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Abstract
Migraine is considered a neurovascular illness involving dilatation of cognitive 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 circadian guanosine monophosphate (cGMP)‐mediated vasodilatation. We examined whether sildenafil (Viagra®), a selective inhibitor of cGMP‐hydrolysing phosphodiesterase 5 (PDE5), which acts exclusively past increasing cGMP, tin induce migraine and dilatation of cerebral arteries. Nosotros included 12 patients with migraine without aura in this double‐blind, placebo‐controlled crossover report, in which placebo or sildenafil 100 mg was administered orally on 2 separate days. Blood period velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler ultrasonography and regional cerebral blood catamenia in the territory of the eye cerebral artery (rCBFmca) was measured using SPECT (unmarried photon emission computed tomography) and xenon 133 inhalation. Radial and temporal artery diameters were studied using loftier‐frequency ultrasonography. Headache response, tenderness of pericranial muscles, blood pressure and eye rate were measured repeatedly. We found that migraine attack was induced by sildenafil in x of 12 migraine patients and by placebo in ii of 12 patients (P = 0.01). Fivemca (P = 0.1) and rCBFmca (P = 0.93) remained unchanged afterwards sildenafil. Temporal (P = 0.47) and radial (P = 0.87) artery diameter and pericranial tenderness (P = 0.16) were unaffected past sildenafil. Systolic and diastolic blood pressures were unchanged simply heart charge per unit increased from a hateful 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 heart cerebral artery. We propose that triggering mechanisms may reside within the perivascular sensory nervus terminals or the brainstem. Withal, other sites of action may also exist possible and futurity studies are needed to elucidate this. In the clinical use of sildenafil, patients who have migraine should be informed about the take a chance of migraine attacks.
Introduction
The search for new causative mechanisms involved in migraine depends on studies performed in patients since no validated animal model exists. However, the study of spontaneous attacks is difficult and can nearly often just be performed hours after onset. This complicates the estimation of the causative role of abnormal findings. The written report of experimental migraine consecration, on the other hand, may reveal important mechanisms involved in the initiation of the attack.
Glyceryl trinitrate (GTN), a prodrug for nitric oxide (NO), induces migraine attacks indistinguishable from spontaneous attacks in ∼80% of migraine sufferers ( Thomsen et al., 1994). Treatment of spontaneous migraine attacks with an inhibitor of nitric oxide synthases, the enzymes that catalyse the production of NO, is effective in lx% of patients ( Lassen et al., 1997). In beast experiments, infusion of GTN is associated with inflammatory changes in the meninges and it potentiates expression of the firsthand early gene c‐fos in the nucleus caudalis of the trigeminal nervus in the brainstem ( Jones et al., 2001; Reuter et al., 2001). Thus, NO may not just initiate the migraine assail merely may besides exist involved in propagating pain throughout the set on.
Likewise, there is evidence of crosstalk between NO and the neurotransmitter calcitonin cistron‐related peptide (CGRP), which has been plant to be released during migraine attacks ( Goadsby et al., 1990) at the level of cyclic nucleotides, and the vasodilating effects of NO and CGRP are suggested to interact at this level (Gray and Marshall, 1992; Wei et al., 1992; Pelligrino and Wang, 1998). However, these links are still being discussed and investigated, and their part in migraine induction is not fully antiseptic.
The principal upshot of NO is to actuate intracellular soluble guanylate cyclase and thus catalyse the formation of cyclic guanosine monophosphate (cGMP). However, NO has a diversity of other actions, such as binding to ion channels, activating phosphokinases, and possibly activating nociceptive nerve fibres directly via the formation of gratuitous radicals such as hydroxyl ions (Garthwaite and Boulton, 1995). It remains to be shown which of these mechanisms are almost important in migraine.
