, Volume 31, Issue 6, pp 487–501 | Cite as

CGRP Monoclonal Antibodies for Migraine: Rationale and Progress

  • Hsiangkuo Yuan
  • Clinton G. Lauritsen
  • Eric A. Kaiser
  • Stephen D. SilbersteinEmail author
Review Article


Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management. The site of action, although still being studied, is likely in nervous system structures outside the blood–brain barrier. To date, four CGRP function-blocking mAbs (three target CGRP and one targets the CGRP receptor) are under clinical investigation for migraine prophylaxis. Phase II and III studies were promising with favorable safety profiles. CGRP function-blocking mAbs may potentially revolutionize the management of migraine. This review discusses in depth the fundamental role of CGRP in migraine pathogenesis as well as the clinical efficacy of CGRP function-blocking mAbs.


Compliance with Ethical Standards


No funding was received for the preparation of this review.

Conflict of interest

Dr. Yuan has received honoraria from Supernus Pharmaceuticals, Inc. Dr. Lauritsen has received honoraria from Cefaly Technology as a consultant and/or advisory panel member. Dr. Kaiser has received royalties from a patent with Alder Biopharmaceuticals. Dr. Stephen Silberstein has received honoraria from Alder Biopharmaceuticals; Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; Curelator, Inc.; Depomed; Dr. Reddy’s Laboratories; eNeura Inc.; electroCore Medical, LLC; Ipsen Biopharmaceuticals; Lilly USA, LLC; Medscape, LLC; Medtronic, Inc.; Mitsubishi Tanabe Pharma America, Inc.; NINDS; St. Jude Medical; Supernus Pharmaceuticals, Inc.; Teva Pharmaceuticals; and Trigemina, Inc.


  1. 1.
  2. 2.
    Institute for Health Metrics and Evaluation. GBD 2015 Heat Map. Accessed 13 June 2017.
  3. 3.
    Hawkins K, Wang S, Rupnow M. Direct cost burden among insured US employees with migraine. Headache. 2008;48(4):553–63.PubMedCrossRefGoogle Scholar
  4. 4.
    Lanteri-Minet M. Economic burden and costs of chronic migraine. Curr Pain Headache Rep. 2014;18(1):385.PubMedCrossRefGoogle Scholar
  5. 5.
    Stokes M, Becker WJ, Lipton RB, Sullivan SD, Wilcox TK, Wells L, et al. Cost of health care among patients with chronic and episodic migraine in Canada and the USA: results from the International Burden of Migraine Study (IBMS). Headache. 2011;51(7):1058–77.PubMedCrossRefGoogle Scholar
  6. 6.
    Bloudek LM, Stokes M, Buse DC, Wilcox TK, Lipton RB, Goadsby PJ, et al. Cost of healthcare for patients with migraine in five European countries: results from the International Burden of Migraine Study (IBMS). J Headache Pain. 2012;13(5):361–78.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Wolff HG. Headache: and other head pain. Oxford: Oxford University Press; 1963.Google Scholar
  8. 8.
    Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol. 1984;16(2):157–68.PubMedCrossRefGoogle Scholar
  9. 9.
    Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55(1):533–52.PubMedCrossRefGoogle Scholar
  10. 10.
    Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett. 1985;62(1):131–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Keller JT, Marfurt CF. Peptidergic and serotoninergic innervation of the rat dura mater. J Comp Neurol. 1991;309(4):515–34.PubMedCrossRefGoogle Scholar
  12. 12.
    Tsai SH, Tew JM, McLean JH, Shipley MT. Cerebral arterial innervation by nerve fibers containing calcitonin gene-related peptide (CGRP): I. Distribution and origin of CGRP perivascular innervation in the rat. J Comp Neurol. 1988;271(3):435–44.PubMedCrossRefGoogle Scholar
  13. 13.
    Kruger L, Silverman JD, Mantyh PW, Sternini C, Brecha NC. Peripheral patterns of calcitonin-gene-related peptide general somatic sensory innervation: cutaneous and deep terminations. J Comp Neurol. 1989;280(2):291–302.PubMedCrossRefGoogle Scholar
  14. 14.
