Effect of Adrenomedullin on Migraine-Like Attacks in Patients With Migraine: A Randomized Crossover Study.

OBJECTIVE: To determine whether the IV infusion of adrenomedullin, a potent vasodilator belonging to calcitonin family of peptides, provokes attacks of migraine in patients. METHODS: Twenty patients with migraine without aura participated in a placebo-controlled and double-blind clinical study. In a randomized crossover design, the patients received an IV infusion of human adrenomedullin (19.9 pmol/kg/min) or placebo (saline) administrated via an automated IV pump (20 minutes). The patients participated in 2 study days with a washout period of minimum of 7 days. The primary outcome of the study was predefined as a difference in migraine incidence (0-12 hours), and the secondary outcomes were the area under curve (AUC0-12 hours) for the headache intensity score and AUC0-90 minutes for mean arterial blood pressure (MAP), flushing, and heart rate (HR). RESULTS: Eleven patients with migraine without aura (55%) fulfilled migraine attacks criteria after adrenomedullin infusion compared to only 3 patients who reported attack (15%) after placebo (p = 0.039). We found that patients reported in a period of 0 to 12 hours stronger headache intensity after adrenomedullin compared to placebo infusion (p = 0.035). AUC0-90 minutes value for HR and flushing (p < 0.05) was significant and for MAP (p = 0.502) remained unchanged. Common reported adverse events were facial flushing, heat sensation, and palpitation (p < 0.001). CONCLUSION: Our data implicate adrenomedullin in migraine pathogenesis. This suggests that adrenomedullin or its receptors are novel therapeutic targets for the treatment of migraine. However, we cannot discount the possibility that adrenomedullin may be acting through the canonical calcitonin gene-related peptide receptor. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT04111484.

PACAP27 induces migraine-like attacks in migraine patients.

INTRODUCTION: Pituitary adenylate cyclase-activating polypeptide (PACAP) is found in two functional isoforms, namely PACAP38 and PACAP27. The migraine-inducing properties of PACAP38 are well studied. However, it is not known whether the lesser-known and under-studied protein isoform, PACAP27, can also induce migraine attacks. Here, we studied the effect of human PACAP27 infusion on induction of migraine in a provocation model. METHODS: In a crossover study, 20 migraine without aura patients were randomly assigned to receive human PACAP27 (10 picomol/kg/min) or saline (placebo) infusion over 20 min. We recorded the migraine and associated symptoms. RESULTS: All patients completed the study. PACAP27 provoked migraine-like attacks in 11 patients (55%) and two developed attacks after placebo (10%) (p = 0.022). The headache intensity and duration after PACAP27 was significantly greater compared to placebo (p = 0.003). CONCLUSION: PACAP27 triggers migraine attacks without aura. These novel data strengthen the role of PACAP and its receptors in migraine pathogenesis.

Carbon monoxide inhalation induces headache but no migraine in patients with migraine without aura.

INTRODUCTION: Carbon monoxide is an endogenously produced signaling gasotransmitter known to cause headache and vasodilation. We hypothesized that inhalation of carbon monoxide would induce migraine-like attacks in migraine without aura patients. METHODS: In a randomized, double-blind, placebo-controlled crossover design, 12 migraine patients were allocated to inhalation of carbon monoxide (carboxyhemoglobin 22%) or placebo on two separate days. Headache and migraine characteristics were recorded during hospital (0-2 hours) and post-hospital (2-13 hours) phases. RESULTS: Six patients (50%) developed migraine-like attacks after carbon monoxide compared to two after placebo (16.7%) ( p = 0.289). The median time to onset of migraine-like attacks after carbon monoxide inhalation was 7.5 h (range 3-12) compared to 11.5 h (range 11-12) after placebo. Nine out of 12 patients (75%) developed prolonged headache after carbon monoxide. The area under the curve for headache score (0-13 hours) was increased after carbon monoxide compared with placebo ( p = 0.033). CONCLUSION: Carbon monoxide inhalation did not provoke more migraine-like attacks in migraine patients compared to placebo, but induced more headache in patients compared to placebo. These data suggest that non-toxic concentrations of carbon monoxide had low potency in migraine induction and that the carbon monoxide inhalation model is not suitable to study migraine.

PACAP38 dose-response pilot study in migraine patients.

