Oral zolmitriptan is effective in the acute treatment of cluster headache.

OBJECTIVE: To evaluate the efficacy and tolerability of oral zolmitriptan 5 mg and 10 mg and placebo in cluster headache. METHODS: A multicenter, double-blind, randomized, three-period, crossover, outpatient study. Adult patients received placebo and zolmitriptan 5 mg and 10 mg orally for the acute treatment of episodic or chronic cluster headache. Headache intensity was rated by a five-point scale: none, mild, moderate, severe, or very severe. Patients only treated moderate to very severe headaches. The primary efficacy measure was headache response (two-point or greater reduction from baseline in the cluster headache rating scale) at 30 minutes. Secondary efficacy measures included proportion of patients with initial headache relief within 15 and 30 minutes, mild or no pain at 30 minutes, meaningful headache relief, and use of escape medication. RESULTS: A total of 124 patients took at least one dose of study medication, with 73% having episodic and 27% chronic cluster headache. For the primary endpoint, there was a treatment-by-cluster-headache-type interaction (p = 0.0453). Therefore, results are presented separately for chronic and episodic cluster headache. In patients with episodic cluster headache, the difference between zolmitriptan 10 mg and placebo at 30 minutes reached significance (47% versus 29%; p = 0.02). Mild or no pain at 30 minutes was reported by 60%, 57%, and 42% patients treated with zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo (both p

Sumatriptan nasal spray (20 mg/dose) in the acute treatment of cluster headache.

Subcutaneous injection of sumatriptan is an effective treatment for attacks of cluster headache with a short onset of action. This open, randomized study evaluates whether sumatriptan nasal spray at its highest commercially available dose (20 mg/dose) is equally effective. In 26 patients, four consecutive attacks were treated alternately with nasal spray and subcutaneous injection. Treatment was given within 5 min of onset of pain, and the time interval for the start and completeness of pain relief, provided these occurred within 15 min of administration, were recorded by the patient. After completion of the study, the patients were also asked to indicate which treatment they preferred, based on efficacy, side effects, and handling of the preparation. Forty-nine of the 52 treatments with injection resulted in complete relief of pain within 15 min, with a mean of 9.6 min. The remaining three attacks were reduced by a mean of 86.7% at 15 min. Only 7 of the 52 treatments with nasal spray in the nostril ipsilateral to pain resulted in complete relief within this time period, with a mean of 13.0 min. In 18 of these treatments pain was reduced by a mean of 42.2% at 15 min, whereas no effect on pain was obtained at this time in the remaining 27 treatments. The effect was almost identical when the nasal spray was administered in the nostril on the non-painful side. As an overall judgement, only 2 of the 26 patients preferred nasal spray to injection. We conclude that sumatriptan nasal spray 20 mg/dose is less effective than subcutaneous injection in relieving pain in the great majority of cluster headache sufferers.

How does sumatriptan nasal spray perform in clinical practice?

Migraineurs (94F, 24M) with previous experience of subcutaneous sumatriptan and/or sumatriptan tablets were asked their opinion on sumatriptan nasal spray treatment particularly with respect to onset of action, total efficacy, tolerability, and user friendliness. The information was obtained by means of a self-administered questionnaire handed out at the time of prescription of the nasal spray. The results are based on the patients' cumulative experience of having treated at least two migraine attacks with the spray (20 mg). Sumatriptan nasal spray (20 mg) was perceived to have a faster onset of action and, with the exception of a bad taste, to have a better tolerability than the tablets. Compared with subcutaneous sumatriptan, the nasal spray was claimed to be less effective in reducing symptoms of migraine attacks but to cause fewer adverse events. A bitter taste was the most commonly reported side effect of sumatriptan nasal spray--reported by 68% (80 out of 118) of the migraineurs. The user friendliness of sumatriptan nasal spray was rated better than that of subcutaneous sumatriptan and/or sumatriptan tablets. The overall impression of sumatriptan nasal spray was reported to be better or equal to that of the tablet and the injection by 57% and 46%, respectively. It is concluded that the results obtained in clinical practice are very much in line with those obtained in controlled clinical trials. The overall impression of sumatriptan nasal spray is that it is user friendly and useful in the acute treatment of migraine attacks of moderate intensity.

