sildenafil-citrate and Migraine-Disorders

Migraine, a common chronic primary headache, has been found to be associated with a high risk of erectile dysfunction (ED).. The present study aims to summarize all the evidence related to this topic and demonstrate a quantified result on the association between migraine and ED, which has not been reported in the literature.. MEDLINE, Excerpta Medica Database, and Cochrane Library were systematically searched for identifying the eligible studies (2000-2021). This study was registered in the PROSPERO (ID: CRD42021248013).. The combined effects were synthesized with the relative risks (RR) or standard mean differences (SMD) with 95% confidence intervals (CI).. 6 trials with a total of 51,657 participants were included, of which 6,175 were men with migraine. The pooled analysis indicated that migraine was associated with a significantly higher risk of ED as compared to the non-migraine general population (RR = 1.63, 95%CI: 1.34 to 2.0, P < .001). Consistently, men with migraine have a significantly lower IIEF-5 score than healthy controls (SMD = -3.64, 95%CI: -6.4 to -0.89, P = .01). Stratification analysis on the mean age indicated that the association between migraine and ED was much stronger in the migraine patients with age < 40 years (RR = 32.29, 95% CI: 6.41-162.64, P < .001; I. ED is a common disease among migraine men, especially those patients whose age is under 40 years old. It shows a 32-fold increased risk of ED compared to the healthy controls. Migraine-induced ED may be correlated with multiple factors, that is, chronic illnesses, chronic pain, and psychosocial causes (like anxiety and depression). Since phosphodiesterase-5 inhibitors (ie, sildenafil) might induce or exacerbate migraine, thus it is not recommended to prescribe these drugs for patients with migraine-mediated ED.. The present study provides evidence that migraine is associated with a significantly high risk of ED, especially in those aged < 40 years. The pathophysiological mechanisms of this action deserve further study. He W, Yang Y, Liang H, et al. Migraine Is Associated With High Risk of Erectile Dysfunction: A Systematic Review and Cumulative Analysis. J Sex Med 2022;19:430-440.

Topics: Adult; Erectile Dysfunction; Humans; Male; Migraine Disorders; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

It has not been established if migraine headache and migraine aura share common pathophysiological mechanisms. Sildenafil, a phosphodiesterase-5 inhibitor, causes cGMP accumulation and provokes migraine-like headache in patients with migraine without aura. We investigated if sildenafil induced aura and migraine-like headache in patients with migraine with aura.. In a randomized, double-blinded, placebo-controlled crossover study, 16 patients with migraine with aura (of whom 11 patients exclusively had attacks of migraine with aura) received 100 mg sildenafil or placebo on two separate days. The development, duration, and characteristics of aura and headache were recorded using a questionnaire. The primary outcome was the incidence of migraine aura.. Aura symptoms were induced in three patients (19%) after sildenafil and none after placebo (P < 0.001). After administration of sildenafil, 12 patients (75%) developed headache compared with two patients (12.5%) after placebo (Fisher's exact test, P < 0.001). The headache in nine patients (56%) after sildenafil and one patient (6%) after placebo fulfilled the criteria for migraine-like attacks (Fisher's exact test, P = 0.002). All patients, who fulfilled the criteria for migraine-like attacks, reported that the attack mimicked the headache phase during their usual migraine attacks.. Sildenafil have a moderate migraine headache-inducing and a modest aura-inducing effect in patients with migraine with aura, even in those who exclusively experienced attacks of migraine with aura in their spontaneous attacks. These findings suggest that accumulation of cGMP by PDE5-inhibition do not play any significant role in the initiation of migraine aura and refute the hypothesis of sildenafil being a tool for pharmacological provocation of this phenomenon. These findings further support dissociation between the aura and the headache phase.

Topics: Cross-Over Studies; Double-Blind Method; Epilepsy; Headache; Humans; Migraine Disorders; Migraine with Aura; Sildenafil Citrate

Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.

Topics: Adult; Arteries; Calcitonin Gene-Related Peptide; Cerebrovascular Circulation; Creatine; Double-Blind Method; Energy Metabolism; Female; Glutamic Acid; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Migraine Disorders; Pons; Proton Magnetic Resonance Spectroscopy; Sildenafil Citrate; Spin Labels; Vasodilator Agents; Young Adult

The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.

Topics: Calcitonin Gene-Related Peptide; Dilatation; Humans; Meningeal Arteries; Migraine Disorders; Sildenafil Citrate

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.. 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.. 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.. 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.

Topics: Adult; Calcitonin Gene-Related Peptide; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Signal Transduction; Sildenafil Citrate; Vasodilator Agents; Young Adult

The authors performed a double-blind, placebo-controlled study in 28 patients to evaluate the effects of sildenafil on cerebral hemodynamics. A significant improvement of cerebrovascular reactivity, without any modification of other variables, was recorded 1 hour after the administration of 50 mg sildenafil. Further investigations are needed to evaluate whether cerebrovascular reactivity improvement could contribute to triggering sildenafil-induced migraine.

