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Neurological Sciences

, Volume 38, Issue 12, pp 2089–2093 | Cite as

Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment

  • Håkan Ashina
  • Lawrence Newman
  • Sait Ashina
Review Article

Abstract

Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov. The search term used was “cluster headache and calcitonin gene related peptide” and “primary headaches and calcitonin gene related peptide.” Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment.

Keywords

Calcitonin gene-related peptide Cluster headache Antagonism Trigeminal system Pathophysiology Pain 

Notes

Authors’ contributions

HA conducted the literature search. All the authors contributed with data interpretation, drafting, and revision of the manuscript. All the authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

Håkan Ashina has no disclosures. Lawrence Newman has received honoraria for his work as a consultant for Allergan, Amgen, Alder, Avanir, Depomed, E Neura, and Supernus. Sait Ashina received honoraria for lecturing from Allergan and Avanir Pharmaceuticals. Sait Ashina is also a principal investigator for Alder Pharmaceuticals trial NCT02974153.

References

  1. 1.
    Robbins MS, Lipton RB (2010) The epidemiology of primary headache disorders. Semin Neurol 30:107–119CrossRefPubMedGoogle Scholar
  2. 2.
    Russell MB (2004) Epidemiology and genetics of cluster headache. Lancet Neurol 3:279–283CrossRefPubMedGoogle Scholar
  3. 3.
    May A (2005) Cluster headache: pathogenesis, diagnosis, and management. Lancet 366:843–855CrossRefPubMedGoogle Scholar
  4. 4.
    Rozen TD, Fishman RS (2012) Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 52:99–113CrossRefPubMedGoogle Scholar
  5. 5.
    Schuster NM, Rapoport AM (2016) New strategies for the treatment and prevention of primary headache disorders. Nat Rev Neurol 12:635–650CrossRefPubMedGoogle Scholar
  6. 6.
    Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298:240–244CrossRefPubMedGoogle Scholar
  7. 7.
    Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM (1983) Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 304:129–135CrossRefPubMedGoogle Scholar
  8. 8.
    Edvinsson L, Ekman R, Jansen I, Ottosson A, Uddman R (1987) Peptide-containing nerve fibers in human cerebral arteries: immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann Neurol 21:431–437CrossRefPubMedGoogle Scholar
  9. 9.
    McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 83:5731–5735CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ashina H, Schytz HW, Ashina M (2016) CGRP in human models of primary headaches. Cephalalgia [Epub ahead of print] Google Scholar
  11. 11.
    Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM; MK-0974 Protocol 004 study group (2008) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–1312Google Scholar
  12. 12.
    Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, Assaid C, Aurora SK, Michelson D (2016) A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 36:887–898CrossRefPubMedGoogle Scholar
  13. 13.
    Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM, BIBN 4096 BS Clinical Proof of Concept Study Group (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110CrossRefPubMedGoogle Scholar
  14. 14.
    Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Lenz R (2016) Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15:382–390CrossRefPubMedGoogle Scholar
  15. 15.
    Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings EL, Diener HC, Burstein R, Loupe PS, Ma Y, Yang R, Silberstein SD (2015) 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 14:1091–1100CrossRefPubMedGoogle Scholar
  16. 16.
    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; ALD403 study investigators (2014) 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 13: 1100–1107Google Scholar
  17. 17.
    Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS (2014) 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 13:885–892CrossRefPubMedGoogle Scholar
  18. 18.
    Eli Lilly and Company. A study of LY2951742 in participants with episodic cluster headache. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2017 March 27] Available from: https://clinicaltrials.gov/ct2/show/NCT02397473