The thigh may not be suitable as an injection site for patients self-injecting sumatriptan.

The objective of our study was to evaluate the differences between injection sites in the midthigh and the upper lateral quadrant of the gluteal area regarding the effect, depth of subcutaneous tissue, side effects, and patient preference in patients with cluster headache who self-inject 6 mg (0.5 ml) of sumatriptan. Our open, prospective clinical study was performed at the outpatient department of a Swedish university clinic. There were 19 male and one female subjects, 34 to 68 years old, suffering from cluster headache. We measured the subcutaneous tissue depth by ultrasound. Subjects performed four self-injections of sumatriptan, two in the thigh and two in the gluteal area. We evaluated the subcutaneous tissue depth from the skin surface to the muscle fascia, the effect on headache, side effects, and patient preference regarding the injection site. Subcutaneous tissue depth laterally in the thigh was 2 to 12 mm (median, 4 mm) and in the gluteal area was 34 to 68 mm (median, 45 mm). The needle of the self-injector protrudes 5 to 6 mm. Forty thigh and 39 gluteal injections were recorded. The effect on headache was equal. Following injection in thigh the patients experienced more bleeding (p < 0.001, chi 2); local pain (p < 0.05, chi 2); and a feeling of oppression in the head, neck, and chest area (p < 0.05, chi 2); compared with injections in the gluteal area. Fifteen patients preferred the gluteal area as the injection site after the study, two patients had no preference, and three preferred the thigh. When using the self-injector in the lateral aspect of the thigh, intramuscular injection is liable to occur frequently in male patients. This may explain the differences in local and general side effects observed in this study. The upper lateral quadrant of the gluteal area is a more suitable injection site for male, and some female, patients when using the sumatriptan self-injector.

Neonatal chronic sympathectomy in normotensive rats affects pial arteries: enhanced stiffness and reduced capacity to dilate.

The functional implication of previously shown effects on pial wall morphology by sympathectomy was tested. Following either ganglionic or pre-ganglionic denervation in 1-week-old rats the passive arterial compliance was reduced in basal cerebral arteries of 20-week-old normotensive, but not of hypertensive animals. The magnitude of the denervation induced stiffness was similar to the alteration seen in spontaneously hypertensive rats when compared with normotensive animals. No difference was seen between the two types of denervation. Following ganglionic sympathectomy in 1-week old normotensive rats-and examined 19 weeks later-the increase in cerebral blood flow (measured with the [14C]butanol sampling technique) induced by high arterial CO2 concentration was attenuated compared with control, whereas basal cerebral blood flow of 20-week-old animals was not different from control. The results indicate a long-term role by the sympathetic nerves not only on vessel wall composition, but also on the regulatory capacity of the cerebral circulation.

Neonatal pre-ganglionic sympathectomy affects morphometrically defined architecture in rat cerebral arteries.

In order to clarify further the nature of the long-term influence on the cerebral vasculature by the sympathetic nerves, a bilateral cervical pre-ganglionic denervation was performed in 1-week-old rats. Four weeks later, morphometric determinations of the vascular dimensions revealed diminished media cross-sectional areas and luminal radii in the middle cerebral and posterior cerebral arteries, whereas these parameters were unaffected in the basilar artery. In the latter artery, however, a 40% increase in the cross-sectional area of the internal elastic membrane was found. No re-innervation of the denervated ganglia occurred during the course of the experiment. The results suggest that the long-term effect exerted by the sympathetic nerves is associated with the nerve activity, rather than being a true trophic influence.

Influence of cerebrovascular sympathetic, parasympathetic, and sensory nerves on autoregulation and spontaneous vasomotion.

