The nitric oxide hypothesis of migraine and other vascular headaches

The molecular mechanisms of migraine pain remain to be determined. Our studies of glyceryl trinitrate (GTN)-induced and histamine-induced headaches have led us to propose that nitric oxide (NO) may be the causative molecule in migraine pain. We also propose that substances capable of inducing experimental vascular headache do so with NO as the common mediator. Finally, we suggest that drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. We believe these observations provide new insight into the mechanisms of vascular headache. The importance of NO as a potential initiator of the migraine attack indicates new directions for the pharmacological treatment of migraine and other vascular headaches.     

Cluster headache pain vs. other vascular headache pain: differences revealed with two approaches to the McGill Pain Questionnaire

We compared cluster headache pain and other vascular (migraine and mixed) headache pain on pain intensity ratings and the McGill Pain Questionnaire (MPQ). Cluster headache sufferers reported not only more intense pain and more affective distress, but also different pain qualities than did migraine and mixed headache sufferers. The pain qualities that best distinguished cluster headaches from other vascular headaches were the presence of punctate pressure and thermal sensations and the absence of dull pain. Although cluster headache sufferers and other vascular headache sufferers endorsed different sensory pain qualities, MPQ subscales proved no better than pain intensity ratings at distinguishing these two groups. This finding may have occurred because MPQ subscale scores include an intensity component and do not provide information about specific pain qualities such as that provided by MPQ sensory items. These findings provide evidence that cluster headaches are characterized by distinct pain qualities and are not simply a more intense version of the same vascular headache pain experienced by migraine and mixed headache sufferers. They further suggest than when the MPQ is used to assess specific pain qualities, sensory items and not the sensory subscale are the preferred units for analysis.     

Nitric oxide: emerging implications for headache mechanics

The involvement of nitric oxide (NO) in the pathophysiology of primary headaches was suggested by several authors during the last decade. Migraine, cluster headache, tension headache, and cervicogenic headache have been extensively studied on the basis of NO donor headache pain. Different mechanisms seem to be involved in the generation of pain in these clearly different clinical head pain disorders. NO could control all the mechanisms leading to head pain. In migraine NO is correlated with endothelial activation, in cluster headache with a brainstem unravelling of the on/off regulatory clocks, in cervicogenic headache with a cytokine-dependent pain, and in tension-type headache with a sensitization of pain pathways at the spinal/trigeminal level. The next natural frontier in the study of pain in primary headaches seems to be the functional study of the relationship between NO and the immune regulatory system. Received: 30 Devember 2000 / Accepted in revised form: 9 April 2001     

Nitric oxide in primary headaches

Nitric oxide (NO) has been proposed to be a key molecule in migraine. Experimental evidence suggests its intervention in vasodilatation and activation of the trigeminovascular system as well as its involvement in the supraspinal pathways implicated in head and pain processing. Other findings suggest the implication of NO in coupling neuronal and vascular changes during spreading depression. A potential role for NO has also been proposed in the pathophysiological mechanisms underlying cluster headache and chronic tension-type headache. The most relevant evidence for an increased response to exogenous NO in all primary headaches emerges from the experimental model of nitroglycerin-induced headache. Moreover, the effectiveness of non-selective NO synthase inhibitor L-N-monomethylarginine (L-NMMA) further supports the involvement of NO in migraine and chronic tension-type headache. The endogenous increase in NO production has been shown only in studies carried out during spontaneous migraine attacks which demonstrated increased levels of nitrites and cGMP in peripheral blood and internal jugular blood; the latter was followed by an increased production of algogenic and vasodilatatory prostanoids. These data suggest the potential activation of cyclooxygenase (COX) due to NO. Additional evidence suggests the increased activity of L-arginine/NO pathway in the platelet model in migraine patients. This increase was also evident between attacks, more accentuated during attacks and expressed to a greater extent during late luteal phase in menstrual migraine. Higher NO production in platelet was also demonstrated in patients affected by chronic daily headache and they are accompanied by significant lower serotonin content and higher levels of intracellular calcium. Whether these changes may be expressed in the central nervous system is a matter of discussion. These data taken together suggest a crucial role played by NO in neurovascular headaches and chronic headaches. Further research concerning NO in all primary headaches will be aimed at verifying changes of reliable markers of NO metabolism and NO effects, to better understand the complex COX/NO synthase (NOS) interactions, to investigate the effectiveness of selective NOS inhibitors in discriminating neural versus vascular involvement of NO. Received: 15 October 2000 / Accepted in revised form: 30 January 2001     