In order to reply this question nosotros conducted a double‐bullheaded crossover trial comparing the issue of placebo with that of sildenafil (Viagra®), a highly selective inhibitor of phosphodiesterase v (PDE5), which is the major enzyme responsible for the breakdown of cGMP. Inhibition of this enzyme results in accumulation of cGMP, and the event of sildenafil therefore mimics 1 of the effects of NO (activation of soluble guanylate cyclase and increased cGMP germination) but not its other furnishings. Our written report gave a clear reply to this question and also, unexpectedly, altered our view of the significance of the initial dilatation of the middle cerebral artery in migraine.
Methods
Patients and study design
This was a double‐blind, randomized, placebo‐controlled crossover study in which migraine patients received on two occasions at least 1 week autonomously a dose of either sildenafil (Viagra, Pfizer A/S, Ballerup, Denmark) 100 mg or placebo in a non‐transparent gelatine sheathing. A nurse non otherwise involved in the written report organized the randomization, in which half of the patients were to receive sildenafil and the other one-half placebo on the commencement twenty-four hour period. The written report was approved past the ethics committee of Copenhagen Canton and the Danish health authorities and was conducted according to the Helsinki II announcement. All patients were recruited from The Danish Headache Heart and gave informed consent before inclusion. We aimed to include 12 patients suffering from migraine without aura. They had an attack frequency ranging between one and three every vi weeks and no more than 6 days of tension‐type headache a month. They were otherwise good for you, had a body weight between sixty and xc kg and had no daily intake of medication except contraceptives. A total of 17 patients were eligible but five patients dropped out after the first study 24-hour interval (ii men and three women) and were replaced, leaving 12 patients completing the study (12 women). They had a hateful age of 37.3 ± SEM, 3.2 years and a mean body weight of 69 ± ii.eight kg. Iii of the dropouts did not wish to continue, because of induction of a severe migraine assault on the first study day, ii after sildenafil and one afterward placebo. One suffered from fear of needles and could not complete the starting time written report mean solar day (placebo) because of hyperventilation, and one had an assail of mild syncope after placebo at the terminate of the showtime examination day and did non wish to return.
On the days of exam we measured baseline values afterwards 30 min of rest and the subject was kept for ascertainment and measurements in the supine position in quiet environment for a menstruation of 180 min. SPECT (single photon emission computed tomography) acquisitions were performed at baseline and at 60 and 120 min. The post-obit measurements were taken at baseline and every 15 min for 180 min: transcranial Doppler ultrasonography (TCD), radial and temporal artery bore; blood pressure; eye rate; and headache score. In one patient it was not possible to measure cerebral blood menstruum (CBF) and temporal avenue diameter on both study days because of technical bug.
Headache recordings
Headache intensity was scored on a exact scale from 0 to 10, where 1 represents a very mild headache (including a feeling of pressing or throbbing), 5 a headache of moderate intensity and 10 the worst possible headache ( Iversen et al., 1989). Headache characteristics, location, side‐effects and intake of medication were recorded and all subjects continued these recordings every hour at dwelling house until thirteen h after drug assistants.
Transcranial Doppler ultrasonography
A time‐averaged hateful of the maximal blood velocity in the middle cerebral artery (Vmca) was recorded bilaterally by TCD (2 MHz, Multidop Ten Doppler; DWL, Sipplingen, Germany) with simultaneous end‐tidal COii (P etCOtwo ) measurements. The boilerplate of four measurements, comprising approximately iv cardiac cycles each over an interval of 30 due south, was used. A fixed indicate for measurement of Vmca was chosen along the eye cerebral avenue, and was used throughout the study in each individual ( Kruuse et al., 2000). The middle cognitive artery was chosen for measurement because of amend reproducibility than measurements in the posterior or anterior cerebral arteries, as shown in previous methodological studies (Thomsen and Iversen, 1993) and because the timeframe for the measurements only allowed measurements in i set of arteries during the study. There are no bachelor techniques for measurement of the diameter of the pial arteries. Only patients suffering from migraine without aureola were studied, and thus the posterior cerebral artery was not of major involvement in the nowadays study, in view of poorer reproducibility of measurement.
