Cilostazol triggers migraine-like attacks in patients with migraine without aura in a reproducible manner, and may thus represent a useful clinical agent for inducing migraine in future studies, according to findings published in Cephalalgia.1
Agents that trigger migraine are useful in endeavors to understand the molecular pathogenesis of acute migraine attacks, identify migraine biomarkers, and investigate the effectiveness of migraine treatments. Cilostazol, a phosphodiesterase-3 inhibitor indicated for treating intermittent claudication, has been shown to induce migraine-like attacks in healthy volunteers and patients with migraine without aura.2-4 In particular, cilostazol was shown to be more effective than other molecules such as calcitonin gene-related peptide for inducing headache in patients with migraine without aura.
In the current study, researchers examined whether cilostazol could reproduce a second migraine-like attack in patients with migraine without aura in a post hoc analysis of 2 brain imaging studies. Study participants received 200 mg of cilostazol on 2 different days (study day 1 and day 2), and had to be migraine-free for ≥48 hours prior to receiving each dose. A total of 56 participants completed study day 1, and only the participants who experienced headache with cilostazol (n=34, 33 women) proceeded to study day 2.
Cilostazol induced migraine-like attacks in 86% of patients on day 1, and in all patients on day 2. No differences between the study days were found for time from cilostazol administration to onset of headache (2 h) and onset of migraine (5 vs 4 h; P =.16). Time to peak headache, peak headache scores, and time to ingestion of rescue medication were also similar on both study days.
The majority of participants (88%) reported that the cilostazol-triggered migraines resembled their acute migraine attacks. Unilateral pain was present in 82% of patients, and identical laterality to their spontaneous attacks was present in 74%. The most frequently reported adverse effects were stiff neck, flushing, and fatigue.
Summary and Applicability
Cilostazol has been shown to induce migraine-like attacks in patients with migraine without aura, but whether or not these attacks can be reproduced was unclear until recently. Researchers found that cilostazol triggered a second migraine-like attack in 100% of patients who had a first attack induced by the drug.
“We found no difference in median time to migraine onset between the two inductions, which facilitates the planning of experimental studies across time. We have also solidified the role of cilostazol as a powerful migraine inducer, and anticipate that this new knowledge will optimize the planning and execution of future human experimental studies of migraine,” the investigators wrote.
Limitations and Disclosures
Whether baseline frequency of migraine attacks affects the reproducibility of cilostazol-induced attacks is unclear. Median days of migraine per month ranged from 2 to 4 in the study population.
This study was funded by Lundbeck Foundation, Novo Nordisk Foundation, and the European Union’s Seventh Framework programme.
- Khan S, Deen M, Hougaard A, Amin FM, Ashina M. Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol [published online July 5, 2017]. Cephalalgia. 2017:333102417719753. doi:10.1177/0333102417719753
- Ratchford EV. Medical management of claudication. J Vasc Surg. 2017;66(1):275-280. doi:10.1016/j.jvs.2017.02.040
- Birk S, Kruuse C, Petersen KA, Tfelt-Hansen P, Olesen J. The headache-inducing effect of cilostazol in human volunteers. Cephalalgia. 2006;26(11):1304-1309. doi:10.1111/j.1468-2982.2006.01218.x
- Guo S, Olesen J, Ashina M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain. 2014;137(Pt 11):2951-2959. doi:10.1093/brain/awu244