The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache

The most important primary headaches (i.e. independent disorders that are not caused by another disease) are migraine, tension-type headache and cluster headache. All primary headaches are in need of better treatments. Migraine has a prevalence of 10% in the general population and its societal costs are high. Although the precise mechanisms underlying the pathophysiology of migraine are still elusive, the last decades have witnessed some progress (e.g. involvement of serotonin, calcitonin gene-related peptide, nitric oxide, etc). Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-NMMA effectively treats attacks of migraine without aura. Similar results have been obtained for chronic tension-type headache and cluster headache. Inhibition of the breakdown of cGMP also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Several relationships exist between NO, calcitonin gene-related peptide and other molecules important in migraine. Also ion channels, particularly the K(ATP) channels, are important for the action of NO. In conclusion, inhibition of NO production or blockade of steps in the NO-cGMP pathway or scavenging of NO may be targets for new drugs for treating migraine and other headaches. Indeed, selective n-NOS and i-NOS inhibitors are already in early clinical development.     

Neuropeptide release in the dura mater encephali in response to nitric oxide--relevance for the development of vascular headaches?

Nitric oxide (NO) and calcitonin gene-related peptide (CGRP), potent vasodilators in the meninges,may be involved in the pathophysiology of vascular headaches such as migraine pain. NO donators can provoke headache attacks in migraineurs and increased levels of CGRP have been found in the venous outflow from the head during migraine attacks. We therefore examined the effect of both NO and CGRP on dural blood, a process which may parallel nociceptive processes in the meninges. 1.Arterial blood flow was measured in the exposed dura mater encephali of the rat using laser Doppler flowmetry. Local application of different NO donors (SNAP,NONOate, and NOC-12) caused dose-dependent increases in meningeal blood flow. CGRP(8-37) at 10(-4) M did not significantly change the basal flow but attenuated increases in blood flow caused by the NO donors at concentrations of 10(-5)-10(-3) M.2. In another series of experiments, the hemisected skulls of adult Wistar rats, complete with intact dura mater, were filled with oxygenated synthetic interstitial fluid (SIF) and the CGRP content of this fluid was assessed every 5 min. When the NO donator NONOate, at concentrations of 10(-5)-10(-3) M, was added to the SIF, or when the SIF was bubbled with NO gas (1000 ppm in N(2) atmosphere) instead of carbogen, CGRP release increased in a concentration-dependent manner. We conclude that the vasodilatory effect of NO that causes increased meningeal blood flow is in part the result of both stimulating the release of CGRP and promoting the vasodilatory action of CGRP. Since NO donors such as nitroglycerin are known to provoke headache and CGRP is released during migraine pain, the NO-stimulated CGRP release may be relevant for the development of vascular headaches that are accompanied by meningeal hyperaemia.     

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.     

Nitric oxide pathway and response to nitroglycerin in cluster headache patients: plasma nitrite and citrulline levels

Nitric oxide (NO) may participate in the mechanisms underlying vascular headaches, such as migraine and cluster headache (CH), by triggering neurogenic inflammation and activation of fibres conveying nociceptive inputs to the trigeminal ganglion. Similarly to migraine, the administration of the NO donor glyceryltrinitrate (GTN) to CH patients is a known model of inducing spontaneous-like attacks. We carried out a GTN test (0.9 mg, sublingually) in 18 patients with episodic CH in active phase and 12 controls. The plasma levels of NO metabolite nitrites (NO2-), after conversion of nitrates to NO2-, were measured spectrophotometrically at baseline, at the maximum intensity of the induced response (or 45 min after GTN in controls), and 120 min after GTN administration. The basal plasma levels of L-citrulline were also assayed in patients and controls using high-performance liquid chromatography. Basal NO2- levels, similar in GTN-responsive patients and controls (48.3 +/- 10.6 and 44.6 +/- 9.5 micromol/l, respectively) were found to be increased significantly at pain peak in patients (76.1 +/- 10.2 micromol/l) and after 45 min in controls (78.2 +/- 9.6 micromol/l) (P < 0.01 vs. respective baseline values), but not after 120 min, without differences between groups. L-citrulline levels in basal conditions showed no differences between groups (patients 64.8 +/- 11.7, controls 67.3 +/- 10.8 micromol/l). These data do not support the presence of a basal hyperactivity of the L-arginine-NO pathway in CH patients. Increased NO production may be of importance in the mechanisms leading to CH attacks, but other factors are likely to render CH patients hyperresponsive to NO, and ultimately to cause the occurrence of pain and associated features.     

