A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks.

Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days.

Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration.

Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients.

References

1. Russell, M, Rasmussen, B, Fenger, K, et al. Migraine without aura and migraine with aura are distinct clinical entities: A study of four hundred and eighty-four male and female migraineurs from the general population . Cephalgia 1996 ; 16: 239 – 245 .

Google Scholar SAGE Journals | ISI

2. Russell, MB, Olesen, J. Increased familial risk and evidence of genetic factor in migraine . BMJ 1995 ; 311: 541 – 544 .

Google Scholar Crossref | Medline

3. Pietrobon, D, Moskowitz, MA. Pathophysiology of migraine . Ann Rev Physiol 2013 ; 75: 365 – 391 .

Google Scholar Crossref | Medline | ISI

4. Ashina, M, Hansen, JM, á Dunga, BO, et al. Human models of migraine – short-term pain for long-term gain . Nat Rev Neurol 2017 ; 13: 713 – 724 .

Google Scholar Crossref | Medline

5. Russell, FA, King, R, Smillie, S-J, et al. Calcitonin gene-related peptide: Physiology and pathophysiology . Physiol Rev 2014 ; 94: 1099 – 1142 .

Google Scholar Crossref | Medline | ISI

6. Corbin, JD, Francis, SH. Cyclic GMP Phosphodiesterase-5: Target of Sildenafil* . J Biol Chem 1999 ; 274: 13729 – 13733 .

Google Scholar Crossref | Medline | ISI

7. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

Google Scholar

8. Guo, S, Christensen, AF, Liu, ML, et al. Calcitonin gene-related peptide induced migraine attacks in patients with and without familial aggregation of migraine . Cephalalgia 2017 ; 37: 114 – 124 .

Google Scholar SAGE Journals | ISI

9. Lassen, LH, Haderslev, PA, Jacobsen, VB, et al. CGRP may play a causative role in migraine . Cephalalgia 2002 ; 22: 54 – 61 .

Google Scholar SAGE Journals | ISI

10. Christensen, CE, Younis, S, Deen, M, et al. Migraine induction with calcitonin gene-related peptide in patients from erenumab trials . J Headache Pain 2018 ; 19: 1 – 9 .

Google Scholar Crossref | Medline

11. Kruuse, C, Thomsen, LL, Birk, S, et al. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter . Brain 2003 ; 126: 241 – 247 .

Google Scholar Crossref | Medline | ISI

12. Rasmussen, BK, Olesen, J. Migraine with aura and migraine without aura: An epidemiological study . Cephalalgia 1992 ; 12: 221 – 228 .

Google Scholar SAGE Journals | ISI

13. Kelman, L . The triggers or precipitants of the acute migraine attack . Cephalalgia 2007 ; 27: 394 – 402 .

Google Scholar SAGE Journals | ISI

14. Fabbretti, E, D’Arco, M, Fabbro, A, et al. Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide . J Neurosci 2006 ; 26: 6163 – 6171 .

Google Scholar Crossref | Medline | ISI

15. Al-Karagholi, MA-M, Hansen, JM, Guo, S, et al. Opening of ATP-sensitive potassium channels causes migraine attacks: A new target for the treatment of migraine . Brain 2019 ; 142: 2644 – 2654 .

Google Scholar Crossref | Medline

16. Nordgaard, JC, Kruse, LS, Møller, M, et al. Phosphodiesterases 3 and 5 express activity in the trigeminal ganglion and co-localize with calcitonin gene-related peptide . Cephalalgia 2013 ; 34: 503 – 513 .

Google Scholar SAGE Journals

17. Barman, SA, Zhu, S, Han, G, et al. cAMP activates BK Ca channels in pulmonary arterial smooth muscle via cGMP-dependent protein kinase . Am J Physiol Cell Mol Physiol 2003 ; 284: L1004 – L1011 .

Google Scholar Crossref | Medline | ISI

18. Jiang, H, Colbran, JL, Francis, SH, et al. Direct evidence for cross-activation of cGMP-dependent protein kinase by cAMP in pig coronary arteries . J Biol Chem 1992 ; 267: 1015 – 1019 .

Google Scholar Medline | ISI

19. Guo, S, Olesen, J, Ashina, M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase . Brain 2014 ; 137: 2951 – 2959 .

Google Scholar Crossref | Medline | ISI

20. Ashina, H, Guo, S, Vollesen, ALH, et al. PACAP38 in human models of primary headaches . J Headache Pain 2017 ; 18: 110 – 110 .

Google Scholar Crossref | Medline

21. Eftekhari, S, Salvatore, CA, Calamari, A, et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion . Neuroscience 2010 ; 169: 683 – 696 .

Google Scholar Crossref | Medline | ISI

22. Eftekhari, S, Warfvinge, K, Blixt, FW, et al. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system . J Pain 2013 ; 14: 1289 – 1303 .

Google Scholar Crossref | Medline | ISI

23. Walker, D, Ackland, MJ, James, G, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man . Xenobiotica 1999 ; 29: 297 – 310 .

Google Scholar Crossref | Medline | ISI

24. Gómez-Vallejo, V, Ugarte, A, García-Barroso, C, et al. Pharmacokinetic investigation of sildenafil using positron emission tomography and determination of its effect on cerebrospinal fluid cGMP levels . J Neurochem 2016 ; 136: 403 – 415 .

Google Scholar Crossref | Medline

25. Hansen, JM, Hauge, AW, Olesen, J, et al. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura . Cephalalgia 2010 ; 30: 1179 – 1186 .

Google Scholar SAGE Journals | ISI

26. Asghar, MS, Hansen, AE, Amin, FM, et al. Evidence for a vascular factor in migraine . Ann Neurol 2011 ; 69: 635 – 645 .

Google Scholar Crossref | Medline | ISI

27. Brain, SD, Grant, AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin . Physiol Rev 2004 ; 84: 903 – 934 .

Google Scholar Crossref | Medline | ISI

28. Nichols, DJ, Muirhead, GJ, Harness, JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: Absolute bioavailability, food effects and dose proportionality . Br J Clin Pharmacol 2002 ; 53: S5 – S12 .

Google Scholar Crossref | Medline | ISI

29. McEwan, JR, Benjamin, N, Larkin, S, et al. Vasodilatation by calcitonin gene-related peptide and by substance P: A comparison of their effects on resistance and capacitance vessels of human forearms . Circulation 1988 ; 77: 1072 – 1080 .

Google Scholar Crossref | Medline

30. Eardley, I, Ellis, P, Boolell, M, et al. Onset and duration of action of sildenafil for the treatment of erectile dysfunction . Br J Clin Pharmacol 2002 ; 53: S61 – S65 .

Google Scholar Crossref | Medline | ISI