Background Intravenous infusion of 10 pmol/kg/min pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces migraine-like attacks in migraine patients without aura (MO). Here, we conducted a pilot study and investigated if lower doses of PACAP38 exert similar migraine-inducing abilities. Methods We randomly allocated six MO patients to receive intravenous infusion of 4, 6, and 8 pmol/kg/min of PACAP38 over 20 minutes in a double-blind, three-way cross-over study. Headache and migraine characteristics were recorded during hospital (0-2 hours) and post-hospital (2-13 hours) phases. Results PACAP38 induced migraine-like attacks in one out of six patients with 4 pmol, two out of six patients with 6 pmol and three out of six patients with 8 pmol ( p = 0.368). All patients reported head pain after 8 pmol/kg/min, whereas five of six participants reported head pain after both 4 and 6 pmol/kg/min. We found no difference between the three doses in the AUC for headache intensity over the 12-hour observation period ( p = 0.142). An exploratory analysis showed a significant difference between 4 pmol and 8 pmol ( p = 0.031). Conclusion A trend of a dose-response relationship between dose of PACAP38 and incidence of migraine was observed. We suggest that 10 pmol/kg/min PACAP38 is the most optimal dose to induce migraine-like attacks.

Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase.

The initiating mechanisms of migraine attacks are very complex but may involve the cyclic AMP signalling pathway. It is unknown whether intracellular cyclic AMP accumulation induces migraine attacks. We investigated whether administration of cilostazol, which causes cyclic AMP accumulation, may induce migraine attacks. We included 14 migraine patients without aura in a double-blind, placebo-controlled crossover study. All participants received oral cilostazol or placebo on two separate days. We recorded migraine headache characteristics, associated symptoms and time of rescue medication intake using a questionnaire. Cilostazol induced delayed migraine-like attacks in 12 patients (86%) compared with two (14%) patients after placebo (P = 0.002). The median time to onset for migraine-like attacks was 6 h (range 3-11 h). Patients reported that the attacks mimicked their usual migraine attacks and that cilostazol-induced attacks responded to their usual migraine treatment. Median time of medication intake was 6 h (range 4-11 h). The present study suggests that intracellular cyclic AMP accumulation plays a crucial role in migraine induction. This knowledge is a further step in our understanding of the intracellular pathway of migraine initiation.

Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks.

Our aim was identify brain areas involved in the premonitory phase of migraine using functional neuroimaging. To this end, we performed positron emission tomography scans with H2(15)O to measure cerebral blood flow as a marker of neuronal activity. We conducted positron emission tomography scans at baseline, in the premonitory phase without pain and during migraine headache in eight patients. We used glyceryl trinitrate (nitroglycerin) to trigger premonitory symptoms and migraine headache in patients with episodic migraine without aura who habitually experienced premonitory symptoms during spontaneous attacks. The main outcome was comparing the first premonitory scans in all patients to baseline scans in all patients. We found activations in the posterolateral hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons and various cortical areas including occipital, temporal and prefrontal cortex. Brain activations, in particular of the hypothalamus, seen in the premonitory phase of glyceryl trinitrate-triggered migraine attacks can explain many of the premonitory symptoms and may provide some insight into why migraine is commonly activated by a change in homeostasis.

Prostaglandins and prostaglandin receptor antagonism in migraine.

Human models of headache may contribute to understanding of prostaglandins' role in migraine pathogenesis. The current thesis investigated the migraine triggering effect of prostaglandin E2 (PGE2) in migraine patients without aura, the efficacy of a novel EP4 receptor antagonist, BGC20-1531, in prevention of PGE2-induced headache and the ability of prostaglandin F2α (PGF2α) to trigger headache without any vasodilatation in healthy volunteers. All studies were designed as double-blind, placebo-controlled, cross-over experiments, where PGE2/PGF2α or saline were infused over 20-25 min. In the study with EP4 receptor antagonist healthy volunteers were pre-treated with two different doses of BGC20-1531 or placebo followed by PGE2 infusion over 25 min. The headache data were collected during the whole study day, whereas the possible vascular changes were measured during the in-hospital phase of 1.5 h. The infusion of PGE2 caused the immediate migraine-like attacks and vasodilatation of the middle cerebral artery in migraine patients without aura. The highly specific and potent EP4 receptor antagonist, BGC20-1531, was not able to attenuate PGE2-induced headache and vasodilatation of both intra- and extra-cerebral arteries. The intravenous infusion of PGF2α did not induce headache or statistically significant vasoconstriction of cerebral arteries in healthy volunteers. Novel data on PGE2-provoked immediate migraine-like attacks suggest that PGE2 may be one of the important final products in the pathogenesis of migraine. The lack of efficacy of EP4 receptor antagonist suggests that a single receptor blockade is not sufficient to block PGE2 responses, hence EP2 receptor should be investigated as a potential drug target for the treatment of migraine. The absence of headache during the PGF2α infusion demonstrates that vasodilating properties are necessary for the induction of headache and migraine.