SPECT
Measurements of CBF were performed by ways of xenon 133 inhalation and single photon emission computed tomography (SPECT), using a brain‐defended photographic camera (Ceraspect; DSI, Waltham, MA, Us) with a stationary annular NaI crystal and a fast‐rotating collimator organization, and a dynamic protocol of 133Xe inhalation using the Kanno–Lassen algorithm (Kanno and Lassen, 1979; Kruuse et al., 2000). Nosotros used a Datex Normocap 200 (Dameca, Rødovre, Kingdom of denmark) for P east CO2 measurements and a Ceretronic (Xenon Administration Arrangement XAS SM 32C; Randers, Denmark) for 133Xe assistants. Hateful regional CBF (rCBF) in the perfusion area of the eye cerebral artery (rCBFmca) for each side was calculated. Since in that location were no changes when the 2 sides were analysed separately, the mean of left and right rCBFmca was used. Global CBF (gCBF) was also calculated.
Diameters of temporal and radial arteries
We measured the diameter of the frontal co-operative of the superficial temporal artery and the diameter of the radial avenue proximal to the distal volar wrist crease using a loftier‐resolution ultrasound unit (Dermascan C; Cortex Technology, Hadsund, Denmark) (20 MHz, bandwidth 15 MHz) ( Nielsen et al., 1993). Marks were drawn on the skin to ensure that the repeated measurements were performed in the same identify and to ensure reproducibility in measurements from 24-hour interval to day.
Tenderness score
The tenderness of pericranial muscles was recorded past bilateral palpation of 8 pairs of musculus and tendon insertions (masseter, temporal, frontal, sternocleidomastoid and trapezius muscles, coronoid and mastoid processes, and cervix muscle insertions) according to the Total Tenderness Scoring organization on a iv‐signal calibration (0–3) (Langemark and Olesen, 1987).
Statistics
All values are presented as mean ± standard mistake of the mean (SEM), and P < 0.05 was considered significant.
Sample size was called on the basis of results from like previous studies performed by our grouping showing induction of migraine in eight of 10 patients afterwards administration of NO donors and in one of 10 later on placebo and changes in cerebral haemodynamic parameters of at to the lowest degree 5–10% ( Thomsen et al., 1994). Primary outcome measures were the induction of migraine similar to a usual migraine attack, analysed using the McNemar test.
The total tenderness and headache scores were plotted confronting fourth dimension, and the surface area nether the curve and the peak responses were compared using the Wilcoxon rank sum test.
The calculated surface area under the curve was chosen as the summary measure when analysing difference in response (Fivemca, CBF, rCBFmca, artery diameters, blood force per unit area, eye rate, P e COtwo ) between treatments, and values were compared using the paired t test. Changes over time for each variable on each treatment day were analysed by ii‐fashion assay of variance with the factors time and subject, and the analysis was repeated for each unmarried variable (Statgraphics 3.3, Manogistics Inc, Rockville, Dr., U.s.).
On the placebo day ane patient experienced migraine during examination and had to accept rescue medication at 90 min. Data post-obit this time‐point on the placebo day were excluded from further analysis.
Results
A dose of 100 mg sildenafil induced symptoms similar to the patient's usual migraine attacks in 10 out of 12 patients suffering from migraine without aura. Nine of these patients fulfilled the criteria for migraine without aura of the International Headache Club, and ane patient took migraine medication before complete fulfilment of these criteria (Table ane). Later on placebo, migraine without aura was induced in ii of 12 patients. Thus, sildenafil induced significantly more than migraine attacks than placebo (P = 0.01). All patients indicated that the symptoms were similar to those of their usual migraine set on. 1 patient reported mild transient headache on both days and one reported no headache on either 24-hour interval. The median time to meridian headache score was 4.v h after administration of sildenafil. Headache intensity progressed slowly over time. Median top headache score during the first iii h was 0 (range 0–8) subsequently placebo and ane (range 0–nine) after sildenafil (P = 0.61). For the total observation period of xiii h after sildenafil administration, the median summit headache score was 0 (range 0–9) for placebo and half dozen.5 for sildenafil (range 0–10) (P = 0.02) (Fig. 1B). The area under the headache curve differed significantly between placebo and sildenafil treatments (P < 0.005).