    Mayberg M, Langer RS, Zervas NT, Moskowitz MA. Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science (New York, NY). 1981;213(4504):228–30.CrossRefGoogle Scholar
  15. 15.
    Kosaras B, Jakubowski M, Kainz V, Burstein R. Sensory innervation of the calvarial bones of the mouse. J Comp Neurol. 2009;515(3):331–48.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Sampaolo S, Liguori G, Vittoria A, Napolitano F, Lombardi L, Figols J, et al. First study on the peptidergic innervation of the brain superior sagittal sinus in humans. Neuropeptides. 2017. Scholar
  17. 17.
    Cooper PE, Fernstrom MH, Rorstad OP, Leeman SE, Martin JB. The regional distribution of somatostatin, substance P and neurotensin in human brain. Brain Res. 1981;218(1–2):219–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Buck SH, Walsh JH, Yamamura HI, Burks TF. Neuropeptides in sensory neurons. Life Sci. 1982;30(22):1857–66.PubMedCrossRefGoogle Scholar
  19. 19.
    Knyihar-Csillik E, Tajti J, Chadaide Z, Csillik B, Vecsei L. Functional immunohistochemistry of neuropeptides and nitric oxide synthase in the nerve fibers of the supratentorial dura mater in an experimental migraine model. Microsc Res Tech. 2001;53(3):193–211.PubMedCrossRefGoogle Scholar
  20. 20.
    Gustavsson N, Wu B, Han W. Calcium sensing in exocytosis. Dordrecht: Springer; 2012. p. 731–57.Google Scholar
  21. 21.
    Durham PL. Diverse physiological roles of calcitonin gene-related peptide in migraine pathology: modulation of neuronal-glial-immune cells to promote peripheral and central sensitization. Curr Pain Headache Rep. 2016;20(8):48.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Russo AF. Overview of neuropeptides: awakening the senses? Headache. 2017;57:37–46.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    Strassman AM, Weissner W, Williams M, Ali S, Levy D. Axon diameters and intradural trajectories of the dural innervation in the rat. J Comp Neurol. 2004;473(3):364–76.PubMedCrossRefGoogle Scholar
  25. 25.
    Levy D, Burstein R, Strassman AM. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol. 2005;58(5):698–705.PubMedCrossRefGoogle Scholar
  26. 26.
    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):240–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Edvinsson L. The journey to establish CGRP as a migraine target: a retrospective view. Headache. 2015;55(9):1249–55.PubMedCrossRefGoogle Scholar
  28. 28.
    Weidner C, Klede M, Rukwied R, Lischetzki G, Neisius U, Skov PS, et al. Acute effects of substance P and calcitonin gene-related peptide in human skin—a microdialysis study. J Investig Dermatol. 2000;115(6):1015–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Mulderry PK, Ghatei MA, Spokes RA, Jones PM, Pierson AM, Hamid QA, et al. Differential expression of alpha-CGRP and beta-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience. 1988;25(1):195–205.PubMedCrossRefGoogle Scholar
  30. 30.
    Schutz B, Mauer D, Salmon AM, Changeux JP, Zimmer A. Analysis of the cellular expression pattern of beta-CGRP in alpha-CGRP-deficient mice. J Comp Neurol. 2004;476(1):32–43.PubMedCrossRefGoogle Scholar
  31. 31.
    Rosenfeld MG, Mermod J-J, Amara SG, Swanson LW, Sawchenko PE, Rivier J, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. 1983;304(5922):129–35.PubMedCrossRefGoogle Scholar
  32. 32.
    Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099–142.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Poyner DR. Calcitonin gene-related peptide: multiple actions, multiple receptors. Pharmacol Ther. 1992;56(1):23–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Kraenzlin ME, Ch’ng JL, Mulderry PK, Ghatei MA, Bloom SR. Infusion of a novel peptide, calcitonin gene-related peptide (CGRP) in man. Pharmacokinetics and effects on gastric acid secretion and on gastrointestinal hormones. Regul Pept. 1985;10(2–3):189–97.PubMedCrossRefGoogle Scholar
  35. 35.