Sumatriptan (50 mg tablets vs. 25 mg suppositories) in the acute treatment of menstrually related migraine and oral contraceptive-induced menstrual migraine: a pilot study.

Migraine attacks are common in the perimenstrual period (menstrually-related migraine, MRM) and can be particularly exacerbated by the cyclic suspension of oral contraceptives (oral contraceptive-induced menstrual migraine, OCMM). This cross-over, randomised study evaluated the efficacy and tolerability of rectal (25 mg) and oral (50 mg) sumatriptan in the treatment of 232 menstrual migraine attacks (135 MRM and 97 OCMM). Two hours after suppository administration, 72% of patients in the MRM group achieved pain relief and 24% were pain free; after tablet administration, the percentages were 66% and 27%, respectively. In the OCMM group 55% of patients improved at 2 h with suppositories and 46% with tablets, 27% of patients were pain-free after suppositories and 18% after tablets. Fifty percent of patients given suppositories were pain-free at 4 h post-treatment and 47% of those given tablets. Sumatriptan also effectively alleviated symptoms associated with migraine, such as nausea, vomiting and photo/phonophobia. A single dose of medication sufficed for pain relief without relapse in 47.4% of the attacks (MRM: 66%; OCMM: 33%). Both formulations were well tolerated.

Coexisting typical migraine in familial hemiplegic migraine.

OBJECTIVE: In contrast to patients with migraine with aura (MA) and migraine without aura (MO), most patients with familial hemiplegic migraine (FHM) do not report migraine-like attacks after pharmacologic provocation with glyceryl trinitrate (GTN), a donor of nitric oxide. In the present study, we examined patients with FHM without known gene mutations and hypothesized that 1) GTN would cause more migraine-like attacks in patients with FHM compared to controls, and 2) GTN would cause more migraine attacks in patients with FHM with coexisting MA or MO compared to the pure FHM phenotype. METHODS: The study design was a balanced provocation study. Twenty-three patients with FHM and 11 healthy controls received a continuous IV infusion of 0.5 mug/kg/min GTN over 20 minutes. RESULTS: We found no difference in the incidence of migraine-like attacks comparing all patients with FHM (30%) to controls (9%) (p = 0.15). Patients with FHM with coexisting MA or MO reported more migraine attacks after GTN (55%) than patients with the pure FHM phenotype (8.3%) (p = 0.02). Compared to healthy controls, more patients with FHM with coexisting MA or MO reported migraine-like attacks than controls (p = 0.03), whereas the FHM group with the pure FHM phenotype did not (p > 0.05). CONCLUSIONS: Compared to patients with migraine with aura (MA) and migraine without aura (MO), patients with familial hemiplegic migraine (FHM) without known gene mutations display a reduced sensitivity to nitric oxide. A subset of patients with FHM with coexisting nonhemiplegic migraine is more sensitive than controls. These data extend our previous findings that pathophysiologic pathways in FHM may differ from those of MO and MA.

Carbachol induces headache, but not migraine-like attacks, in patients with migraine without aura.

Carbachol induces headache in healthy subjects, but the migraine eliciting effect of carbachol has not previously been studied. We hypothesized that the cholinomimetic agonist carbachol would induce headache and migraine-like attacks in migraineurs. Carbachol (3 µg/kg) or placebo was randomly infused into 18 patients with migraine without aura in a double-blind crossover study. Headache was scored on a verbal rating scale from 0 to 10. Velocity in the middle cerebral artery (V(MCA)) and diameter of the superficial temporal artery (STA) were recorded. Fifteen patients experienced headache after carbachol compared with eight after placebo (P = 0.039). There was no difference in incidence of migraine-like attacks after carbachol (n = 8) compared with placebo (n = 6) (P = 0.687). Carbachol caused a decrease in V(MCA) (P = 0.044), but no change in STA (P = 0.089) compared with placebo. The study demonstrated that carbachol provocation is not a good model for experimental migraine.