Topics: Aged; Brain Ischemia; Cerebral Arteries; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Double-Blind Method; Endothelial Cells; Humans; Male; Middle Aged; Migraine Disorders; Phosphodiesterase Inhibitors; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones; Time Factors; Ultrasonography, Doppler, Transcranial; Vasodilation

Migraine is considered a neurovascular disease involving dilatation of cerebral arteries. Nitric oxide (NO) donors induce dilatation of cerebral and extracranial arteries and migraine, but NO has several mechanisms of action in addition to its cyclic guanosine monophosphate (cGMP)-mediated vasodilatation. We examined whether sildenafil (Viagra), a selective inhibitor of cGMP-hydrolysing phosphodiesterase 5 (PDE5), which acts exclusively by increasing cGMP, can induce migraine and dilatation of cerebral arteries. We included 12 patients with migraine without aura in this double-blind, placebo-controlled crossover study, in which placebo or sildenafil 100 mg was administered orally on two separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler ultrasonography and regional cerebral blood flow in the territory of the middle cerebral artery (rCBF(mca)) was measured using SPECT (single photon emission computed tomography) and xenon 133 inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasonography. Headache response, tenderness of pericranial muscles, blood pressure and heart rate were measured repeatedly. We found that migraine attack was induced by sildenafil in 10 of 12 migraine patients and by placebo in two of 12 patients (P = 0.01). V(mca) (P = 0.1) and rCBF(mca) (P = 0.93) remained unchanged after sildenafil. Temporal (P = 0.47) and radial (P = 0.87) artery diameter and pericranial tenderness (P = 0.16) were unaffected by sildenafil. Systolic and diastolic blood pressures were unchanged but heart rate increased from a mean of 62 +/- 2 to 74 +/- 3 beats/min (P = 0.01) after sildenafil. Our results demonstrate that migraine may be induced via a cGMP-dependent mechanism, and we show for the first time that this occurs without initial dilatation of the middle cerebral artery. We propose that triggering mechanisms may reside within the perivascular sensory nerve terminals or the brainstem. However, other sites of action may also be possible and future studies are needed to elucidate this. In the clinical use of sildenafil, patients who have migraine should be informed about the risk of migraine attacks.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Blood Flow Velocity; Cross-Over Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Double-Blind Method; Female; Headache; Heart Rate; Humans; Male; Middle Cerebral Artery; Migraine Disorders; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Radial Artery; Sildenafil Citrate; Sulfones; Temporal Arteries; Tomography, Emission-Computed, Single-Photon; Ultrasonography, Doppler

Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery.. Five subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design.. Standard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T.. Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies.. The study is part of a parent study, which is registered at ClinicalTrials.gov ( NCT03143465 ).

Topics: Adult; Brain; Calcitonin Gene-Related Peptide; Cerebral Angiography; Cross-Over Studies; Double-Blind Method; Female; Humans; Magnetic Resonance Angiography; Male; Meningeal Arteries; Migraine Disorders; Sildenafil Citrate; Young Adult

Migraine attacks occur spontaneously in those who suffer from the condition, but migraine-like attacks can also be induced artificially by a number of substances. Previously published evidence makes the meninges a likely source of migraine related pain. This article investigates the effect of several vasodilators on meningeal arteries in order to find a connection between the effect of a substance on a meningeal vessel and its ability to artificially induce migraine.. A myograph setup was used to test the vasodilator properties of the substances acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil, prostaglandin E2 (PGE2), pituitary adenylate cyclase activating peptide-38 (PACAP-38), calcitonin gene-related peptide (CGRP) and NaCl buffer on meningeal arteries from human and rat. An unpaired t-test was used to statistically compare the mean Emax(%) at the highest concentration of each substance to the Emax(%) of NaCl buffer.. In the human experiments, all substances except PACAP-38 had an Emax (%) higher than the NaCl buffer, but the difference was only significant for SNP and CGRP. For the human samples, clinically tested antimigraine compounds (sumatriptan, telcagepant) were applied to the isolated arteries, and both induced a significant decrease of the effect of exogenously administrated CGRP. In experiments on rat middle meningeal arteries, pre-contracted with PGF2α, similar tendencies were seen. When the pre-contraction was switched to K+ in a separate series of experiments, CGRP and sildenafil significantly relaxed the arteries.. Still no definite answer can be given as to why pain is experienced during an attack of migraine. No clear correlation was found between the efficacy of a substance as a meningeal artery vasodilator in human and the ability to artificially induce migraine or the mechanism of action. Vasodilatation could be an essential trigger, but only in conjunction with other unknown factors. The vasculature of the meninges likely contributes to the propagation of the migrainal cascade of symptoms, but more research is needed before any conclusions can be drawn about the nature of this contribution.

Topics: Animals; Humans; Male; Meningeal Arteries; Migraine Disorders; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Species Specificity; Sulfonamides; Sumatriptan; Vasodilation; Vasodilator Agents

Topics: Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Endothelial Cells; Erectile Dysfunction; Humans; Male; Migraine Disorders; Patient Selection; Piperazines; Purines; Risk Assessment; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Topics: Erectile Dysfunction; Humans; Male; Middle Aged; Migraine Disorders; Migraine without Aura; Phosphodiesterase Inhibitors; Piperazines; Purines; Serotonin Receptor Agonists; Sildenafil Citrate; Sulfones

Topics: Amnesia, Transient Global; Contraindications; Humans; Male; Middle Aged; Migraine Disorders; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents