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Published in: The Journal of Headache and Pain 1/2018

Open Access 01-12-2018 | Research article

Cilostazol induced migraine does not respond to sumatriptan in a double blind trial

Authors: Katrine Falkenberg, Bára Óladóttir á Dunga, Song Guo, Messoud Ashina, Jes Olesen

Published in: The Journal of Headache and Pain | Issue 1/2018

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Abstract

Background

Cilostazol is an inhibitor of phosphodiesterase 3 and thus causes accumulation of cAMP. It induces migraine-like attacks in migraine patients. Whether the cilostazol model responds to sumatriptan in migraine patients and therefore is valid for testing of future anti-migraine medications has never been investigated.

Methods

In a cross-over study, 30 patients received cilostazol (200 mg p.o.) on two separate days each day followed by oral self-administered placebo or sumatriptan 50 mg. We recorded headache characteristics and associated symptoms using a questionnaire. The 30 participants were asked to subsequently treat their spontaneous attacks with sumatriptan (50 mg) or placebo in a double-blind cross-over design and 15 participants did so.

Results

Cilostazol induced headache with some migraine characteristics in all participants; 18 patients on the sumatriptan day and 19 patients on the placebo day fulfilled criteria for a migraine-like attack. The difference in median headache intensity between sumatriptan and placebo at 2 h was not significant (p = 0.09), but it was at 4 h (p = 0.017). During spontaneous attacks, the difference between placebo and sumatriptan was not significant at 2 h (p = 0.26), but it was highly significant at 4 h (p = 0.006).

Conclusion

The cilostazol model in migraine patients could not be validated by a sufficient sumatriptan response. The model may perhaps respond to new drugs that act intracellularly or directly on ion channels.