The effect of removal of cerebrovascular sympathetic, parasympathetic or sensory nerve on brain cortical blood flow and spontaneous vasomotion during changes in systemic blood pressure was studied by laser-Doppler flowmetry in anaesthetized rats. Selective section of sympathetic fibres along the internal carotid artery markedly affected the ability to autoregulate, as measured in microvessels of the middle cerebral arterial territory. Removal of the parasympathetic nerves tended to reduce the ability to autoregulate, whereas no significant influence was found after sensory denervation. Following the denervations, spontaneous vasomotion was not significantly affected in frequency or amplitude.

A morphometric study of the effect of bilateral cervical sympathetic ganglionectomy on the architecture of pial arteries in spontaneously hypertensive and normotensive rats.

The influence of the cranial sympathetic nerves on the architecture of pial arteries in normo- and hypertension was examined. For this purpose the effect of bilateral superior cervical ganglionectomy was evaluated in normotensive rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). The operations were performed at the age of 1 wk, which is just prior to the onset of ganglionic transmission. The length of the inner media contour was measured and the media cross-sectional area was determined planimetrically, with computerized digitalization of projected photographic images of transversely sectioned pial arteries. Four wk after sympathectomy there was a 20% reduction in media cross-sectional area and a consequent reduction in the ratio between media area and calculated luminal radius in the major pial arteries at the base of the brain in WKY but not in SHRSP. Conversely, in small pial arteries linear regression analysis showed that in WKY subjected to ganglionectomy the relationship between media cross-sectional area and luminal radius was significantly larger in arteries with a radius less than 21 microns compared to untreated WKY. No such effect was seen in the corresponding SHRSP vessels. In addition, the cross-sectional area of the internal elastic membrane (IEM) in the basilar arteries of WKY was measured by means of a computerized image-analysing system. Mean cross-sectional area of the IEM was approximately 45% larger following SE than in control animals. The present findings propose a 'trophic' role for the sympathetic perivascular nerves in large pial arteries of the rat. The increased media-radius ratio in the small pial arteries of the WKY following sympathectomy might reflect a compensatory hypertrophy due to reduced protection from the larger arteries against the pressure load. The inability to detect any morphometrically measurable effect of the sympathectomy in the cerebral arteries of SHRSP is probably explained by a marked growth-stimulating effect of the high pressure load in these animals.

Influence of cerebrovascular parasympathetic nerves on resting cerebral blood flow, spontaneous vasomotion, autoregulation, hypercapnic vasodilation and sympathetic vasoconstriction.

Activation of perivascular parasympathetic nerves enhances cerebral blood flow. In the present experiments, functional aspects of this flow regulating capacity were investigated. It was found that parasympathetic nerve stimulation does not facilitate the normalization of the cerebral blood flow reduced by sympathetic stimulation. In contrast, activation of sympathetic nerves may contribute to a rapid normalization of the cerebral blood flow increased by parasympathetic stimulation. The lower limit of cerebral autoregulation is shifted towards higher blood pressures in parasympathetically denervated rats. Parasympathetic nerves do not influence hypercapnic cerebral vasodilatation, but CO2 influence the effect of parasympathetic stimulation on cerebral blood flow. We conclude that activity in parasympathetic nerves does not contribute to cerebral vasomotion.

The role of nitric oxide in the cerebrovascular flow response to stimulation of postganglionic parasympathetic nerves in the rat.

Stimulation of cerebrovascular parasympathetic nerves markedly increases cortical blood flow. Nitric oxide (NO) or a NO containing compound is present in these nerves, and its release may therefore be partly responsible for the flow increase. In addition, transmitters released from the nerves may cause synthesis and release of this compound from the endothelium. The contribution of NO synthesis to the cortical blood flow increase during parasympathetic stimulation was elucidated in rats by laser-Doppler flowmetry. Thirty min exposure to circulating N omega-nitro-L-arginine methyl ester (L-NAME) 50 mg.kg-1 eliminated most of the response (from 104 to 8% increase), whereas 10 min exposure to this dose or 30 min exposure to 5 mg.kg-1 caused a less marked reduction. The reducing effect was particularly evident after elimination of the systemic blood pressure increase caused by L-NAME (only 3% increase after the high dose). In fusion of L-arginine restored the flow response. Resting cortical blood flow was not substantially affected by blockade of NO formation. Thus, release of a NO containing compound constitutes a major component of the increase in cortical blood flow caused by parasympathetic nerve stimulation, but does not seem to contribute to cortical flow regulation during resting conditions.