9 patients took medication to treat their migraine assail and 1 tried to sleep through the attack. All patients except one responded well to their usual migraine treatment, which was mostly a triptan (Tabular array 1). Later sildenafil, i patient reported very short‐lasting palpitation, four patients complained of nasal congestion, nine felt warm in the confront or torso and all patients showed objective flushing. Afterwards placebo, eight patients had objective flushing and six reported a feeling of warmth; none had nasal congestion or palpitations.
gCBF (P = 1.0) and rCBFmca (P = 0.93) did not differ between sildenafil and placebo. Baseline rCBFmca was 49.1 ± two.ane ml/100 g brain tissue/min on the day of placebo and 49.4 ± ane.7 ml/100 m brain tissue/min on the mean solar day of sildenafil. P east CO2 (P = 0.18) and Vmca (P = 0.i) did not differ between placebo and sildenafil and was unchanged compared with baseline (P = 0.4 on both days for P e CO2 ; P = 0.57 and P = 0.82 for Vmca) (Fig. ii). In five patients migraine criteria were fulfilled within the 3 h period in the laboratory. Four of these patients reported an initial unilateral headache, i of which changed into a bilateral headache within 45 min. 5mca and rCBFmca showed no systematic change on the headache side compared with the non‐headache side before or during migraine.
No significant modify in radial (P = 0.87) or temporal (P = 0.47) artery diameter was seen after sildenafil when compared with placebo.
Systolic and diastolic blood pressures were unchanged but heart rate increased from a hateful of 62 ± 2 to 74 ± iii beats/min within the start hour after sildenafil (P = 0.01).
There was no difference in tenderness score on either side or in total tenderness score between placebo and sildenafil (P = 0.16). Median total tenderness score was 0 (range 0–17) at baseline on the twenty-four hour period of placebo and 2 (range 0–24) at baseline on the sildenafil day. Only two of the v patients experiencing a migraine attack during the 3 h observation period showed an increase in total tenderness score; this was non seen on the day of placebo (P = 0.v).
Word
For more than a decade we have explored methods of experimentally inducing migraine in club to understand the bones biology of the disease and develop new targets for drug evolution for this disabling condition (Iversen, 1995; Humphrey et al., 2001). The NO donor GTN induces headache in normal volunteers and migraine in migraine suffers ( Olesen et al., 1995). In migraine patients a temporary mild headache occurs during the infusion, concomitant with dilatation of the centre cerebral and temporal arteries, and this headache usually returns to baseline shortly later on the infusion. However, at a median of five h after GTN, patients get increasing headache and accompanying symptoms that are similar to those of their usual spontaneous migraine attacks. These migraine attacks are relieved by sumatriptan to the same extent as spontaneous migraine attacks. The marked cerebral artery dilatation disappears shortly after the infusion and long earlier the migraine assail develops.
A similar firsthand dilatation of the middle cerebral artery has been seen after treatment with other migraine‐inducing substances, such as histamine, CGRP and dipyridamole, and has therefore been considered to play a causative role in the induction of migraine attacks ( Olesen et al., 1995). However, the present study clearly shows that migraine can be induced without a similar initial dilatation of the heart cerebral avenue. The median time to peak headache is most equal to that seen after GTN, suggesting that similar pathways are activated despite the lack of significant artery dilatation. The present written report thus indicates that the cGMP‐elevating action of NO seems to play a pregnant office in migraine induction. First, sildenafil has no other actions than inhibiting the breakdown of cGMP; secondly, it was at to the lowest degree as effective as GTN in causing migraine. Information technology was more effective than CGRP and probably also more effective than histamine (Lassen et al., 1996, 2002). It must be noted, however, that the present findings do non exclude the possibility that NO is involved in migraine induction by other mechanisms as well, but further studies investigating other mechanisms of action separately are needed to elucidate this.