Trial registration

The study is registered on clinicaltrials.gov (NCT02486276)
Appendix
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Literature
1.
go back to reference Hansen EK, Olesen J (2017) Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals. Cephalalgia 37:11–19CrossRefPubMed Hansen EK, Olesen J (2017) Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals. Cephalalgia 37:11–19CrossRefPubMed
2.
go back to reference Hansen EK, Guo S, Ashina M et al (2016) Toward a pragmatic migraine model for drug testing: I. Cilostazol in healthy volunteers. Cephalalgia 36:172–178CrossRefPubMed Hansen EK, Guo S, Ashina M et al (2016) Toward a pragmatic migraine model for drug testing: I. Cilostazol in healthy volunteers. Cephalalgia 36:172–178CrossRefPubMed
3.
go back to reference Guo S, Olesen J, Ashina M (2014) Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 137:2951–2959CrossRefPubMed Guo S, Olesen J, Ashina M (2014) Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 137:2951–2959CrossRefPubMed
4.
go back to reference Khan S, Deen M, Hougaard A et al (2017) Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol. Cephalalgia 033310241771975 Khan S, Deen M, Hougaard A et al (2017) Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol. Cephalalgia 033310241771975
5.
go back to reference National Center for clinical trial registrations. Raske forsøgspersoner søges til migræneforsøg. www.forsøgsperson.dk, (2017, Accessed 28 Aug 2017). National Center for clinical trial registrations. Raske forsøgspersoner søges til migræneforsøg. www.forsøgsperson.dk, (2017, Accessed 28 Aug 2017).
6.
go back to reference (IHS) HCC of the IHS (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33:629–808CrossRef (IHS) HCC of the IHS (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33:629–808CrossRef
7.
go back to reference Birk S, Kruuse C, Petersen KA et al (2006) The headache-inducing effect of cilostazol in human volunteers. Cephalalgia 26:1304–1309CrossRefPubMed Birk S, Kruuse C, Petersen KA et al (2006) The headache-inducing effect of cilostazol in human volunteers. Cephalalgia 26:1304–1309CrossRefPubMed
8.
go back to reference Evaluation of a multiple-dose regimen of oral sumatriptan for the acute treatment of migraine. The Oral Sumatriptan International Multiple-Dose Study Group. Eur Neurol 1991; 31: 306–313. Evaluation of a multiple-dose regimen of oral sumatriptan for the acute treatment of migraine. The Oral Sumatriptan International Multiple-Dose Study Group. Eur Neurol 1991; 31: 306–313.
9.
go back to reference Ho TW, Mannix LK, Fan X et al (2008) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–1312CrossRefPubMed Ho TW, Mannix LK, Fan X et al (2008) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–1312CrossRefPubMed
10.
go back to reference Hougaard A, Tfelt-Hansen P (2015) Review of dose–response curves for acute antimigraine drugs: triptans, 5-HT 1F agonists and CGRP antagonists. Expert Opin Drug Metab Toxicol 11:1409–1418CrossRefPubMed Hougaard A, Tfelt-Hansen P (2015) Review of dose–response curves for acute antimigraine drugs: triptans, 5-HT 1F agonists and CGRP antagonists. Expert Opin Drug Metab Toxicol 11:1409–1418CrossRefPubMed
11.
go back to reference Durham PL, Russo AF (2002) New insights into the molecular actions of serotonergic antimigraine drugs. Pharmacol Ther 94:77–92CrossRefPubMed Durham PL, Russo AF (2002) New insights into the molecular actions of serotonergic antimigraine drugs. Pharmacol Ther 94:77–92CrossRefPubMed
12.
go back to reference Olesen J, Ashina M (2011) Emerging migraine treatments and drug targets. Trends Pharmacol Sci 32:352–359CrossRefPubMed Olesen J, Ashina M (2011) Emerging migraine treatments and drug targets. Trends Pharmacol Sci 32:352–359CrossRefPubMed
13.
go back to reference Juhasz G, Zsombok T, Jakab B et al (2005) Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 25:179–183CrossRefPubMed Juhasz G, Zsombok T, Jakab B et al (2005) Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 25:179–183CrossRefPubMed
14.
go back to reference Eltorp CT, Jansen-Olesen I, Hansen AJ (2000) Release of calcitonin gene-related peptide (CGRP) from guinea pig dura mater in vitro is inhibited by sumatriptan but unaffected by nitric oxide. Cephalalgia 20:838–844CrossRefPubMed Eltorp CT, Jansen-Olesen I, Hansen AJ (2000) Release of calcitonin gene-related peptide (CGRP) from guinea pig dura mater in vitro is inhibited by sumatriptan but unaffected by nitric oxide. Cephalalgia 20:838–844CrossRefPubMed
15.
go back to reference Ahn S-K, Khalmuratova R, Jeon S-Y et al (2009) Colocalization of 5-HT1F receptor and calcitonin gene-related peptide in rat vestibular nuclei. Neurosci Lett 465:151–156CrossRefPubMed Ahn S-K, Khalmuratova R, Jeon S-Y et al (2009) Colocalization of 5-HT1F receptor and calcitonin gene-related peptide in rat vestibular nuclei. Neurosci Lett 465:151–156CrossRefPubMed
17.
go back to reference Ferrari MD, Saxena PR (1995) 5-HT1 receptors in migraine pathophysiology and treatment. Eur J Neurol 2:5–21CrossRefPubMed Ferrari MD, Saxena PR (1995) 5-HT1 receptors in migraine pathophysiology and treatment. Eur J Neurol 2:5–21CrossRefPubMed
18.
go back to reference Adham N, Kao HT, Schecter LE et al (1993) Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci U S A 90:408–412CrossRefPubMedPubMedCentral Adham N, Kao HT, Schecter LE et al (1993) Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci U S A 90:408–412CrossRefPubMedPubMedCentral
19.
go back to reference Miller KJ, King A, Demchyshyn L, Niznik H, Teitler M (1992) Agonist activity of sumatriptan and metergoline at the human 5-HTtD receptor: further evidence for a role of the 5-HT D receptor in the action of sumatriptan. Eur J Ptlarmacolo:99–112 Miller KJ, King A, Demchyshyn L, Niznik H, Teitler M (1992) Agonist activity of sumatriptan and metergoline at the human 5-HTtD receptor: further evidence for a role of the 5-HT D receptor in the action of sumatriptan. Eur J Ptlarmacolo:99–112
20.
go back to reference Nordgaard JC, Kruse LS, Møller M et al (2013) Phosphodiesterases 3 and 5 express activity in the trigeminal ganglion and co-localize with calcitonin gene-related peptide. Cephalalgia 0:1–11 Nordgaard JC, Kruse LS, Møller M et al (2013) Phosphodiesterases 3 and 5 express activity in the trigeminal ganglion and co-localize with calcitonin gene-related peptide. Cephalalgia 0:1–11
21.
go back to reference Degerman E, Belfrage P, Manganiello VC (1997) Structure, Localization, and Regulation of cGMP-inhibited Phosphodiesterase (PDE3). J Biol Chem 272:6823–6826CrossRefPubMed Degerman E, Belfrage P, Manganiello VC (1997) Structure, Localization, and Regulation of cGMP-inhibited Phosphodiesterase (PDE3). J Biol Chem 272:6823–6826CrossRefPubMed
Metadata
Title
Cilostazol induced migraine does not respond to sumatriptan in a double blind trial
Authors
Katrine Falkenberg
Bára Óladóttir á Dunga
Song Guo
Messoud Ashina
Jes Olesen
Publication date
01-12-2018
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2018
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-018-0841-7

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