Dynorphin B is present in sensory and parasympathetic nerves innervating pial arteries.

Dynorphin B (dyn B) in trigeminal ganglion cells and in perivascular nerve fibers in pial arteries was demonstrated in rat, guinea-pig, and monkey by immunohistochemistry. The pathway from the trigeminal ganglion, which runs via the nasociliary nerve and ethmoidal foramen to the pial arteries, was shown in rat by retrograde tracer technique and nerve section. In the guinea-pig the peptide was demonstrated to coexist with substance P and calcitonin gene-related peptide in neurons of the trigeminal ganglion and pial nerve fibers, i.e., it was present in cerebrovascular sensory nerves with primarily nociceptive function. Another finding in guinea-pig was a coexistence of dyn B with vasoactive intestinal polypeptide in the pial nerve fibers and neurons of the sphenopalatine ganglion, indicating a presence also in parasympathetic nerves to the cerebral vessels. No vasomotor effect of dyn B could be detected in isolated segments of rat pial arteries, which rules out a direct postsynaptic effect on vascular tone. The peptide did not display a prejunctional modulatory action on the adrenergic nerves present in the vessels. The function of dyn B in the cerebrovascular nerves is discussed.

How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibers.

A large body of evidence points to an inflammatory process in the cavernous sinus and tributary veins as being primarily responsible for cluster headaches. The inflammation obliterates the venous outflow from the cavernous sinus on one side and injures the through-running sympathetic fibers to the eye, upper eye lid, forehead skin, and the intracranial internal carotid artery and its branches. The active period ends when the inflammation is suppressed and the sympathetic fibers partially or fully recover. Evidence is presented that the symptoms suggestive of an enhanced parasympathetic activity during attacks may alternatively be explained as local pain fiber activation or a stasis in the outflow from the cavernous sinus. Vasodilator agents like nitroglycerin induce an attack by enhancing the venous load on the cavernous sinus. Constriction of the proximal intracranial internal carotid artery, spontaneously induced by stressful pain activation of the perivascular sympathetic nerves, or by exogenous administration of serotonin 1D-like receptor agonists or oxygen, terminates the venous load and thus the pain and associated symptoms.

Inhibition of nitric oxide synthase attenuates the cerebral blood flow response to stimulation of postganglionic parasympathetic nerves in the rat.

Stimulation of cerebrovascular parasympathetic nerves markedly increases cortical blood flow. Nitric oxide (NO) or a NO-containing compound is present in these nerves and may therefore, upon release, be partly responsible for the flow increase. In addition, transmitters released from the nerves may cause synthesis and release of this compound from the endothelium. The contribution of NO synthesis to the cortical blood flow (CoBF) increase during parasympathetic stimulation was elucidated in rat by laser-Doppler flowmetry. Thirty-minute exposure to circulating N omega-nitro-L-arginine methyl ester (L-NAME) 50 mg kg-1 eliminated most of the response (from 104 to 8% increase), whereas 10-min exposure to this dose or 30-min exposure to 5 mg kg-1 caused a less marked reduction. The reducing effect was particularly evident after elimination of the systemic blood pressure increase caused by L-NAME (only 3% increase after the high dose). Infusion of L-arginine restored the flow response. Resting CoBF was not substantially affected by blockade of NO formation. Thus, release of an NO-containing compound constitutes a major component of the increase in CoBF caused by parasympathetic nerve stimulation but does not seem to contribute to cortical flow regulation during resting conditions.

Interaction between cerebrovascular sympathetic, parasympathetic and sensory nerves in blood flow regulation.