    Iyengar S, Ossipov MH, Johnson KW. The role of CGRP in peripheral and central pain mechanisms including migraine. Pain. 2016;158(4):543–59.CrossRefGoogle Scholar
  36. 36.
    Zhang Z, Winborn CS, Marquez de Prado B, Russo AF. Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci. 2007;27(10):2693–703.PubMedCrossRefGoogle Scholar
  37. 37.
    Lundy FT, Salmon AL, Lamey PJ, Shaw C, Linden GJ. Carboxypeptidase-mediated metabolism of calcitonin gene-related peptide in human gingival crevicular fluid—a role in periodontal inflammation? J Clin Periodontol. 2000;27(7):499–505.PubMedCrossRefGoogle Scholar
  38. 38.
    Sternini C. Enteric and visceral afferent CGRP neurons. Targets of innervation and differential expression patterns. Ann N Y Acad Sci. 1992;657:170–86.PubMedCrossRefGoogle Scholar
  39. 39.
    Assas BM, Miyan JA, Pennock JL. Cross-talk between neural and immune receptors provides a potential mechanism of homeostatic regulation in the gut mucosa. Mucosal Immunol. 2014;7(6):1283–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Skofitsch G, Jacobowitz DM. Calcitonin gene-related peptide: detailed immunohistochemical distribution in the central nervous system. Peptides. 1985;6(4):721–45.PubMedCrossRefGoogle Scholar
  41. 41.
    Csati A, Tajti J, Tuka B, Edvinsson L, Warfvinge K. Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion—interaction with the sensory system. Brain Res. 2012;1435:29–39.PubMedCrossRefGoogle Scholar
  42. 42.
    Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain. 2013;14(11):1289–303.PubMedCrossRefGoogle Scholar
  43. 43.
    Miller S, Liu H, Warfvinge K, Shi L, Dovlatyan M, Xu C, et al. Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies. Neuroscience. 2016;328:165–83.PubMedCrossRefGoogle Scholar
  44. 44.
    Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb Blood Flow Metab. 1987;7(6):720–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Jansen I, Uddman R, Ekman R, Olesen J, Ottosson A, Edvinsson L. Distribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries. Peptides. 1992;13(3):527–36.PubMedCrossRefGoogle Scholar
  46. 46.
    Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 2015;1600:93–109.PubMedCrossRefGoogle Scholar
  47. 47.
    Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30(10):1179–86.PubMedCrossRefGoogle Scholar
  48. 48.
    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.PubMedCrossRefGoogle Scholar
  49. 49.
    Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158(4):543–59.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Hay DL, Walker CS. CGRP and its receptors. Headache. 2017;57(4):625–36.PubMedCrossRefGoogle Scholar
  51. 51.
    Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache. 2017;57:47–55.PubMedCrossRefGoogle Scholar
  52. 52.
    Hostetler ED, Joshi AD, Sanabria-Bohorquez S, Fan H, Zeng Z, Purcell M, et al. In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. J Pharmacol Exp Ther. 2013;347(2):478–86.PubMedCrossRefGoogle Scholar
  53. 53.
    Eftekhari S, Gaspar RC, Roberts R, Chen TB, Zeng Z, Villarreal S, et al. Localization of CGRP receptor components and receptor binding sites in rhesus monkey brainstem: a detailed study using in situ hybridization, immunofluorescence, and autoradiography. J Comp Neurol. 2016;524(1):90–118.PubMedCrossRefGoogle Scholar
  54. 54.
    Lennerz JK, Rühle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, et al. Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol. 2008;507(3):1277–99.PubMedCrossRefGoogle Scholar
  55. 55.
