Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Drugs
Published in: Drugs 9/2018

01-06-2018 | Review Article

CGRP and Migraine: The Role of Blocking Calcitonin Gene-Related Peptide Ligand and Receptor in the Management of Migraine

Authors: Kasra Maasumi, Rebecca L. Michael, Alan M. Rapoport

Published in: Drugs | Issue 9/2018

Login to get access

Abstract

Migraine is a highly prevalent, complex neurological disorder. The burden of disease and the direct/indirect annual costs are enormous. Thus far, treatment options have been inadequate and mostly based on trial and error, leaving a significant unmet need for effective therapies. While the underlying pathophysiology of migraine is incompletely understood, blocking the calcitonin gene-related peptide (CGRP) using monoclonal antibodies targeting CGRP or its receptor and small molecule CGRP receptor antagonists (gepants) have emerged as a promising therapeutic opportunity for the management of migraine. In this review, we discuss new concepts in the pathophysiology of migraine and the role of CGRP, the current guidelines for treating migraine preventively, the medications that are being used, and their limitations. We then discuss small molecule CGRP receptor antagonists, monoclonal antibodies to CGRP ligand and receptor, as well as the detailed results of Phase II and III trials involving these novel treatments. We conclude with a discussion of the implications of blocking CGRP and its receptor.
Literature
1.
Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41:646–57.CrossRefPubMed
2.
Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. Headache. 2005;45(Suppl 1):S3–s13.CrossRefPubMed
3.
Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800.
4.
Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA. 1992;267:64–9.CrossRefPubMed
5.
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–7.CrossRefPubMed
6.
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553–622.CrossRefPubMedPubMedCentral
7.
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;62:131–6.CrossRefPubMed
8.
Uddman R, Goadsby PJ, Jansen I, Edvinsson L. PACAP, a VIP-like peptide: immunohistochemical localization and effect upon cat pial arteries and cerebral blood flow. J Cereb Blood Flow Metab. 1993;13:291–7.CrossRefPubMed
9.
Uddman R, Edvinsson L. Neuropeptides in the cerebral circulation. Cerebrovasc Brain Metab Rev. 1989;1:230–52.PubMed
10.
Edvinsson L, Emson P, McCulloch J, Tatemoto K, Uddman R. Neuropeptide Y: cerebrovascular innervation and vasomotor effects in the cat. Neurosci Lett. 1983;43:79–84.CrossRefPubMed
11.
Edvinsson L. Functional role of perivascular peptides in the control of cerebral circulation. Trends Neurosci. 1985;8:126–31.CrossRef
12.
Edvinsson L, Brodin E, Jansen I, Uddman R. Neurokinin A in cerebral vessels: characterization, localization and effects in vitro. Regul Pept. 1988;20:181–97.CrossRefPubMed
13.
Edvinsson L, Goadsby PJ. Neuropeptides in the cerebral circulation: relevance to headache. Cephalalgia. 1995;15:272–6.CrossRefPubMed
14.
May A, Goadsby PJ. Substance P receptor antagonists in the therapy of migraine. Expert Opin Investig Drugs. 2001;10:673–8.CrossRefPubMed
15.
16.
Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132:16–25.CrossRefPubMed
17.
Arimura A. Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research. Regul Pept. 1992;37:287–303.PubMed
18.
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;298:240–4.CrossRefPubMed
19.
20.
Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache. 2017;57(Suppl 2):47–55.CrossRefPubMed
21.
Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, Messlinger K. 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;507:1277–99.CrossRefPubMed
22.
Eftekhari S, Edvinsson L. Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci. 2011;12:112.CrossRefPubMedPubMedCentral
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;169:683–96.CrossRefPubMed
24.
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;14:1289–303.CrossRefPubMed
25.
McCulloch J, Uddman R, Kingman TA, Edvinsson L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci USA. 1986;83:5731–5.CrossRefPubMedPubMedCentral
26.
Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G, Trequattrini A, Palumbo R. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia. 1995;15:384–90.CrossRefPubMed
27.
28.
Edvinsson L, Ekman R, Goadsby PJ. Measurement of vasoactive neuropeptides in biological materials: problems and pitfalls from 30 years of experience and novel future approaches. Cephalalgia. 2010;30:761–6.CrossRefPubMed
29.
Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010;6:573–82.CrossRefPubMed
30.
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;23:193–6.CrossRefPubMed
31.
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30:1179–86.CrossRefPubMed
32.
Cernuda-Morollon E, Larrosa D, Ramon C, Vega J, Martinez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81:1191–6.CrossRefPubMed
33.
Akerman S, Goadsby PJ. Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine. Sci Transl Med. 2015;7:308ra157.CrossRefPubMed
34.
35.
Raddant AC, Russo AF. Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med. 2011;13:e36.CrossRefPubMedPubMedCentral
36.
van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997;21:649–78.CrossRefPubMed