Morphological and pharmacological findings support that different cerebrovascular nerve types have close relationships in the vessel wall and that interactions may contribute to the control of vascular tone. This study in rat investigates whether interaction in blood flow regulation occurs between sympathetic, parasympathetic and sensory nerves in the cerebral vessels. Cortical blood flow (CBF) was measured with a laser-Doppler flowmeter during electrical stimulation of one of the nerves, with or without prior denervation of one or two of the other nerves. Unilateral sympathetic stimulation significantly decreased CBF ipsilaterally. The response was unaffected in magnitude and time course by parasympathetic or sensory denervation. Sensory nerve stimulation did not significantly affect CBF, even after sympathetic denervation. Parasympathetic nerve stimulation caused a marked increase in CBF, which was similar in magnitude in the presence or absence of sympathetic innervation. However, the return to the basal CBF level after parasympathetic stimulation was prolonged after sympathetic denervation. Thus, activation of the sympathetic nerves may contribute to a rapid normalization of the enhanced CBF during parasympathetic nerve stimulation, whereas the reverse phenomenon, parasympathetic normalization of the sympathetically induced CBF reduction, does not occur.

Effects of nitric oxide synthesis blockade and angiotensin II on blood flow and spontaneous vasomotion in the rat cerebral microcirculation.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME) an inhibitor of NO synthesis, or angiotensin II on the frequency and amplitude of rhythmic variations (vasomotion) in blood flow of the intact rat cerebral circulation were investigated using laser-Doppler flowmetry (LDF). Experiments were performed on Sprague-Dawley rats anaesthetized with alpha-chloralose. The rat's head was fixed on a stereotaxic frame and the microvascular blood flow of the parietal cortex on the right or on both sides was measured via a small hole in the parietal bone, keeping the dura and a thin bone layer intact. Following the intravenous injection of L-NAME, the mean arterial blood pressure (MABP) increased to 123 +/- 1 mmHg (1.25 mg kg-1) or to 144 +/- 3 mmHg (5.0 mg kg-1) but no significant changes in cerebral blood flow (CBF) or vasomotion could be detected. The observed increase in MABP was sustained until L-arginine was administered. In the presence of L-NAME, during stepwise reduction of MABP, CBF remained constant when MABP was kept between 60 and 130 mmHg, the vasomotion frequency was lower when MABP was above 80 mmHg but its amplitude was two times higher than in the control group. In another group of animals, angiotensin was infused to give comparable increments in blood pressure. In contrast to L-NAME, angiotensin II had no effect on either frequency or amplitude of vasomotion, compared to the control group, within the whole range of MABP studied.(ABSTRACT TRUNCATED AT 250 WORDS)

The cerebrovascular parasympathetic innervation.

Until recent years, little has been known about the parasympathetic innervation of cerebral vessels, in contrast to the sympathetic innervation. Recent histochemical and biochemical studies on cerebrovascular parasympathetic nerves have revealed their sources and pathways. Histochemical studies have demonstrated nerve fibers containing choline acetyltransferase, a reliable marker for cholinergic nerves, and vasoactive intestinal polypeptide (VIP) in the cerebral vessels. By combining histochemistry with a retrograde tracer technique and selective denervations, the cerebrovascular parasympathetic innervation has been mapped in the rat, cat, and monkey. Acetylcholine (ACh) has been measured biochemically in the pial arteries of several species. A high-affinity uptake, local synthesis, and tetrodotoxin-sensitive release of ACh have been demonstrated in the pial vessels. Pharmacological studies on isolated pial arteries have revealed ACh- and VIP-induced relaxation through the stimulation of muscarinic and VIPergic receptors, respectively. The action of ACh requires an intact endothelial function. An increase in cerebral blood flow upon stimulation of pre- or postganglionic fibers of the sphenopalatine ganglion has been demonstrated in some animals, and can be mimicked by local administration of ACh and VIP in vivo. This indicates a role of the parasympathetic nerves in tone regulation of the cerebral vessels. The pathophysiological conditions during which these nerves become activated are currently being revealed.

Subcutaneous sumatriptan in cluster headache: a time study of the effect on pain and autonomic symptoms.

