Induction of migraine-like headache, but not aura, by cilostazol in patients with migraine with aura

Abstract

Whether migraine headache and migraine aura share common pathophysiological mechanisms remains to be understood. Cilostazol causes cAMP accumulation and provokes migraine-like headache in migraine patients without aura. We investigated if cilostazol induces aura and migraine-like headache in patients with migraine with aura and alters peripheral endothelial function and levels of endothelial markers. In a randomized, double-blinded, placebo-controlled crossover study, 16 patients with migraine with aura (of whom 12 patients exclusively had attacks of migraine with aura) received 200 mg cilostazol (Pletal®) or placebo on two separate days. The development, duration, and characteristics of aura and headache were recorded using a questionnaire. Peripheral endothelial function was assessed by digital pulse amplitude tonometry using EndoPAT2000, and endothelial markers (VCAM1, E-selectin, and VEGFA) were measured. After administration of cilostazol, 14 patients (88%) experienced headache compared with six patients (38%) after placebo (P = 0.009). The headache in 12 patients (75%) after cilostazol and one patient (6%) after placebo fulfilled the criteria for migraine-like attacks (P = 0.0002). Patients reported that the attack mimicked the headache phase during their usual migraine attacks. However, aura symptoms were elicited in one patient after cilostazol and one patient after placebo. Further, endothelial function, as assessed by peripheral arterial tonometry, and endothelial markers were not significantly altered by cilostazol. Accumulation of cAMP by cilostazol induces migraine-like headache, but not aura, in patients with migraine with aura, even in those who exclusively reported attacks of migraine with aura in their spontaneous attacks. These findings further support dissociation between the aura and the headache phase with a yet unknown trigger for the aura and link between aura and headache. In addition, cilostazol administration did not significantly alter endothelial function, as assessed by peripheral arterial tonometry, or the endothelial markers, VCAM1, E-selectin, and VEGFA. However, post hoc analyses showed that our study was statistically underpowered for these outcomes.

Intravenous Endothelin‐1 Infusion Does Not Induce Aura or Headache in Migraine Patients With Aura

“…8 Migraine provocation using vasodilating drugs (glyceryl trinitrate, calcitonin-gene related peptide, and cilostazol) has been attempted in patients suffering from migraine with aura specifically. [40][41][42][43] Interestingly, in these studies, the drugs generally induced migraine attacks without aura, even in patients who previously experienced attacks with aura exclusively, while migraine attacks with aura were only rarely triggered. The present study is, to our knowledge, the first attempt of experimental migraine provocation, in migraine patients, using a vasoconstrictor drug.…”

“…Since there is a substantial pulmonary clearance of ET‐1, with a mean first‐pass clearance of approximately 50%, an explanation for this could be that a higher concentration of intravascular ET‐1 would reach the cerebral circulation in patients with a PFO. Another, more likely, explanation is based on the observation that microemboli, for example, in the form of air bubbles, entering the cerebral circulation can induce CSD in animals and that intravenous administration of agitated saline in migraine patients with PFO may occasionally induce migraine aura . Further, rare occurrences of suspected transient ischemic attacks and neuroimaging‐verified ischemic stroke following sclerotherapy have been reported almost exclusively in patients with right‐to‐left cardiac shunts, mostly PFOs .…”

“…A robust method for experimental provocation of migraine aura, however, has not yet been established . Migraine provocation using vasodilating drugs (glyceryl trinitrate, calcitonin‐gene related peptide, and cilostazol) has been attempted in patients suffering from migraine with aura specifically . Interestingly, in these studies, the drugs generally induced migraine attacks without aura, even in patients who previously experienced attacks with aura exclusively, while migraine attacks with aura were only rarely triggered.…”

“…Another, more likely, explanation is based on the observation that microemboli, for example, in the form of air bubbles, entering the cerebral circulation can induce CSD in animals 8,37 and that intravenous administration of agitated saline in migraine patients with PFO may occasionally induce migraine aura. 38,[40][41][42][43] Further, rare occurrences of suspected transient ischemic attacks and neuroimaging-verified ischemic stroke following sclerotherapy have been reported almost exclusively in patients with right-to-left cardiac shunts, mostly PFOs. 39,44 Thus, intravenous injection of a sclerosant agent in a patient with a PFO could potentially cause CSD and migraine aura due to formation of small thrombi or air bubbles that reach the cerebral cortex, while increase of ET-1 due to endothelial irritation could occur simultaneously as an unrelated effect.…”

ABCC5 Gene Variant c.1146A>G Reduces MRP5 Expression and Can be a Potential Marker to Manage Cilostazol Induced Headache

“…Several studies reported that cilostazol induced a migraine-like headache. Those reports suggested the mechanism of headache was due to accumulation of cyclic adenosine monophosphate (cAMP) in brain cells that induced by cilastazol [4][5][6]. The PDE III enzymes catalyzes the degradation of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).…”