    Gonzalez-Hernandez A, Marichal-Cancino BA, Lozano-Cuenca J, Lopez-Canales JS, Munoz-Islas E, Ramirez-Rosas MB, et al. Heteroreceptors modulating CGRP release at neurovascular junction: potential therapeutic implications on some vascular-related diseases. Biomed Res Int. 2016;2016(4):2056786.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol. 2015;80(2):193–9.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010;6(10):573–82.PubMedCrossRefGoogle Scholar
  58. 58.
    Buzzi MG, Carter WB, Shimizu T, Heath 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):1193–200.PubMedCrossRefGoogle Scholar
  59. 59.
    McCulloch J, Uddman R, Kingman TA, Edvinsson L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci USA. 1986;83(15):5731–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Fabbretti E, D’Arco M, Fabbro A, Simonetti M, Nistri A, Giniatullin R. Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J Neurosci. 2006;26(23):6163–71.PubMedCrossRefGoogle Scholar
  61. 61.
    Cieslak M, Czarnecka J, Roszek K, Komoszynski M. The role of purinergic signaling in the etiology of migraine and novel antimigraine treatment. Purinergic Signal. 2015;11(3):307–16.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Simonetti M, Giniatullin R, Fabbretti E. Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J Biol Chem. 2008;283(27):18743–52.PubMedCrossRefGoogle Scholar
  63. 63.
    Ma QP, Hill R, Sirinathsinghji D. Colocalization of CGRP with 5-HT1B/1D receptors and substance P in trigeminal ganglion neurons in rats. Eur J Neurosci. 2001;13(11):2099–104.PubMedCrossRefGoogle Scholar
  64. 64.
    Li JL, Ding YQ, Li YQ, Li JS, Nomura S, Kaneko T, et al. Immunocytochemical localization of mu-opioid receptor in primary afferent neurons containing substance P or calcitonin gene-related peptide. A light and electron microscope study in the rat. Brain Res. 1998;794(2):347–52.PubMedCrossRefGoogle Scholar
  65. 65.
    Buldyrev I, Tanner NM, Hsieh HY, Dodd EG, Nguyen LT, Balkowiec A. Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons. J Neurochem. 2006;99(5):1338–50.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Durham PL, Vause CV. Calcitonin gene-related peptide (CGRP) receptor antagonists in the treatment of migraine. CNS Drugs. 2010;24(7):539–48.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    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.PubMedCrossRefGoogle Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V. Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia. 2000;20(10):907–18.PubMedCrossRefGoogle Scholar
  71. 71.
    Sarchielli P, Alberti A, Vaianella L, Pierguidi L, Floridi A, Mazzotta G, et al. Chemokine levels in the jugular venous blood of migraine without aura patients during attacks. Headache. 2004;44(10):961–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G, et al. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia. 1995;15(5):384–90.PubMedCrossRefGoogle Scholar
  73. 73.
    Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81(14):1191–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Cernuda-Morollón E, Ramón C, Martínez-Camblor P, Serrano-Pertierra E, Larrosa D, Pascual J. OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. Pain. 2015;156(5):820–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Cady RK, Vause CV, Ho TW, Bigal ME, Durham PL. Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Headache. 2009;49(9):1258–66.PubMedCrossRefGoogle Scholar
  76. 76.
    Cady R, Turner I, Dexter K, Beach ME, Cady R, Durham P. An exploratory study of salivary calcitonin gene-related peptide levels relative to acute interventions and preventative treatment with onabotulinumtoxinA in chronic migraine. Headache. 2014;54(2):269–77.PubMedCrossRefGoogle Scholar
  77. 77.
    Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J. No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol. 2005;58(4):561–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Friberg L, Olesen J, Olsen TS, Karle A, Ekman R, Fahrenkrug J. Absence of vasoactive peptide release from brain to cerebral circulation during onset of migraine with aura. Cephalalgia. 1994;14(1):47–54.PubMedCrossRefGoogle Scholar
  79. 79.
