neurotherapeutics. 2010;7(2):183–90.

    Article  CAS  PubMed  Google Scholar 

  67. Palmer JE, Guillard FL, Laurijssens BE, Wentz AL, Dixon RM, Williams PM. A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective iNOS inhibitor, in the treatment of acute migraine. Cephalalgia. 2009;29:124.

    Google Scholar 

  68. Hoivik HO, Laurijssens BE, Harnisch LO, Twomey CK, Dixon RM, Kirkham AJ, et al. Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia. 2010;30(12):1458–67.

    Article  PubMed  Google Scholar 

  69. Høye KLB, Harnisch LO, Twomey CK, Dixon RM, Kirkham A, Williams PM, Wentz AL. Efficacy and tolerability of the iNOS inhibitor GW274150 administered up to 120 mg daily for 12 weeks in the prophylactic treatment of migraine. Cephalalgia. 2009;29:132.

    Google Scholar 

  70. Alderton WK, Angell ADR, Craig C, Dawson J, Garvey E, Moncada S, et al. GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 2005;145(3):301–12.

    Article  CAS  PubMed  Google Scholar 

  71. De Alba J, Clayton NM, Collins SD, Colthup P, Chessell L, Knowles RG. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (NOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain. 2006;120(1–2):170–81.

    Article  PubMed  Google Scholar 

  72. Bhatt DK, Gupta S, Jansen-Olesen I, Andrews JS, Olesen J. NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models. Cephalalgia. 2013;33(2):87–100.

    Article  PubMed  Google Scholar 

  73. Deval E, Gasull X, Noel J, Salinas M, Baron A, Diochot S, et al. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther. 2010;128(3):549–58.

    Article  CAS  PubMed  Google Scholar 

  74. Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Holland PR, Akerman S, Andreou AP, Karsan N, Wemmie JA, Goadsby PJ. Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann Neurol. 2012;72(4):559–63.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

JH has received honoraria for editorial work from Journal Watch Neurology and travel support from Allergan.

PJG is on Advisory Boards for Allergan, Colucid, MAP pharmaceuticals, Merck, Sharpe and Dohme, eNeura, Neuraxon, Autonomic Technologies Inc., Boston Scientific, Electrocore, Eli-Lilly, Medtronic, Linde Industrial Gases, Arteaus, AlderBio, and Bristol-Myers Squibb. He has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix, Impax, and Dr.Reddy’s, and has been compensated for expert legal testimony. He has grant support from Allergan, Amgen, MAP pharmaceuticals, and Merck, Sharpe and Dohme. He has received honoraria for editorial work from Journal Watch Neurology and for developing educational materials and teaching for the American Headache Society.

JH and PJG have received no funding for writing this review.

Author information

Authors and Affiliations

  1. Headache Group, Department of Neurology, University of California, San Francisco, 1701 Divisadero St, San Francisco, CA, 94115, USA

    Jan Hoffmann & Peter J. Goadsby

Authors
  1. Jan Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Goadsby
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Goadsby.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoffmann, J., Goadsby, P.J. Emerging Targets in Migraine. CNS Drugs 28, 11–17 (2014). https://doi.org/10.1007/s40263-013-0126-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-013-0126-2

Keywords

Search

Navigation