Prednisolone reduces nitric oxide-induced migraine.

BACKGROUND AND PURPOSE: Glyceryl trinitrate (GTN) induces delayed migraine attacks in migraine patients. The purpose of this study was to investigate whether pre-treatment with prednisolon could decrease this effect of GTN. METHODS: In this double-blind, randomized and placebo-controlled, crossover study 15 migraineurs with migraine without aura were pre-treated with 150 mg of prednisolone or placebo followed by a 20-min infusion of GTN (0.5 ug/kg/min). One hour after the GTN-infusion, the participants were sent home, but continued to rate headache and possible associated symptoms by filling out a headache diary every hour for 12 h. There were two equal primary efficacy end-points: frequency of delayed migraine and intensity of delayed headache. RESULTS: Nine patients experienced a GTN headache fulfilling the diagnostic criteria for migraine without aura on the placebo day compared with four patients on the prednisolone day (P = 0.14). Prednisolone pre-treatment did not alter the summed or peak immediate headache responses to GTN significantly (P = 0.08, P = 0.07), whereas the peak headache scores during the following 12 h were significantly lower after prednisolone pre-treatment (median peak score = 1, range 0-8) compared with placebo (median = 4, range 0-8) (P < 0.01). There was no difference between the two treatment days in the effect of GTN on blood flow velocity of the middle cerebral artery (a decrease) or on the dilation of the superficial temporal artery or the radial artery. CONCLUSION: Pre-treatment with prednisolone did not reduce the immediate GTN-induced headache, did not inhibit the frequency of delayed headache but significantly decreased the intensity of delayed GTN-induced headache. These findings suggest that GTN causes induction of inflammatory mediators, and that this is the mechanism of delayed GTN-induced migraine. They also support a role of inflammatory mediators in spontaneous migraine attacks.

Delayed migraine-like headache in healthy volunteers after a combination of acetazolamide and glyceryl trinitrate.

Glyceryl trinitrate (GTN) is a pro-drug dissociating nitric oxide throughout the body. It dilates cephalic arteries without increasing cerebral blood flow (CBF). GTN induces headache in healthy volunteers and migraine attacks in migraineurs. Acetazolamide (Az) increases CBF but does not dilate cerebral arteries. The hypothesis tested here was that Az, by dilating cerebral arterioles but not arteries and thereby decreasing pulsatile stretching of the wall of the large arteries and their perivascular sensory nerves, would reduce or prevent the GTN-induced headache We tested this hypothesis in 14 healthy volunteers. In a randomized, double-blind, cross-over study, they were pretreated with Az or placebo followed on both study days by a GTN infusion of 0.5 microg kg(-1) min(-1) for 20 min. Headache was scored on a verbal rating scale and a headache diary was kept for 12 h. Mean blood velocity of the middle cerebral artery was measured (transcranial Doppler). Our hypothesis was disproved, as Az did not decrease GTN-induced headache. Unexpectedly but interestingly, GTN combined with Az induced more delayed headache than GTN alone. Furthermore, a migraine-like headache was observed in three volunteers, who did not develop migraine after GTN alone. The fact that a suitable pharmacological intervention may trigger migraine in individuals with no prior migraine may suggest that the ability to develop migraine without aura is a quantitative genetic trait.

PACAP38 induces migraine-like attacks in patients with migraine without aura.

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

Intravenous valproate aborts glyceryl trinitrate-induced migraine attacks: a clinical and quantitative EEG study.