Acetazolamide Testing of Cerebral Vasodilator Capacity Provokes "Vascular" But Not Tension Headaches

Cerebrovascular capacitance was tested by measuring local cerebral blood flow (LCBF) by xenon-contrasted CT scanning before and after the oral administration of 14.3 mg/kg of acetazolamide among 45 subjects including 15 age-matched controls without history of headache, 20 migraineurs with and without aura, 3 patients with cluster headache, and 7 patients with tension-type headache. Percentage increases of LCBF were measured in 10 regions located throughout both hemispheres. Laterality indices for asymmetric LCBF increases were calculated. Local cerebral blood flow in cortical gray matter increased 5.9% in controls, 9.9% in patients with tension headaches, but 18.6% in both migraine and cluster headache patients; significantly greater LCBF increases than among controls or among patients with tension headaches (P<0.05). Increases in LCBF were significantly asymmetric among migraine and cluster patients and provoked typical unilateral vascular headaches which responded to sumatriptan. Maximal asymmetric LCBF increases also corresponded to the reported side of the induced headaches confirming their vascular pathogenesis. Patients with tension headaches and controls without history of headache did not develop head pain after acetazolamide.     

Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.     

Facial temperature in migraine, tension-vascular and tension headache

The relationship between clinical features and changes in the extracranial circulation was studied during 209 separate attacks of headache affecting the anterior part of the head. Extracranial vascular changes were assessed thermographically and by the change in headache intensity when pressure was applied over the superficial temporal and common carotid arteries. In unilateral headaches, increased heat loss from the affected frontotemporal region was observed most frequently in attacks which were temporarily relieved by compression to the superficial temporal artery; thermographic asymmetry disappeared as the headache abated. Although such headaches were associated more frequently with migrainous features than attacks which did not respond to arterial compression, many headaches with clinical features of migraine had no vascular component detectable by thermography or vascular compression. Furthermore, the response to arterial compression was not consistent from one headache to another in the same patient. It was concluded that extracranial vascular changes recur intermittently in headache-prone patients, depending on the severity of pain and association with other features commonly regarded as migrainous. However, there was no clear demarcation point between entities diagnosed clinically as "migraine" and "tension headache".     

The Relationship of Locus of Control and PsychosociaI-Behavioral Response in Chronic Headache

It has been suggested that patients' perceptions of the impact chronic headache has on their lives as well as perceived control of their headaches may be associated with the intensity, duration, and exacerbation of pain they experience. The present study examined associations among International Headache Society (IHS) diagnostic category, pain characteristics such as severity and duration, perceived impact and control of headaches, and adaptive response. Two hundred twenty-five patients with migraine, tension-type, or combined migraine and tension-type headache served as subjects. General activity level was related to IHS diagnosis, with migraine headache patients reporting that they are more active than tension-type headache patients (F(2, 196) = 5.69, P < .01). Headache locus of control was not significantly related to IHS diagnosis, however external headache locus of control was significantly related to headache intensity (r = .32, P < .001, r = .25, P < .001), as well as to patients' perceptions of the extent to which pain interfered with various domains of their lives (r = .33, P < .001, r = .28, P < .001), and adaptive response (F(6, 402) = 4.68, P < .001). It appeared that perceived control over headaches and perceived impact of headaches were not related to IHS diagnostic category and were not strongly related to each other, but were related to headache severity.     

Relationships among migrainous, vascular and orthostatic symptoms

A headache symptom questionnaire was filled out by 766 undergraduate university students and 258 reported one or more headaches per month. Headaches characterized by one or more of the main migrainous symptoms (unilateral pain, gastrointestinal disturbance and focal neurological symptoms) were reported to be more severe, pulsatile, of longer duration, and associated with facial pallor and signs of cerebral vascular instability more frequently than headaches accompanied by few or none of the major migrainous symptoms. Additionally, hunger was reported to trigger headaches associated with migrainous symptoms more frequently than non-migrainous headaches. The results are consistent with the proposal that vascular involvement is one of the factors underlying a continuum of headache with migraine as one extreme.     

Acupuncture for Cancer Pain and Related Symptoms

A headache is a common neurological disorder, and large numbers of patients suffer from intractable headaches including migraine, tension headache and cluster headache, etc., with no clear therapeutic options. Despite the advances made in the treatment of headaches over the last few decades, subsets of patients either do not achieve adequate pain relief or cannot tolerate the side effects of typical migraine medications. An electrical stimulation of the peripheral nerves via an implantable pulse generator appears to be good alternative option for patients with treatment-refractory headaches. A number of clinical trials show considerable evidence supporting the use of peripheral nerve stimulator (PNS) for headaches not responding to conservative therapies. However, the mechanism by which PNS improves headaches or predicts who will benefit from PNS remains uncertain. The decision to use PNS should be individualized based on patient suffering and disability. Hence, further work is imperative. Here, we discuss the mechanism, indication, efficacy, implant technique, and complications of PNS.     