    Edvinsson L, Erlinge D, Ekman R, Thulin T. Sensory nerve terminal activity in severe hypertension as reflected by circulating calcitonin gene-related peptide (CGRP) and substance P. Blood Press. 1992;1(4):223–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Stevenson JC, Macdonald DW, Warren RC, Booker MW, Whitehead MI. Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed). 1986;293(6558):1329–30.PubMedCentralCrossRefGoogle Scholar
  81. 81.
    Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain. 2000;86(1–2):133–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Valdemarsson S, Edvinsson L, Hedner P, Ekman R. Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Investig. 1990;50(4):385–8.CrossRefGoogle Scholar
  83. 83.
    Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature. 1996;384(6609):560–4.PubMedCrossRefGoogle Scholar
  84. 84.
    Leao AA. The slow voltage variation of cortical spreading depression of activity. Electroencephalogr Clin Neurophysiol. 1951;3(3):315–21.PubMedCrossRefGoogle Scholar
  85. 85.
    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(2):136–42.PubMedCrossRefGoogle Scholar
  86. 86.
    Melo-Carrillo A, Strassman A, Reuven-Nir R, Schain A, Burstein R. Prolonged activation and sensitization of central trigeminovascular neurons by a single wave of CSD in male and female rats (P2.145). Neurology. 2017;88(16 Suppl):P2–145.Google Scholar
  87. 87.
    Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol. 1998;79(2):964–82.PubMedCrossRefGoogle Scholar
  88. 88.
    Melo-Carrillo A, Noseda R, Nir R, Schain AJ, Stratton J, Strassman AM, et al. Selective inhibition of trigeminovascular neurons by fremanezumab: a humanized monoclonal anti-CGRP antibody. J Neurosci. 2017;37(30):7149–63.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Melo-Carrillo A, Strassman AM, Nir RR, Schain A, Noseda R, Stratton J, et al. Fremanezumab—a humanized monoclonal anti-CGRP antibody—inhibits thinly myelinated (Adelta) but not unmyelinated (C) meningeal nociceptors. J Neurosci. 2017. Scholar
  90. 90.
    Bhatt DK, Ramachandran R, Christensen SL, Gupta S, Jansen-Olesen I, Olesen J. CGRP infusion in unanesthetized rats increases expression of c-Fos in the nucleus tractus solitarius and caudal ventrolateral medulla, but not in the trigeminal nucleus caudalis. Cephalalgia. 2015;35(3):220–33.PubMedCrossRefGoogle Scholar
  91. 91.
    Covasala O, Stirn SL, Albrecht S, De Col R, Messlinger K. Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity. J Neurophysiol. 2012;108(2):431–40.PubMedCrossRefGoogle Scholar
  92. 92.
    Capuano A, Greco MC, Navarra P, Tringali G. Correlation between algogenic effects of calcitonin-gene-related peptide (CGRP) and activation of trigeminal vascular system, in an in vivo experimental model of nitroglycerin-induced sensitization. Eur J Pharmacol. 2014;740:97–102.PubMedCrossRefGoogle Scholar
  93. 93.
    Lafata JE, Tunceli O, Cerghet M, Sharma KP, Lipton RB. The use of migraine preventive medications among patients with and without migraine headaches. Cephalalgia. 2010;30(1):97–104.PubMedCrossRefGoogle Scholar
  94. 94.
    Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the 5-HT1B/1D receptor agonists. Arch Neurol. 2002;59(7):1084–8.PubMedCrossRefGoogle Scholar
  95. 95.
    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):1157–68.PubMedCrossRefGoogle Scholar
  96. 96.
    Chu MK, Buse DC, Bigal ME, Serrano D, Lipton RB. Factors associated with triptan use in episodic migraine: results from the American Migraine Prevalence and Prevention Study. Headache. 2012;52(2):213–23.PubMedCrossRefGoogle Scholar
  97. 97.
    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.PubMedCrossRefGoogle Scholar
  98. 98.
    Pascual J. Efficacy of BMS-927711 and other gepants vs triptans: there seem to be other players besides CGRP. Cephalalgia. 2014;34(12):1028–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Walker CS, Hay DL. CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? Br J Pharmacol. 2013;170(7):1293–307.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    MK0974 (Telcagepant) for Migraine Prophylaxis in Patients With Episodic Migraine (0974-049). Accessed 30 May 2017.