  19. 19.
    Eli Lilly and Company. A study of LY2951742 in participants with chronic cluster headache. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2017 June 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT02438826
  20. 20.
    Teva Branded Pharmaceutical Products, R&D Inc. A study to evaluate the efficacy and safety of TEV-48125 for the prevention of episodic cluster headache (ECH). Bethesda (MD): National Library of Medicine (US). 2000-[cited 2017 June 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT02945046
  21. 21.
    Teva Branded Pharmaceutical Products, R&D Inc. A study comparing the efficacy and safety of TEV-48125 (fremanezumab) for the prevention of chronic cluster headache (CCH). Bethesda (MD): National Library of Medicine (US). 2000-[cited 2017 June 4] Available from: https://clinicaltrials.gov/ct2/show/NCT02964338
  22. 22.
    Goadsby PJ (2002) Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol 1:251–257CrossRefPubMedGoogle Scholar
  23. 23.
    Obermann M, Matharu M (2015) Pathophysiology of cluster headache: current status and future directions. In: Ashina, Messoud, Geppetti, Pierangelo (eds) Pathophysiology of headaches—from molecule to man. Springer International Publishing, Switzerland, pp 247–258Google Scholar
  24. 24.
    The International Classification of Headache Disorders, 3rd edition (beta version) (2013) Cephalalgia 33:629–808Google Scholar
  25. 25.
    Goadsby PJ, Edvinsson L (1994) Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117:427–434CrossRefPubMedGoogle Scholar
  26. 26.
    Schoenen J, Jensen RH, Lantéri-Minet M, Láinez MJ, Gaul C, Goodman AM, Caparso A, May A (2013) Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia 33:816–830CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schytz HW, Barløse M, Guo S, Selb J, Caparso A, Jensen R, Ashina M (2013) Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans. Cephalalgia 33:831–841CrossRefPubMedGoogle Scholar
  28. 28.
    Jürgens TP, Barloese M, May A, Láinez JM, Schoenen J, Gaul C, Goodman AM, Caparso A, Jensen RH (2017) Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia 37:423–434CrossRefPubMedGoogle Scholar
  29. 29.
    Leone M, Bussone G (2009) Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol 8:755–764CrossRefPubMedGoogle Scholar
  30. 30.
    May A, Ashburner J, Büchel C, McGonigle DJ, Friston KJ, Frackowiak RS, Goadsby PJ (1999) Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 5:836–838CrossRefPubMedGoogle Scholar
  31. 31.
    Matharu MS (2006) Functional and structural neuroimaging in primary headache disorders. PhD thesis. Headache Group, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, LondonGoogle Scholar
  32. 32.
    Sprenger T, Boecker H, Tolle TR, Bussone G, May A, Leone M (2004) Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 62:516–517CrossRefPubMedGoogle Scholar
  33. 33.
    May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ (1998) Hypothalamic activation in cluster headache attacks. Lancet 352:275–278CrossRefPubMedGoogle Scholar
  34. 34.
    Leone M, Franzini A, Broggi G, Mea E, Cecchini AP, Bussone G (2006) Acute hypothalamic stimulation and ongoing cluster headache attacks. Neurology 67:1844–1845CrossRefPubMedGoogle Scholar
  35. 35.
    Leone M, Franzini A, Cecchini AP, Broggi G, Bussone G (2010) Hypothalamic deep brain stimulation in the treatment of chronic cluster headache. Ther Adv Neurol Disord 3:187–195CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Leone M, Franzini A, Broggi G, Bussone G (2006) Hypothalamic stimulation for intractable cluster headache: long-term experience. Neurology 67:150–152CrossRefPubMedGoogle Scholar
  37. 37.
    van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678CrossRefPubMedGoogle Scholar
  38. 38.
    Deutch AY, Roth RH (1987) Calcitonin gene-related peptide in the ventral tegmental area: selective modulation of prefrontal cortical dopamine metabolism. Neurosci Lett 74:169–174CrossRefPubMedGoogle Scholar
  39. 39.
    D’Andrea G, Granella F, Perini F, Farruggio A, Leone M, Bussone G (2006) Platelet levels of dopamine are increased in migraine and cluster headache. Headache 46:585–591CrossRefPubMedGoogle Scholar
  40. 40.