Migraine and Tension Headache: Is There a Physiological Difference?

SYNOPSIS
The purpose of this study was to conduct a controlled comparison of tension and migraine headache under several experimental conditions.
Ten subjects from each of the following diagnostic groups - tension headache, migraine headache, and healthy controls - were observed under conditions of unstructured relaxation, mild stress, and recovery from stress. Forearm and forehead muscle potential, peripheral temperature, electrodermal response, heart rate, and systolic and diastolic blood pressure were monitored during these sessions. In addition, ratings of pain were obtained, and booklets II and III of the Edwards Personality Inventory were completed by each subject. The hypotheses that tension headache is associated with increased frontalis muscle tension and that migraine headache is associated with increased vasomotor activity were not supported with respect to resting levels, response to physical or psychological stress, or in relationship to pain. Personality differences between the three groups were observed. Migraine subjects appeared to be more perfectionistic and success-oriented than the other groups: and tension headache subjects, more anxious and insecure. It was suggested that although personality differences indicate the existence of two distinct disorders, physiological variables that were believed to be basic to the pathophysiology of these headaches (e.g. frontalis EMG in tension headache) do not distinguish these two types of headache.     

Transformation of Episodic Migraine Into Daily Headache: Analysis of Factors

SYNOPSIS
Seventy-six percent of patients with daily headaches were found to have a history of episodic migraine in the past, more than half of them hormone dependent headache such as menstrual migraine. Various factors possibly influencing the transformation of episodic migraine into daily headaches were analyzed in a series of 61 patients who presented with daily headaches. Abnormal personality profile, especially neuroticism including depression, excessive stress, excessive use of medications such as caffeine containing analgesics, narcotic analgesics and ergotamine, and development of hypertension were found to be significant in the transformation of episodic migraine into daily headache.
The problem of daily headache is discussed. It is suggested that the majority of daily headaches are a continuum of episodic migraine, influenced and perpetuated by various factors such as neuroticism, excessive medication, stress, and development of hypertension. It is pointed out that diagnosis of tension headache under those circumstances is not justified.     

Human migraine models

The need for experimental models is obvious. In animal models it is possible to study vascular responses, neurogenic inflammation, c-fos expression etc. However, the pathophysiology of migraine remains unsolved, why results from animal studies not directly can be related to the migraine attack, which is a human experience. A set-up for investigations of experimental headache and migraine in humans, has been evaluated and headache mechanisms explored by using nitroglycerin and other headache-inducing agents. Nitric oxide (NO) or other parts of the NO activated cascade seems to be responsible for the induced headache and migraine. Perspectives are discussed.     

The trigeminocervical complex and migraine: current concepts and synthesis

Neurones in the trigeminocervical complex are the major relay neurones for nociceptive afferent input from the meninges and cervical structures; therefore, they are the neural substrates of head pain. This review highlights the importance of two basic mechanisms in headache physiology: convergence of nociceptive afferents and sensitization of trigeminocervical neurones. These physiologic findings have clinical correlates such as hypersensitivity and spread and referral of pain frequently seen in patients with primary headache, such as migraine. Special reference is made to the influence of structures from the upper cervical spine in generating and contributing to migraine headaches. The pathophysiology and functional relevance of these basic mechanisms to headaches is discussed in the context of recent experimental findings with regard to pain processing.     

Side-Locked Unilaterality and Pain Localization in Long-Lasting Headaches: Migraine, Tension-Type Headache, and Cervicogenic Headache

SYNOPSIS
Side-locked unilaterality and specific localization of pain are not as well-defined clinical characteristics in long-lasting headaches (duration more than 4 hours) as they are in short-lasting forms. We examined side-locked unilaterality and pain distribution at onset and at peak headache in 74 patients with different forms of long-lasting headache: migraine and tension-type headache (IHS) and cervicogenic headache (according to Sjaastad et al). Side-locked unilaterality of pain was found in all forms, but to differing extents-20.8% in migraine, 12.5% in tension-type headache, while it was a mandatory criterion for cervicogenic headache. The pain tended to localize anteriorly, particularly at onset, in migraine; was more diffuse in tension-type headache; and always began in the occipitonuchal region in cervicogenic headache. Our results may contribute to a better clinical definition of long-lasting headaches.