  101. 101.
    Bell IM. Calcitonin gene-related peptide receptor antagonists: new therapeutic agents for migraine. J Med Chem. 2014;57(19):7838–58.PubMedCrossRefGoogle Scholar
  102. 102.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Shi L, Lehto SG, Zhu DX, Sun H, Zhang J, Smith BP, et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J Pharmacol Exp Ther. 2016;356(1):223–31.PubMedCrossRefGoogle Scholar
  104. 104.
    Karasek C, Ojala E, Allison D, Latham J. Characterization of the intrinsic binding features of three anti-CGRP therapeutic antibodies effective in preventing migraine: a comparative pre-clinical case study of ALD403, LY-2951742, TEV-48125. Accessed 30 May 2017.
  105. 105.
    Shah DK, Betts AM. Antibody biodistribution coefficients: Inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human. mAbs. 2013;5(2):297–305.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Garg A, Balthasar JP. Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn. 2007;34(5):687–709.PubMedCrossRefGoogle Scholar
  107. 107.
    Dostalek M, Gardner I, Gurbaxani BM, Rose RH, Chetty M. Pharmacokinetics, pharmacodynamics and physiologically-based pharmacokinetic modelling of monoclonal antibodies. Clin Pharmacokinet. 2013;52(2):83–124.PubMedCrossRefGoogle Scholar
  108. 108.
    Richter WF, Jacobsen B. Subcutaneous absorption of biotherapeutics: knowns and unknowns. Drug Metab Dispos. 2014;42(11):1881–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Tibbitts J, Canter D, Graff R, Smith A, Khawli LA. Key factors influencing ADME properties of therapeutic proteins: a need for ADME characterization in drug discovery and development. mAbs. 2016;8(2):229–45.PubMedCrossRefGoogle Scholar
  110. 110.
    Bernards CM, Hill HF. Morphine and alfentanil permeability through the spinal dura, arachnoid, and pia mater of dogs and monkeys. Anesthesiology. 1990;73(6):1214–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M, Damon L, et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood. 2003;101(2):466–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J Neuroimmunol. 2001;114(1–2):168–72.PubMedCrossRefGoogle Scholar
  113. 113.
    Schankin CJ, Maniyar FH, Seo Y, Kori S, Eller M, Chou DE, et al. Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine. Brain. 2016;139(Pt 7):1994–2001.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Maneesri S, Patamanont J, Patumraj S, Srikiatkhachorn A. Cortical spreading depression, meningeal inflammation and trigeminal nociception. Neuroreport. 2004;15(10):1623–7.PubMedCrossRefGoogle Scholar
  115. 115.
    Fried NT, Maxwell CR, Elliott MB, Oshinsky ML. Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia. Cephalalgia. 2017. Scholar
  116. 116.
    Masaaki A, Sano Y, Nishihara H, Sano H, Takeshita Y, Maeda T, et al. Difference between the blood-brain barrier and blood-nerve barrier: analyses using new human in vitro blood- brain and blood-nerve barrier models. (P2.106). Neurology. 2015;84(14 Supplement).Google Scholar
  117. 117.
    Takeshita Y, Omoto M, Fujikawa S, Kanda T. Immunohistochemical analysis of laminin components in the blood–nerve barrier and blood–brain barrier. Clin Exp Neuroimmunol. 2017;8(1):49–53.CrossRefGoogle Scholar
  118. 118.
    Anzil AP, Blinzinger K, Herrlinger H. Fenestrated blood capillaries in rat cranio-spinal sensory ganglia. Cell Tissue Res. 1976;167(4):563–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Knyazeva LA, Banin VV, Charyeva IG, Dreval AA, Pylaev AS. Localization of serum immunoglobulins in tissue of rat autonomic ganglia. Bull Exp Biol Med. 1995;120(2):836–8.CrossRefGoogle Scholar
  120. 120.