Sildenafil is a very selective inhibitor of the cGMP‐degrading enzyme PDE5 (Wallis, 1999). PDE5 is located at several different sites throughout the trunk, including the vascular smooth muscle of the penis. This latter location underlies the utilize of sildenafil as a remedy for male impotence. There are non yet whatsoever published studies showing the effects of sildenafil on cognitive artery dilatation in full general or on the specific function of PDE5 in the regulation of homo cerebral artery tone. This is partly the result of difficulty in obtaining plenty human tissue for enzyme assay and the limited availability of selective PDE5 inhibitors. Withal, the awakening interest in the role of cGMP‐related phosphodiesterases in the brain and cognitive apportionment volition nearly likely shed light on this aspect in near future.
In preliminary studies we found the presence of both PDE5A mRNA and PDE5A protein in human being middle cognitive, basilar and meningeal arteries obtained from post‐mortem examinations (unpublished). This is consistent with the finding that PDE5A protein is present and agile in the guinea‐hog basilar artery ( Kruuse et al., 2001). PDE5 has also recently been reported to be present in encephalon tissue, more often than not cerebellum and hippocampus, and in the superior cervical ganglion ( Giorgi et al., 1994; Loughney et al., 1998; Giordano et al., 2001), and sildenafil has been suspected to have primal effects in humans ( Schultheiss et al., 2001).
The plasma concentration after ingestion of sildenafil 100 mg is i µg/ml and is maximal afterward ∼1 h ( Jackson et al., 1999). The intracellular increase in cGMP and the enhancement of relaxation by NO occurs well beneath this plasma concentration of sildenafil ( Jeremy et al., 1997; Ballard et al., 1998). With the study pattern and the number of patients included, nosotros have previously been able to observe a 6% change in the diameter of the centre cognitive arteries ( Kruuse et al., 2000). To our surprise, sildenafil was not able to amplify the middle cerebral arteries significantly in the presently used dose when including a similar number of subjects. Thus, the increase in the smooth muscle cells of cGMP may not be plenty for a dilatory response. This could be due to a low basic level of cGMP production in the cerebral arteries or to rapid emptying by cGMP‐degrading phosphodiesterases other than PDE5. Alternatively, the PDE5 in the cerebral arteries may be an isoform that is not sufficiently inhibited past sildenafil, or sildenafil may not exist well distributed in the polish muscle cells of the cerebral arteries.
The possible threshold for pain induction by arterial dilatation is non known, which makes it impossible to exclude the possibility that even a small-scale dilatation (non measurable by the methods used here) is of importance. However, the normal day‐to‐day variation in blood velocity has been establish to be 16% and variation from heartbeat to heartbeat to be 10% for the center cerebral artery (Thomsen and Iversen, 1993), and this is not associated with headache. Previous studies have shown that an initial change in claret velocity in a higher place this threshold is associated with concomitant headache and subsequently development of migraine ( Thomsen et al., 1994; Lassen et al., 1995, 2002). Because sildenafil did not change the bore of the middle cerebral arteries significantly with methods similar to those used in previous studies of migraine consecration, we propose that the site of activeness of sildenafil in the induction of migraine is either the perivascular sensory nerve terminals or the CNS, including the brainstem. This seems consistent with previous studies showing that sildenafil acts not but on vascular smooth muscle cells merely also on sensory nerve fibres in the stimulation of penile erection ( Ballard et al., 1998; Medina et al., 2000), and that it modulates central NO–cGMP pathways in the rat brain ( Sato et al., 2001). The increment in cGMP activates circadian nucleotide‐dependent poly peptide kinases and cyclic nucleotide‐gated ion channels in vascular and perhaps neuronal tissue (Garthwaite and Boulton, 1995). This might crusade hyperexcitability of perivascular nerve terminals and sensory nervus fibres, or information technology might facilitate impulse transmission in the CNS. However, further studies are needed for a full understanding of the mechanisms and possible interactions with the effects of other signalling molecules, such as CGRP.