We evaluated EEG changes and pain relief in migraineurs with glyceryl trinitrate (GTN)-induced attacks treated with intravenous sodium valproate (iSVP). EEG frequency analysis was performed in 45 migraineurs without aura and in 19 controls at baseline, at the time of maximum GTN-induced headache, and 30 min after 300 mg iSVP. Nineteen migraineurs presented early specific headache (migraine identical to spontaneous attacks; MSp) and 26 presented early non-specific headache (MnSp). During attacks in MSp there was an increase of theta [16.6% (14.8-19.3) to 19.4% (17.4-22.1), P = 0.02] and delta activity [3.6% (3.1-4.4) to 5.4% (3.9-6.5), P = 0.009], whereas there was no decrease in alpha [41.4% (36.2-45.1) to 39.7% (34.7-44.8)] or beta activity [37.6% (34.7-40.3) to 35.1% (33.5-38.8)]. iSVP reduced migraine from severe/moderate to mild/no pain in 17 (90%) MSp patients, and was associated with reversion of the slow rhythmic activity to baseline levels [theta 16.9% (14.6-18.9); delta 3.2% (3-4.1)]. There was no change in EEG frequency activity after administration of GTN or iSVP in controls and in MnSp. iSVP is well tolerated and effective in treating GTN-induced migraine in migraineurs without aura, and appears to restore the disturbances of cortical electrogenesis associated with these attacks.

Dipyridamole may induce migraine in patients with migraine without aura.

Dipyridamole inhibits phosphodiesterase 5 (PDE5) and adenosine re-uptake. The most prominent side-effect is headache. We examined the migraine-generating effects of dipyridamole as well as the cerebral blood velocity response in a single-blind study, including 10 patients with migraine without aura and 10 healthy subjects. Dipyridamole 0.142 mg/kg per min was administered intravenously. Headache intensity was scored on a verbal rating scale along with pain characteristics and accompanying symptoms. Blood velocity in the middle cerebral artery (V(mca)), blood pressure and heart rate were recorded repeatedly. Headache was induced in all migraine patients and in eight of 10 healthy subjects (P = 0.47) with no significant difference in headache intensity (P = 0.53). However, five patients but only one healthy subject experienced the symptoms of migraine without aura, according to ICHD-2 criteria, within 12 h (P = 0.14). Four patients reported photophobia after dipyridamole compared with no healthy subjects (P = 0.087). V(mca) decreased (P < 0.001) during and after dipyridamole infusion with no difference between groups (P = 0.15) coinciding with initiation, but not cessation of immediate headache. Thus, dipyridamole induces symptoms of migraine and an initial decrease in V(mca) in migraine patients, but not significantly more than in healthy subjects. This relatively low frequency of migraine induction, compared with nitric oxide donors and sildenafil, is probably due to the less specific action of dipyridamole on the cGMP signalling pathway as well as a possible bidirectional effect of adenosine on migraine induction.

Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack.

Sumatriptan-induced changes in plasma calcitonin gene-related peptide (CGRP) concentration and headache intensity were investigated in 19 female migraineurs during nitroglycerin-induced migraine attack. Sumatriptan nasal spray was administered 120 min after the onset of the attack. Blood samples were obtained immediately before and 60 min after sumatriptan administration. In those subjects whose migraine attack improved considerably 60 min after the treatment the plasma CGRP concentration decreased significantly (P<0.05). In contrast, plasma CGRP concentration failed to change in patients whose headache did not improve. In addition, plasma CGRP concentrations showed significant positive correlations with the headache scores both 60 and 120 min after sumatriptan administration (P<0.05). According to our results plasma CGRP concentration decreases parallel to headache intensity during sumatriptan treatment and this decrease in CGRP predicts effectiveness of antimigraine drug therapy. This supports that one of the main effects of triptans is to decrease CGRP release.

New international classification of migraine with aura (ICHD-2) applied to 362 migraine patients.