    Johnson M, Ellis B, Maren D, Morin SM, Wroblewski V, Johnson K. Peripheral and Central Nervous System Distribution of a CGRP Neutralizing Antibody [125I]-LY2951742 in Male Rats (S26.007). Neurology. 2016;86(16 Suppl):S26.007.Google Scholar
  121. 121.
    Kiernan JA. Vascular permeability in the peripheral autonomic and somatic nervous systems: controversial aspects and comparisons with the blood-brain barrier. Microsc Res Tech. 1996;35(2):122–36.PubMedCrossRefGoogle Scholar
  122. 122.
    MaassenVanDenBrink A, Meijer J, Villalon CM, Ferrari MD. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37(9):779–88.PubMedCrossRefGoogle Scholar
  123. 123.
    Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1081–90.PubMedCrossRefGoogle Scholar
  124. 124.
    Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings EL, Diener HC, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1091–100.PubMedCrossRefGoogle Scholar
  125. 125.
    Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. 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):1100–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Dodick DW, Goadsby PJ, Spierings EL, 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(9):885–92.PubMedCrossRefGoogle Scholar
  127. 127.
    Geppetti P, Benemei S, De Cesaris F. CGRP receptors and TRP channels in migraine. J Headache Pain. 2015;16(Suppl 1):A21.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    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.PubMedCrossRefGoogle Scholar
  129. 129.
    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.PubMedCrossRefGoogle Scholar
  130. 130.
    Lipton RB, Dodick DW, Goadsby PJ, Silberstein SD, hirman J, Smith J, et al. 75% responder rates provide improvement in HIT-6 scores from week 4 through 12 following a single infusion of ALD403, or placebo. (P2.165) 2017 American Academy of Neurology Annual Meeting; 4/24/2017; Boston, MA; 4/24/2017.Google Scholar
  131. 131.
    Smith JT. Randomized, Double-blind, Placebo-controlled Trial of ALD403 (eptinezumab), an anti-CGRP monoclonal antibody for the prevention of chronic migraine. 59th Annual Scientific Meeting of the American Headache Society; 6/10/2017 6/10/2017; Boston, MA; 6/10/2017.Google Scholar
  132. 132.
    Alder Biopharmaceuticals. Alder BioPharmaceuticals Announces Positive Eptinezumab Phase 3 Results for Prevention of Frequent Episodic Migraine. Accessed 27 June 2017.
  133. 133.
    Bigal ME, Dodick DW, Krymchantowski AV, VanderPluym JH, Tepper SJ, Aycardi E, et al. TEV-48125 for the preventive treatment of chronic migraine: efficacy at early time points. Neurology. 2016;87(1):41–8.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Teva’s Fremanezumab Meets all Primary & Secondary Endpoints Across Both Monthly and Quarterly Dosing Regimens in Phase III Study in Episodic Migraine Prevention. Accessed 20 June 2017.
  135. 135.
    Teva Announces Positive Results for Phase III Study of Fremanezumab for the Prevention of Chronic Migraine. 5/31/2017. Accessed 20 June 2017.
  136. 136.
    Regev A, Camporeale A, Sklijarevski V, Wang S, Carter J. Hepatic safety of galcanezumab in patients with migraine: Results of three Phase 2 double-blind placebo-controlled trials (P2.164) 2017 American Academy of Neurology Annual Meeting; 4/24/2017; Boston, MA; 4/24/2017.Google Scholar
  137. 137.
    Aurora SK, Oakes T, Zhang Q, Ahi J, Martinez J. Factors Associated with Significant Reduction in Migraine Headache Days: A Post Hoc Analysis of a Phase II Placebo-Controlled Trial in Patients Treated with Galcanezumab (P2.177) 2017 American Academy of Neurology Annual Meeting; 4/24/2017; Boston, MA; 4/24/2017.Google Scholar
  138. 138.