37.
Edvinsson L, Eftekhari S, Salvatore CA, Warfvinge K. Cerebellar distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) in rat. Mol Cell Neurosci. 2011;46:333–9.CrossRefPubMed
38.
Recober A, Russo AF. Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment. IDrugs. 2007;10:566–74.PubMed
39.
Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, Lines C, Edvinsson L, Goadsby PJ, Michelson D. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology. 2014;83:958–66.CrossRefPubMed
40.
Hoffmann J, Goadsby PJ. New agents for acute treatment of migraine: CGRP receptor antagonists, iNOS inhibitors. Curr Treat Options Neurol. 2012;14:50–9.CrossRefPubMed
41.
Joshi S, Rapoport AM. Diclofenac potassium for oral solution (CAMBIA((R))) in the acute management of a migraine attack: clinical evidence and practical experience. Ther Adv Neurol Disord. 2017;10:217–26.CrossRefPubMedPubMedCentral
42.
May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12:455–64.CrossRefPubMed
43.
Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337–45.CrossRefPubMedPubMedCentral
44.
Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener HC, Brin MF. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled Phase of the PREEMPT 1 trial. Cephalalgia. 2010;30:793–803.CrossRefPubMed
45.
Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein SD, Brin MF. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled Phase of the PREEMPT 2 trial. Cephalalgia. 2010;30:804–14.CrossRefPubMed
46.
Hepp Z, Dodick DW, Varon SF, Chia J, Matthew N, Gillard P, Hansen RN, Devine EB. Persistence and switching patterns of oral migraine prophylactic medications among patients with chronic migraine: a retrospective claims analysis. Cephalalgia. 2017;37:470–85.CrossRefPubMed
47.
Edvinsson L. Clinical data on the CGRP antagonist BIBN4096BS for treatment of migraine attacks. CNS Drug Rev. 2005;11:69–76.CrossRefPubMed
48.
Silberstein S, Lenz R, Xu C. Therapeutic monoclonal antibodies: what headache specialists need to know. Headache. 2015;55:1171–82.CrossRefPubMed
49.
Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–32.CrossRefPubMed
50.
Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113–22.CrossRefPubMed
51.
52.
Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Lenz R. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, Phase 2 trial. Lancet Neurol. 2016;15:382–90.CrossRefPubMed
53.
Ashina M, Dodick D, Goadsby PJ, Reuter U, Silberstein S, Zhang F, Gage JR, Cheng S, Mikol DD, Lenz RA. Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study. Neurology. 2017;89:1237–43.CrossRefPubMed
54.
Tepper S, Ashina M, Reuter U, Brandes JL, Dolezil D, Silberstein S, Winner P, Leonardi D, Mikol D, Lenz R. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled Phase 2 trial. Lancet Neurol. 2017;16:425–34.CrossRefPubMed
55.
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;13:885–92.CrossRefPubMed
56.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J, ALDs 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;13:1100–7.CrossRefPubMed
57.
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, Burstein R, Newman LC, Lipton RB. 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;14:1081–90.CrossRefPubMed
58.
Bigal ME, Dodick DW, Krymchantowski AV, VanderPluym JH, Tepper SJ, Aycardi E, Loupe PS, Ma Y, Goadsby PJ. TEV-48125 for the preventive treatment of chronic migraine: efficacy at early time points. Neurology. 2016;87:41–8.CrossRefPubMedPubMedCentral
59.
Cohen JM, Dodick DW, Yang R, Newman LC, Li T, Aycardi E, Bigal ME. Fremanezumab as add-on treatment for patients treated with other migraine preventive medicines. Headache. 2017;57:1375–84.CrossRefPubMed
60.
Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, Picard H, Mikol DD, Lenz RA. ARISE: a Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38:1026–37.CrossRefPubMed
61.
62.
Giamberardino MA, Affaitati G, Martelletti P, Tana C, Negro A, Lapenna D, Curto M, Schiavone C, Stellin L, Cipollone F, Costantini R. Impact of migraine on fibromyalgia symptoms. J Headache Pain. 2015;17:28.CrossRefPubMed
63.
Pellesi L, Guerzoni S, Pini LA. Spotlight on anti-CGRP monoclonal antibodies in migraine: the clinical evidence to date. Clin Pharmacol Drug Dev. 2017;6:534–47.CrossRefPubMedPubMedCentral
64.
Mitsikostas DD, Reuter U. Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Curr Opin Neurol. 2017;30:272–80.CrossRefPubMed
65.
Metadata
Title
CGRP and Migraine: The Role of Blocking Calcitonin Gene-Related Peptide Ligand and Receptor in the Management of Migraine
Authors
Kasra Maasumi
Rebecca L. Michael
Alan M. Rapoport
Publication date
01-06-2018
Publisher
Springer International Publishing
Published in
Drugs / Issue 9/2018
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-018-0923-5

Other articles of this Issue 9/2018

Drugs 9/2018 Go to the issue

Adis Drug Evaluation

Telotristat Ethyl: A Review in Carcinoid Syndrome Diarrhoea

Leading Article

Drugs in Development for Malaria

Leading Article

Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab

Adis Drug Evaluation

Regorafenib: A Review in Hepatocellular Carcinoma

Review Article

Targeting EGFR in Lung Cancer: Current Standards and Developments

AdisInsight Report

Fostamatinib: First Global Approval