A subcutaneous injection of 6 mg sumatriptan rapidly and effectively stopped attacks of cluster headache. After a time lag of 4-14 minutes (mean 7 minutes) pain dramatically dropped to zero within seconds to single minutes (mean 56 seconds). This rapid effect may indicate that mere vasoconstriction is the mechanism behind the beneficial effect of sumatriptan in cluster pain. The findings support a scenario in cluster headache where an inflammation in the cavernous sinus affects the sympathetic fibers traversing the cavernous region. This leads to the miosis, ptosis and forehead anhidrosis but also to a dilated internal carotid arterial tree distal to the lesion. The dilatation, in combination with an obliterated drainage of the cavernous sinus by the inflammatory process, leads to progressive stasis in the sinus, to cause the painful attack. The attack terminates when the enhanced load on the sinus is reduced by constriction of vessels supplying the sinus, as is achieved by administration of sumatriptan. The present observation that other accompanying symptoms during attacks (nasal congestion, rhinorrhea, lacrimation and swelling of eyelids) disappeared in parallel with the pain points to the possibility that these symptoms may be directly related to venous stasis or activation of pain fibers, rather than resulting from a primary parasympathetic activation.

Vasomotion in the rat cerebral microcirculation recorded by laser-Doppler flowmetry.

In the present study, changes in frequency and amplitude of the rhythmic variations (vasomotion) in blood flow in the intact cerebral circulation of the rat were investigated using laser-Doppler flowmetry (LDF) during stepwise decrease in mean arterial blood pressure (MABP) and hyper- and hypocapnia. Experiments were performed on 12 adult Sprague-Dawley rats of either sex, anesthetized with alpha-chloralose. The rat's head was fixed on a stereotaxic frame and a small hole was made in the parietal bone but the dura and a thin inner bone layer were kept intact. The microvascular blood flow of the parietal cortex on the right or on both sides was continuously recorded by the laser-Doppler flowmeter (Periflux PF2B, Perimed, Stockholm, Sweden). The cerebral circulation of the rat exhibited vasomotion in control conditions with a frequency of 8-10 cycles per minute (cpm) and an amplitude of 5-10% of the cerebral blood flow (CBF). No significant changes in CBF could be detected when the MABP was above 60 mmHg, but it decreased significantly when MABP was reduced below 50 mmHg. However, during stepwise pressure reduction the vasomotion frequency decreased progressively while its amplitude showed a reversed U-shaped curve with a peak at 60-80 mmHg. During hypercapnia, the rhythmical oscillations showed a decrease in both frequency and amplitude, whereas during hypocapnia their frequency did not change but their amplitude increased. These results support the hypothesis that the vasomotion frequency might be dependent of the wall tension and cellular pH while its amplitude could be related to decreased tissue oxygenation.

Vasoreactivity of the intracranial internal carotid artery.

The vasoreactivity of the intracranial segment of the internal carotid artery to transmitters, present in the perivascular sympathetic, parasympathetic and sensory nerves, as well as to other vasoactive agents of relevance for headache, was tested in man and monkey. The total arterial segment from both species is equipped with contractile receptors for noradrenaline, serotonin, prostaglandin F2 alpha, ergotamine and sumatriptan. Further, the total arterial segment dilated upon exposure to calcitonin gene-related peptide in both species. Other vascoactive transmitters, acetylcholine, substance P and neurokinin A, caused only weak dilatation, restricted to the proximal extracavernous segment in the monkey. The findings are discussed in relation to the pathogenesis and treatment of cluster headache.

Presence of gastrin-releasing peptide in neurons of the geniculate ganglion in rat and man.

Gastrin-releasing peptide (GRP) was demonstrated by immunohistochemistry and high-performance liquid chromatography to be present in the great majority of neurons in the geniculate ganglion of rat and man. This was in contrast to findings in the sphenopalatine ganglion of rat, where only little GRP was found, and in the otic, trigeminal, glossopharyngeal-vagal and internal carotid ganglia, where no GRP-containing cells could be demonstrated. The peptide was not detected by immunohistochemistry in nerve fibers within structures innervated from the ganglion (tongue, soft palate, retroauricular skin and facial musculature). The retrograde axonal tracer True blue accumulated in these neurons of rat after application not only in the tongue and soft palate but also in the retroauricular skin.