    Ford J, Ayer D, Nyhius A, Aurora SK, Carter J. Measures of functioning using MSQ v2.1 in patients with a history of episodic migraine and treated with galcanezumab or placebo injections in a Phase 2 clinical trial (P2.179) 2017 American Academy of Neurology Annual Meeting; 4/24/2017; Boston, MA; 4/24/2017.Google Scholar
  139. 139.
    Lilly Announces Positive Results for Three Phase 3 Studies of Galcanezumab for the Prevention of Episodic and Chronic Migraine. 5/12/2017. Accessed 20 June 2017.
  140. 140.
    Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, et al. Safety and efficacy of A MG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):382–90.PubMedCrossRefGoogle Scholar
  141. 141.
    Lenz R, Dodick D, Goadsby P, Silberstein S, Reuter U, Ashina M, et al. Prevention of episodic migraine with AMG 334, a human anti-calcitonin gene-related peptide receptor monoclonal antibody: phase 2 study results and 52-week analysis of open-label extension (S26.002). Neurology. 2016;86(16 Suppl).Google Scholar
  142. 142.
    Tepper S, Ashina M, Reuter U, Brandes JL, Dolezil D, Silberstein S, 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(6):425–34.PubMedCrossRefGoogle Scholar
  143. 143.
    Dodick D, Ashina M, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, et al. A phase 3, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab in migraine prevention: primary results of the arise trial. J Neurol Neurosurg Psychiatry. 2017;88(5):e1.CrossRefGoogle Scholar
  144. 144.
    Goadsby PJ, Reuter U, Bonner J, Broessner G, Hallstrom Y, Zhang F, et al. Phase 3, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab (AMG 334) in migraine prevention: primary results of the strive trial. J Neurol Neurosurg Psychiatry. 2017;88(5):e1.CrossRefGoogle Scholar
  145. 145.
    Schuster NM, Rapoport AM. Calcitonin gene-related peptide-targeted therapies for migraine and cluster headache: a review. Clin Neuropharmacol. 2017;40(4):169–74.PubMedCrossRefGoogle Scholar
  146. 146.
    Benschop RJ, Collins EC, Darling RJ, Allan BW, Leung D, Conner EM, et al. Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain. Osteoarthr Cartil. 2014;22(4):578–85.PubMedCrossRefGoogle Scholar
  147. 147.
    Cohen JM, Dodick DW, Yang R, Newman LC, Li T, Aycardi E, et al. Fremanezumab as add-on treatment for patients treated with other migraine preventive medicines. Headache. 2017;57(9):1375–84.PubMedCrossRefGoogle Scholar
  148. 148.
    Hou M, Xing H, Cai Y, Li B, Wang X, Li P, et al. The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis. J Headache Pain. 2017;18(1):42.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Smillie SJ, King R, Kodji X, Outzen E, Pozsgai G, Fernandes E, et al. An ongoing role of alpha-calcitonin gene-related peptide as part of a protective network against hypertension, vascular hypertrophy, and oxidative stress. Hypertension (Dallas, Tex: 1979). 2014;63(5):1056–62.CrossRefGoogle Scholar
  150. 150.
    Lee J-K, Jung J-S, Park S-H, Sim Y-B, Suh H-W. Deficiency of alpha-calcitonin gene-related peptide induces inflammatory responses and lethality in sepsis. Cytokine. 2013;64(2):548–54.PubMedCrossRefGoogle Scholar
  151. 151.
    Kandilis AN, Papadopoulou IP, Koskinas J, Sotiropoulos G, Tiniakos DG. Liver innervation and hepatic function: new insights. J Surg Res. 2015;194(2):511–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Hashikawa-Hobara N, Ogawa T, Sakamoto Y, Matsuo Y, Ogawa M, Zamami Y, et al. Calcitonin gene-related peptide pre-administration acts as a novel antidepressant in stressed mice. Sci Rep. 2015;5(1):12559.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Hansen JM, Thomsen LL, Olesen J, Ashina M. Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype. Neurology. 2008;71(11):841–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Jefferson Headache CenterThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Department of NeurologyUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations