Christina Kruuse

A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks.

Supersensitivity to induction of headache and arterial dilatation by a donor of nitric oxide (nitroglycerin) has recently been demonstrated in migraine sufferers. The aims of the present study were to examine whether the nitric oxide donor nitroglycerin may induce a typical migraine attack, to exclude placebo‐related effects and to describe the relation between middle cerebral artery dilatation and provoked migraine. Nitroglycerin (0.5 μg/kg/min for 20 min) or placebo was infused into 12 migraine patients in a double‐blind cross‐over trial. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and characteristics of headache and accompanying symptoms were recorded frequently. Headache occurred during the nitroglycerin infusion as previously described but peak headache intensity did first occur 5.5 h after infusion. At this time the induced headaches in 8 of 10 completing patients fulfilled the diagnostic criteria for migraine without aura of the International Headache Society. Furthermore, all patients who normally had unilateral spontaneous migraine attacks also had unilateral headaches after nitroglycerin. Only one subject developed migraine after placebo (p < 0.03). The time pattern of headache and estimated middle cerebral artery dilatation corresponded well. The study therefore demonstrates that activation of the nitric oxide cGMP pathway may cause typical migraine attacks.

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.

The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers

BIBN4096BS is a CGRP-antagonist effective in the treatment of migraine. Blocking the receptor of a strong vasodilator involves a theoretical risk of causing cerebral vasoconstriction, a probability not previously investigated with BIBN4096BS. Seven healthy volunteers completed this double-blinded placebo-controlled crossover study. The volunteers received randomly 10 min infusions of either placebo, 2.5 mg or 10 mg of BIBN4096BS on 3 separate days. Transcranial Doppler was used to measure the middle cerebral artery blood flow velocity (VMCA); global and regional cerebral blood flow (rCBFMCA) was measured by 133-Xenon inhalation SPECT. The diameter of the temporal and radial artery was measured by highresolution ultrasound. Systemic haemodynamics and partial pressure of CO2 (PetCO2), and adverse events were monitored regularly. BIBN4096BS had no influence on global or regional cerebral blood flow, or on the blood flow velocity in the middle cerebral artery. There was no effect on systemic haemodynamics and adverse events were minor. We conclude that there is no effect of CGRP-receptor blockade on the cerebral or systemic circulation in humans. Circulating CGRP is therefore not likely to exert a vasodilatory activity in the resting state and the use of BIBN4096BS for acute migraine seems to be without risk of cerebral vasoactivity. These data suggest that BIBN4096BS is the first specific antimigraine drug without vasoactive effect.

The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects.

Cyclic nucleotides are important hemodynamic regulators in many tissues. Glyceryl trinitrate markedly dilates large cerebral arteries and increases cGMP. Here, the authors study the effect of sildenafil, a selective inhibitor of cGMP-hydrolyzing phosphodiesterase 5 on cerebral hemodynamics and headache induction. Ten healthy subjects were included in a double-blind, placebo-controlled crossover study where placebo or sildenafil 100 mg (highest therapeutic dose) were administered on two separate days. Blood velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler, and regional cerebral blood flow in the perfusion area of the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133xenon inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasound. Blood pressure and heart rate were recorded repeatedly. Headache responses and tenderness of pericranial muscles were scored verbally. Sildenafil caused no significant changes in rCBFmca, Vmca, or in temporal or radial artery diameter, but heart rate increased and diastolic blood pressure decreased significantly compared to placebo. Despite the lack of cerebral arterial dilatation, sildenafil caused significantly more headache than placebo. The present results show that sildenafil 100 mg does not dilate cerebral or extracerebral arteries but nevertheless causes headache, which may be attributed to nonvascular mechanisms.

The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers

PACAP38 is an endogenous peptide located in trigeminal perivascular nerve fibers in the brain. It reduces neuronal loss and infarct size in animal stroke models and has been proposed a candidate substance for human clinical studies of stroke. The effect on systemic hemodynamics and regional cerebral blood flow (rCBF) is not well understood. We here present the first study of the effect of PACAP38 on cerebral hemodynamics in humans. PACAP (10 pmol kg(-1) min(-1)) or placebo (0.9% saline) was infused for 20 min into 12 healthy young volunteers in a cross over, double blind study. rCBF was measured with SPECT and (133)Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO(2) (P(et)CO(2)) and vital parameters were recorded throughout the 2 hour study period. PACAP38 decreased rCBF in all regions of interest (ROIs) by approximately 3-10%, though not uniformly significant. P(et)CO(2) decreased significantly during PACAP38 infusion compared to placebo (P=0.032), peak decrease was 8.9+/-3.8%. After correction for P(et)CO(2), rCBF remained unchanged in most ROIs. Heart rate increased 61.9+/-22.4% (P<0.0001 vs. placebo). These findings suggest that PACAP38 has no major direct effect on rCBF in healthy volunteers. The marked increase in heart rate and the reduction in rCBF caused by decreased P(et)CO(2) are important dose-limiting factors to consider in future clinical studies.

The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow.

Cilostazol, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using 133Xe inhalation and single photon emission computerized tomography. Mean flow velocity in the middle cerebral arteries (VMCA) was measured with transcranial Doppler, and the superficial temporal and radial arteries diameters were measured with ultrasonography. During the 4-hour observation period, there was no effect on systolic blood pressure (P = 0.28), but diastolic blood pressure decreased slightly compared with placebo (P = 0.04). VMCA decreased 21.5 ± 5.7% after cilostazol and 5.5 ± 12.2% after placebo (P = 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 ± 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 ± 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.

The headache-inducing effect of cilostazol in human volunteers.

We have previously shown that nitric oxide (NO) and cyclic guanosine monophosphate (GMP) may cause headache and migraine. However, not all findings in previous studies can be explained by an activation of the NO-cGMP pathway. Calcitonin gene-related peptide (CGRP) causes headache and migraine in migraine patients, but CGRP receptor activation causes an increase in cyclic adenosine monophosphate (cAMP). In order to investigate the role of cAMP in vascular headache pathogenesis, we studied the effect of cilostazol, an inhibitor of cAMP degradation, in our human experimental headache model. Twelve healthy volunteers were included in a double-blind, randomized, crossover study. Placebo or cilostazol (200 mg p.o.) was administered on two separate study days. Headache was scored on a verbal rating scale (0-10) and mechanical pain thresholds were measured with von Frey hairs. The median peak headache score 0-16 h postdose was 0 (range 0-2) after placebo and 3.5 (range 0-7) after cilostazol (P = 0.003). The median headache curve peaked at 6-9 h postdose. The headaches induced were usually bilateral and pulsating. Nausea occurred in two volunteers, photo- and phonophobia were not seen. Two volunteers had a headache that fulfilled International Headache Society criteria for migraine without aura after cilostazol. No change in mechanical pain thresholds in the forehead was seen (P = 0.25). The headache after cilostazol was equal to or more severe than headache induced by glyceryl trinitrate in previous experiments. The present study thus indicates that increased levels of cAMP may play a role in headache and migraine pathogenesis.

Reference programme: Diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 2nd Edition, 2012

Headache and facial pain are among the most common, disabling and costly disorders in Europe. Correct diagnosis and treatment is important for achieving a high quality of care. As a national organisation whose role is to educate and advocate for the needs of patients with primary headaches, the Danish Headache Society has set up a task force to develop a set of guidelines for the diagnosis, organisation and treatment of the most common types of headaches and for trigeminal neuralgia in Denmark. The guideline was published in Danish in 2010 and has been a great success. The Danish Headache Society decided to translate and publish our guideline in English to stimulate the discussion on optimal organisation and treatment of headache disorders and to encourage other national headache authorities to produce their own guidelines. The recommendations regarding the most common primary headaches and trigeminal neuralgia are largely in accordance with the European guidelines produced by the European Federation of Neurological Societies. The guideline provides a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organised in Denmark. This description is followed by individual sections on the characteristics, diagnosis, differential diagnosis and treatment of each of the major headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular problems regarding headache in children and headache in relation to female hormones and pregnancy are described.

Dipyridamole Dilates Large Cerebral Arteries Concomitant to Headache Induction in Healthy Subjects

Dipyridamole is used for secondary prophylaxis in ischemic stroke and as a vasodilator agent in myocardial scintigraphy. An important side effect to administering dipyridamole is headache. The aim of the current study was to investigate the effects of dipyridamole on cerebral blood flow, large artery diameter, and headache induction. Twelve healthy subjects were included in this single-blind placebo-controlled study in which placebo (0.9% NaCl) and dipyridamole 0.142 mg/kg·min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler and regional cerebral blood flow in the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133Xenon-inhalation. Blood pressure, heart rate, and pCO2 were measured repeatedly. Headache response was scored every 10 minutes on a verbal scale from 0 to 10 (10 = worst). Dipyridamole caused a decrease in pCO2 (P < 0.001). pCO2 corrected rCBFmca was 41.7 ± 6.9 mL/100 g ·min after placebo versus 41.2 ± 6.9 after dipyridamole (P ≥ 0.05). pCO2 corrected Vmca decreased 8.4% ± 11.7 (P < 0.001) after dipyridamole, indicating a mean 5.6% ± 6.7 (P = 0.005) relative increase of the arterial diameter. After dipyridamole the median peak headache score was 2 (range 0 to 7) compared with 0 (range 0 to 3) after placebo (P = 0.02). Dilatation of the middle cerebral artery outlasted the headache response. In conclusion, dipyridamole causes a modest pCO2 independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.

Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine

It has previously been shown that in migraine sufferers infusion of glyceryl trinitrate (GTN) and histamine causes an immediate headache during the infusion and a genuine migraine attack one to several hours after the infusion. This identical time profile indicates a common mechanism of action. To evaluate whether GTN causes headache via liberation of histamine, we studied the effect of GTN 0.5 ώg · kg−1·min−1 for 20 min in seven migraine sufferers, once after pretreatment with the histamine-1(H1)-receptor blocker mepyramine (0.5 mg · kg−1) and once without pretreatment. This mepyramine dose is known to completely abolish histamine-induced headache. After pretreatment with mepyramine five patients experienced migraine, and without pretreatment six patients did so. The median peak headache score was 7 on a 0–10 scale with and without mepyramine pretreatment. The arterial responses, evaluated with transcranial Doppler, were also unaffected by the mepyramine pretreatment. Our results demonstrate that neither headache nor arterial dilatation due to GTN infusion is caused by histamine release. In all likelihood the common mediator of migraine induction by GTN and histamine is nitric oxide.