    D'Andrea G, Leone M, Bussone G, Fiore PD, Bolner A, Aguggia M, Saracco MG, Perini F, Giordano G, Gucciardi A, Leon A (2017) Abnormal tyrosine metabolism in chronic cluster headache. Cephalalgia 37:148–153CrossRefPubMedGoogle Scholar
  41. 41.
    Eftekhari S, Edvinsson L (2011) Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci 12:112–112CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hostetler ED, Joshi AD, Sanabria-Bohórquez S, Fan H, Zeng Z, Purcell M, Gantert L, Riffel K, Williams M, O'Malley S, Miller P, Selnick HG, Gallicchio SN, Bell IM, Salvatore CA, Kane SA, Li CC, Hargreaves RJ, de Groot T, Bormans G, Van Hecken A, Derdelinckx I, de Hoon J, Reynders T, Declercq R, De Lepeleire I, Kennedy WP, Blanchard R, Marcantonio EE, Sur C, Cook JJ, Van Laere K, Evelhoch JL (2013) In vivo quantification of calcitonin gene-related peptide (CGRP) receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography (PET) tracer [11C]MK-4232. J Pharmacol Exp Ther 347:478–486CrossRefPubMedGoogle Scholar
  43. 43.
    Tajti J, Uddman R, Edvinsson L (2001) Neuropeptide localization in the “migraine generator” region of the human brainstem. Cephalalgia 21:96–101CrossRefPubMedGoogle Scholar
  44. 44.
    van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678CrossRefPubMedGoogle Scholar
  45. 45.
    May A, Goadsby PJ (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19:115–127CrossRefPubMedGoogle Scholar
  46. 46.
    Mason RT, Peterfreund RA, Sawchenko PE, Corrigan AZ, Rivier JE, Vale WW (1984) Release of the predicted calcitonin gene-related peptide from cultured rat trigeminal ganglion cells. Nature 308:653–655CrossRefPubMedGoogle Scholar
  47. 47.
    Goadsby PJ, Edvinsson L, Ekman R (1988) Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 23:193–196CrossRefPubMedGoogle Scholar
  48. 48.
    Asghar MS, Becerra L, Larsson HB, Borsook D, Ashina M (2016) Calcitonin gene-related peptide modulates heat nociception in the human brain—an fMRI study in healthy volunteers. PLoS One 11:e0150334CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Levy D, Burstein R, Strassman AM (2005) Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 58:698–705CrossRefPubMedGoogle Scholar
  50. 50.
    Feistel S, Albrecht S, Messlinger K (2013) The calcitonin gene-related peptide receptor antagonist MK-8825 decreases spinal trigeminal activity during nitroglycerin infusion. J Headache Pain 14:93CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Fanciullacci M, Alessandri M, Sicuteri R, Marabini S (1997) Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients. Brain 120:283–288CrossRefPubMedGoogle Scholar
  52. 52.
    Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S (1995) Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 60:119–123CrossRefPubMedGoogle Scholar
  53. 53.
    Neeb L, Anders L, Euskirchen P, Hoffmann J, Israel H, Reuter U (2015) Corticosteroids alter CGRP and melatonin release in cluster headache episodes. Cephalalgia 35:317–326CrossRefPubMedGoogle Scholar
  54. 54.
    Buzzi MG, Carter WB, Shimizu T, Health H 3rd, Moskowitz MA (1991) Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology 30:1193–1200CrossRefPubMedGoogle Scholar
  55. 55.
    Hansen JM, Petersen J, Wienecke T, Olsen KS, Jensen LT, Ashina M (2009) Sumatriptan does not change calcitonin gene-related peptide in the cephalic and extracephalic circulation in healthy volunteers. J Headache Pain 10:85–91CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Hansen JM, Hauge AW, Olesen J, Ashina M (2010) Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30:1179–1186CrossRefPubMedGoogle Scholar
  57. 57.
    Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Pv K, Larsson HB, Olesen J, Ashina M (2011) Evidence for a vascular factor in migraine. Ann Neurol 69:635–645CrossRefPubMedGoogle Scholar
  58. 58.
    Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 22:54–61CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l. 2017

Authors and Affiliations

  1. 1.Danish Headache Center and Department of Neurology, Rigshospitalet GlostrupUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of Neurology, New York University School of MedicineNYU Langone Medical CenterNew YorkUSA

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