The International Classification of Headache Disorders 2nd edition (ICHD-2) subdivides migraine with aura (MA) differently from the ICHD-1 and includes new diagnostic criteria. The aim of the present study was to evaluate how the new classification works in practice and in comparison with the ICHD-1. The patients were recruited from a screen of the Danish National Patient Registry and from Danish neurologists. We included 362 patients diagnosed with MA according to the ICHD-1 in a validated semistructured physician-conducted interview. According to the ICHD-2, 89% (322 of 362) had MA and 11% (40 of 362) had probable MA. The MA patients had one or more ICHD-2 subtype of MA: 54% (173 of 322) had typical aura with migraine headache (MA-MH), 40% (129 of 322) had typical aura with non-migraine headache (MA-NMH), 37% (120 of 322) had aura without headache (MA-WOH), and 7% (26 of 322) had basilar-type migraine (MA-B). Of patients with MA-MH 34% (59 of 173) had co-occurrence of MA-WOH, 9% (16 of 173) had co-occurrence of MA-B and 5% (8 of 173) had co-occurrence of both MA-WOH and MA-B. Of patients with MA-NMH 27% (35 of 129) had co-occurrence of MA-WOH. Only 6% (18 of 322) of the MA patients had exclusively MA-WOH and <1% (2 of 322) had exclusively MA-B. Patients with MA-MH had an earlier age at onset (P = 0.044), an increased lifetime number of MA attacks (P = 0.054) and a higher co-occurrence of migraine without aura (P = 0.002) than patients with MA-NMH. Patients with MA-B tended to have an earlier age at onset and more severe attacks and patients with MA-WOH had a higher age at onset and less severe attacks than patients with MA-MH. The variations between ICHD-2 subtypes of MA indicate that patients with similar subtype of MA share phenotype and very likely have similar underlying aetiology.

Plasma levels of cAMP, cGMP and CGRP in sildenafil-induced headache.

Sildenafil, a selective inhibitor of the cyclic guanosine monophosphate (cGMP) degrading phosphodiestrase 5 (PDE5), induced migraine without aura in 10 of 12 migraine patients and in healthy subjects it induced significantly more headache than placebo. The aim of the present study was to determine whether the pain-inducing effects of sildenafil would be reflected in plasma levels of important signalling molecules in migraine: cGMP, cyclic adenosine monophosphate (cAMP) and calcitonin gene-related peptide (CGRP). Ten healthy subjects (four women, six men) and 12 patients (12 women) suffering from migraine without aura were included in two separate double-blind, placebo-controlled, cross-over studies in which placebo or sildenafil 100 mg was administered orally. Plasma levels of CGRP, cAMP and cGMP were determined in blood from the antecubital vein. Despite the ability of sildenafil to induce headache and migraine, no significant differences in plasma levels of CGRP, cGMP and cAMP were detected after sildenafil compared with placebo. In conclusion, plasma levels of CGRP, cGMP and cAMP remain normal during sildenafil-induced headache or migraine. However, since previous studies indicate an important role of these signalling molecules, the present study questions whether cAMP and cGMP in peripheral blood can be used for monitoring pathophysiological events in headache and migraine mechanisms.

The prophylactic effect of valproate on glyceryltrinitrate induced migraine.

In this study the human glyceryltrinitrate (GTN) model of migraine was for the first time used to test the effect of a prophylactic drug. We chose to test valproate due to its well documented effect as a migraine prophylactic drug. Efficacy of this compound would support the usefulness of the model in prophylactic antimigraine drug development. Twelve patients with migraine without aura were included in a randomized double blind crossover study. Valproate 1000 mg or placebo was given daily, each for a minimum of 13 days. On the last treatment day of each arm a 20 min intravenous infusion of GTN (0.25 microg/kg/min) was given. Headache was registered for 12 h after the infusion and headache intensity was scored on a scale from 0 to 10. Fulfillment of IHS criteria was recorded for 24 h. The middle cerebral arteries were evaluated by transcranial Doppler and the diameter of the superficial temporal and radial arteries were measured with high frequency ultrasound. GTN evoked migraine fulfilling IHS criteria 1.1 in 6 patients after placebo and in 2 patients after valproate (P = 0.125). Including additionally 3 patients on placebo and 1 patient on valproate who felt they had suffered a migraine attack, but who had as associated symptoms only photophobia or phonophobia, a significant reduction in the number of patients with induced migraine after valproate was seen (P = 0.031). Median peak headache intensity was 1 (range 0-9) after valproate compared to 4.5 (range 0-8) after placebo (P = 0.120). Pretreatment with valproate as compared to placebo reduced the velocity in both middle cerebral arteries after GTN (left P = 0.021, right P = 0.031). No effect of valproate was seen in the diameter of the superficial temporal artery (P = 0.781) or the radial artery (P = 0.367) before or after GTN. The study indicates that a prophylactic effect of valproate may be demonstrated using the GTN human migraine model. Although, all headache parameters were reduced after valproate compared to placebo, only one parameter was statistically significantly reduced probably because of the small number of patients. The size of the effect was similar to that of valproate in clinical trials. The GTN model may therefore be a valid tool for testing new prophylactic antimigraine drugs.