The possibility that the migraine‐generating effect of sildenafil is caused by an effect on the cerebral veins cannot be ruled out. Even so, sildenafil has been constitute to have just a minor upshot on veins ( Jackson et al., 1999; Wallis et al., 1999). Furthermore, awarding of Queckensted's manoeuvre to increase the pressure on the venous sinuses did not increase the pain in migraine patients during a migraine assail, which argues against a role of dilating venous sinuses in migraine pain ( Daugaard et al., 1998).
If sildenafil induces migraine by increasing the responsiveness of central hurting neurons, it should exist possible to demonstrate increased responses to sensory stimuli. How ever, we constitute no pregnant increase in the tenderness of the pericranial muscles in the initial phase of headache generation, which argues against primary CNS sensitization. Nosotros therefore favour the hypothesis that sensitization and hyperexcitability of perivascular sensory nerve terminals or beginning‐order sensory neurons are involved in migraine generation. Nonetheless, new studies applying techniques for the quantitative measurement of the effects of migraine‐generating compounds on the sensory nerve organization should exist performed in order to elucidate this aspect of migraine generation.
The nowadays results are not only important for our understanding of migraine mechanisms but also have implications for the clinical utilize of sildenafil in male impotence. Since 80% of migraine sufferers are likely to get an set on of migraine after the use of sildenafil at a therapeutic dose, patients should exist warned in the package insert that, if they have migraine, there is a high likelihood of having an attack later the use of sildenafil.
In conclusion, the nowadays study suggests a novel biochemical mechanism for induction of migraine which seems independent of an initial dilatation of the middle cerebral arteries. In the clinical use of sildenafil, better information most the risk of migraine should be given.
Acknowledgements
We thank the patients for participating, L. Elkaer, Yard. Brunsgaard and O. Jonassen for technical assistance and H. Dige‐Petersen for the apply of equipment. Pfizer A/Southward, Denmark supplied the sildenafil tablets. The study was supported by grants from the University of Copenhagen and the P. Carl Petersens Foundation.
Fig. 1 Headache score over time later on placebo (A) and after 100 mg sildenafil (B). Individual headache scores are shown as thin lines. A thick line with filled circles indicates median headache scores (n = 12). The maximum headache score possible is 10, which equals worst possible headache. Patients were immune to treat their migraine attack with their usual migraine medication. This accounts for the steep decreases in pain intensity seen along the private curves. The median time to top headache score was iv.5 h later on sildenafil.
Fig. one Headache score over time subsequently placebo (A) and later on 100 mg sildenafil (B). Individual headache scores are shown every bit thin lines. A thick line with filled circles indicates median headache scores (northward = 12). The maximum headache score possible is ten, which equals worst possible headache. Patients were allowed to care for their migraine attack with their usual migraine medication. This accounts for the steep decreases in pain intensity seen forth the individual curves. The median time to peak headache score was 4.5 h after sildenafil.
Fig. 2 Mean blood flow velocity in the heart cerebral artery (5mca). Mean absolute values for Vmca are shown with the standard fault of the mean (n = 12). Filled circles represent sildenafil and open circles placebo. In that location was no significant difference between Vmca later placebo and after sildenafil and no significant difference betwixt rCBF after placebo compared with sildenafil. The equation rCBF = velocity × lumen expanse indicates that 5mca may be taken as an indirect measure of change in diameter of the center cerebral avenue (Sorteberg, 1992). Thus, in the present study 100 mg sildenafil had no pregnant effect on cognitive artery bore compared with placebo.
Fig. 2 Mean blood flow velocity in the eye cognitive avenue (5mca). Mean absolute values for Vmca are shown with the standard error of the hateful (due north = 12). Filled circles correspond sildenafil and open circles placebo. There was no pregnant difference between Vmca later on placebo and after sildenafil and no significant difference between rCBF subsequently placebo compared with sildenafil. The equation rCBF = velocity × lumen expanse indicates that Fivemca may be taken as an indirect measure out of change in diameter of the heart cerebral avenue (Sorteberg, 1992). Thus, in the present study 100 mg sildenafil had no significant effect on cerebral artery bore compared with placebo.
Table 1
Headache characteristics later on sildenafil administration
| Bailiwick | Headache (location/peak intensity*/quality) | Time to peak (h) | Aggravated | Accompanying symptoms† (nausea/photophobia/phonophobia) | Similar to usual migraine | Handling/fourth dimension to treatment after sildenafil |
| i | Right/4/pressing | 6 | No | No/no/no/ | Aye‡ | Sumatriptan/6 h |
| two | Bilateral/nine/throbbing | 3 | Aye | Minor/astringent/minor | Yeah | Zolmitriptan/3 h |
| 3 | Right/10/throbbing | nine | Yes | Severe/severe/no | Aye | Zolmitriptan/eight h |
| 4 | Left/viii/throbbing | 6 | Yes | Moderate/no/no | Yep | Rizatriptan/6 h |
| 5 | Right/8/pressing | 5 | Yes | Severe/pocket-size/small-scale | Yes | Rizatriptan/five h |
| half-dozen | Left/nine/throbbing | viii | Aye | Severe/moderate/no | Yeah | Sumatriptan/4 and 8 h |
| seven | Bilateral/7/throbbing | 3 | Yes | Severe/minor/minor | Yes | Rizatriptan + plainly analgesics and metoclopramide/3 h |
| 8 | No headache | 0 | – | – | None | |
| 9 | Correct/iv/throbbing | two | Yep | Small-scale/minor/no | Aye | Plain analgesics/6 h |
| ten | Left/3/pressing | 4 | Yes | Minor/small/pocket-sized | Yes§ | Plain analgesics/12 h |
| 11 | Bilateral/six/pressing | half-dozen | Yes | Severe/severe/severe | Yes | Slept |
| 12 | Right/1/pressing | 2 | No | No/no/no | No | None |
| Subject | Headache (location/peak intensity*/quality) | Time to elevation (h) | Aggravated | Accompanying symptoms† (nausea/photophobia/phonophobia) | Similar to usual migraine | Treatment/time to handling after sildenafil |
| 1 | Right/4/pressing | six | No | No/no/no/ | Aye‡ | Sumatriptan/6 h |
| 2 | Bilateral/9/throbbing | iii | Yes | Minor/severe/pocket-size | Yes | Zolmitriptan/iii h |
| three | Right/10/throbbing | 9 | Yes | Severe/severe/no | Yes | Zolmitriptan/8 h |
| 4 | Left/8/throbbing | vi | Yes | Moderate/no/no | Yes | Rizatriptan/6 h |
| 5 | Right/8/pressing | 5 | Aye | Severe/minor/minor | Yeah | Rizatriptan/5 h |
| 6 | Left/nine/throbbing | eight | Yes | Astringent/moderate/no | Yeah | Sumatriptan/iv and eight h |
| seven | Bilateral/7/throbbing | 3 | Yes | Severe/small-scale/minor | Yes | Rizatriptan + evidently analgesics and metoclopramide/three h |
| eight | No headache | 0 | – | – | None | |
| 9 | Correct/four/throbbing | 2 | Yes | Minor/small-scale/no | Yes | Plain analgesics/6 h |
| 10 | Left/3/pressing | 4 | Yes | Minor/minor/small | Yep§ | Apparently analgesics/12 h |
| 11 | Bilateral/6/pressing | 6 | Yeah | Severe/severe/severe | Yes | Slept |
| 12 | Right/i/pressing | 2 | No | No/no/no | No | None |
*Headache pain was scored on a verbal calibration of 0–10; †accompanying symptoms were graded none, minor, moderate, astringent; ‡patients were allowed to care for the headache with their usual migraine handling (Patient i treated her headache earlier the migraine criterion concerning accompanying symptoms was fulfilled; this patient besides experienced migraine fulfilling all criteria on the twenty-four hours of placebo and had to receive rescue medication subsequently xc min); §similar in characteristics to the known migraine, just unremarkably with more severe headache.
Table one
Headache characteristics after sildenafil assistants
| Subject area | Headache (location/peak intensity*/quality) | Fourth dimension to pinnacle (h) | Aggravated | Accompanying symptoms† (nausea/photophobia/phonophobia) | Similar to usual migraine | Treatment/fourth dimension to treatment subsequently sildenafil |
| ane | Right/4/pressing | six | No | No/no/no/ | Yes‡ | Sumatriptan/6 h |
| 2 | Bilateral/9/throbbing | 3 | Yeah | Minor/severe/minor | Yes | Zolmitriptan/3 h |
| 3 | Right/10/throbbing | 9 | Yes | Severe/severe/no | Yes | Zolmitriptan/viii h |
| 4 | Left/8/throbbing | 6 | Yeah | Moderate/no/no | Yes | Rizatriptan/6 h |
| 5 | Right/8/pressing | 5 | Yes | Severe/minor/minor | Yeah | Rizatriptan/v h |
| six | Left/9/throbbing | 8 | Yes | Severe/moderate/no | Yes | Sumatriptan/4 and viii h |
| vii | Bilateral/vii/throbbing | 3 | Yes | Severe/modest/small-scale | Yes | Rizatriptan + plain analgesics and metoclopramide/3 h |
| 8 | No headache | 0 | – | – | None | |
| ix | Right/4/throbbing | two | Yes | Minor/minor/no | Yes | Plain analgesics/six h |
| ten | Left/3/pressing | 4 | Yeah | Minor/small-scale/pocket-sized | Yep§ | Manifestly analgesics/12 h |
| xi | Bilateral/vi/pressing | six | Aye | Severe/severe/astringent | Yes | Slept |
| 12 | Right/1/pressing | 2 | No | No/no/no | No | None |
| Discipline | Headache (location/peak intensity*/quality) | Time to peak (h) | Aggravated | Accompanying symptoms† (nausea/photophobia/phonophobia) | Like to usual migraine | Handling/time to handling after sildenafil |
| 1 | Correct/4/pressing | 6 | No | No/no/no/ | Yes‡ | Sumatriptan/6 h |
| 2 | Bilateral/ix/throbbing | 3 | Yes | Minor/severe/minor | Yes | Zolmitriptan/3 h |
| 3 | Right/10/throbbing | 9 | Yes | Severe/severe/no | Yes | Zolmitriptan/8 h |
| 4 | Left/8/throbbing | 6 | Yes | Moderate/no/no | Yep | Rizatriptan/6 h |
| five | Right/8/pressing | 5 | Yes | Severe/minor/small | Yeah | Rizatriptan/5 h |
| 6 | Left/9/throbbing | 8 | Yep | Severe/moderate/no | Aye | Sumatriptan/4 and 8 h |
| seven | Bilateral/vii/throbbing | 3 | Aye | Severe/minor/pocket-size | Yes | Rizatriptan + plain analgesics and metoclopramide/three h |
| 8 | No headache | 0 | – | – | None | |
| 9 | Right/4/throbbing | 2 | Yeah | Minor/minor/no | Yes | Patently analgesics/6 h |
| 10 | Left/3/pressing | 4 | Yes | Minor/pocket-sized/minor | Yeah§ | Plain analgesics/12 h |
| eleven | Bilateral/half-dozen/pressing | 6 | Yeah | Severe/severe/astringent | Yes | Slept |
| 12 | Right/1/pressing | 2 | No | No/no/no | No | None |
*Headache hurting was scored on a verbal scale of 0–10; †accompanying symptoms were graded none, minor, moderate, severe; ‡patients were immune to treat the headache with their usual migraine treatment (Patient ane treated her headache before the migraine criterion concerning accompanying symptoms was fulfilled; this patient also experienced migraine fulfilling all criteria on the 24-hour interval of placebo and had to receive rescue medication after ninety min); §like in characteristics to the known migraine, but ordinarily with more severe headache.
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