Chronic frequent headache in the general population: comorbidity and quality of life

We studied the nature and extent of comorbidity of chronic frequent headache (CFH) in the general population and the influence of CFH and comorbidity on quality of life. Subjects with CFH (headache on >14 days/month) were identified in a general health survey. We sent a second questionnaire including questions on comorbidity and quality of life to subjects with CFH and subjects with infrequent headache (IH) (1-4 days/month). We recoded comorbidity by using the Cumulative Illness Rating Scale (CIRS) and measured quality of life with the RAND-36, a Dutch version of Short Form-36. CFH subjects (n = 176) had higher comorbidity scores than the IH subjects (n = 141). Mean CIRS scores were 2.94 for CFH and 1.55 for IH [mean difference 1.40, 95% confidence interval (CI) 0.91, 1.89]. The mean number of categories selected was 1.92 in CFH and 1.10 in IH (mean difference 0.82, 95% CI 0.54, 1.11). Fifty percent of CFH subjects had a comorbidity severity level of at least 2, indicating disorders requiring daily medication, compared with 28% of IH subjects (mean difference 22%, 95% CI 12, 33). CFH subjects had more musculoskeletal, gastrointestinal, psychiatric and endocrine/breast pathology than IH subjects. Quality of life in CFH subjects was lower than that of IH subjects in all domains of the RAND-36. Both headache frequency and CIRS score had a negative influence on all domains. We conclude that patients with CFH have more comorbid disorders than patients with infrequent headaches. Many CFH patients have a comorbid chronic condition requiring daily medication. Both high headache frequency and comorbidity contribute to the low quality of life in these patients.     

Die atypische Odontalgie – ein wenig bekannter Phantomschmerz

BACKGROUND: Atypical odontalgia (AO) was described in the dental literature more than 200 years ago, and it is included in most taxonomies and textbooks of pain. Nonetheless, it remains one of the most frequently misdiagnosed intraoral pain conditions. TERMINOLOGY: Due to similarities with phantom pain, AO is also referred to as "phantom tooth pain". CLINICAL FEATURES: AO is characterized by persistent throbbing pain in or around a former or present permanent tooth (preferably molars and premolars). Clinical and radiographic examination, however, does not reveal any organic cause of the pain. The complaints associated with AO usually begin after deafferentiation of primary afferent trigeminal nerve fibers, e. g., after pulp extirpation, apicectomy, or extraction of a tooth. DIAGNOSIS: AO is a diagnosis by exclusion. MANAGEMENT: Patients and dentists must be aware of the fact that the therapeutic options are limited. AO is primarily managed with topically or systemically administered pharmacological agents. Unnecessary and harmful procedures around teeth and jaws must be avoided by all means. OUTLOOK: A concept was recently proposed which aims to unify a group of four types of orofacial pain under the term "idiopathic orofacial pain" (Woda & Pionchon 1999, 2000). These pain conditions - AO, atypical facial pain, burning mouth syndrome ("stomatodynia"), and subgroups of temporomandibular disorders ("idiopathic facial arthromyalgia") - are characterized by unknown etiology, but common clinical characteristics. It is to be hoped that the suggested classification will stimulate reflection on these enigmatic orofacial pain disorders.     

Headache and temporomandibular disorders: evidence for diagnostic and behavioural overlap

To assess the diagnostic and behavioural overlap of headache patients with temporomandibular disorders (TMD), individuals recruited from the general population with self-described headaches were compared with non-headache controls. The examination and diagnostic procedures in the Research Diagnostic Criteria (RDC) for TMD were applied to both sets of subjects by a blinded examiner. Following their examination, subjects used experience sampling methods to obtain data on pain, tooth contact, masticatory muscle tension, emotional states and stress. Results showed that a significantly higher proportion of the headache patients received an RDC/TMD diagnosis of myofascial pain than non-headache controls. Headache patients also reported significantly more frequent and intense tooth contact, more masticatory muscle tension, more stress and more pain in the face/head and other parts of the body than non-headache controls. These results are similar to those reported for TMD patients and they suggest that headache patients and TMD patients overlap considerably in diagnosis and oral parafunctional behaviours.     

Tooth pulp-driven neurons in somatosensory cortex of primates: Role in pain mechanisms including a review of the literature

The tooth pulp of primates was stimulated electrically while searching for evoked unit potentials in the cerebral cortex. Control procedures were employed to assure that the electrical stimuli reached only tooth pulp fibers but no extrapulpal sensory fibers. In addition, an electrode was inserted in soft tissue surrounding the tooth for separate excitation of extrapulpal axons. A tooth pulp projection area was identified in the “face area” of primary somatosensory cortex. Two major neuron groups were encountered, one excited only by the extrapulpal soft tissue stimulus, the other by tooth pulp stimuli. Within the pulp-projection area, soft tissue-driven neurons were most numerous in superficial cortex of the postcentral gyrus, pulp-driven neurons dominated in deep cortex in the base of the central sulcus. The pulp-driven population divided into several functional subsets: those excited from one pulp only (conceivably capable of localizing pulpal stimuli), those excited from more than one pulp and those excited from both pulp and extrapulpal soft tissue. Within each of these 3 pulp-driven subsets, some units responded to single shock, others only to a train of shocks. Mean discharge latency was shortest for the population excited only from soft tissue, intermediate for pulp-driven units excited by single shock and longest for pulp-driven units excited only by trains of shocks. Both soft tissue and pulp stimuli evoked extensive inhibitory effects.In the Discussion, the possible role of pulp-driven neurons in pain is considered. The functional properties of some neurons are consistent with a role in stimulus localization but those of the remaining neurons suggest other roles in pain. An examination of the literature on cortex and pain suggests that normally somatosensory cortex is important for localizing painful stimuli and that it contributes to other pain mechanisms as well. After certain lesions, somatosensory cortex has the capacity for generating “central” pain just like other structures in the nociceptive pathway.     

Unmasking Latent Dysnociception in Healthy Subjects

SYNOPSIS
Headache is the most common side effect of nitroglycerin, administered for angina pectoris. Two phases can be distinguished in nitroglycerin-induced headache: the first phase (immediate headache), a mild sensation of temporal pulsating pain, can be due, at least in part, to the vasodilation provoked by nitroglycerin; the second phase (delayed headache), an increasing pain, possibly with nausea and vomiting, lasting even for a number of hours, is independent from the vasomotility, since it arises and persists when all vasomotor and metabolic nitroglycerin-induced changes are over. The present investigation demonstrates that healthy subjects, neither suffering from idiopathic headache nor with a family headache history, never complain of delayed headache after nitroglycerin ; healthy subjects not suffering from headache but who have one or both parents suffering from migraine, exhibit the delayed long-lasting headache in 28.6% of cases; finally, 66.7% of their migrainous parents complain of the delayed long-lasting headache after nitroglycerin. The following conclusions can be drawn: nitroglycerin-induced delayed headache 1) is not a true side effect of nitroglycerin, since it is never present in healthy subjects; 2) is peculiar to migraine sufferers: or 3) is an index of migraine predisposition, as it may be present in healthy subjects, but only if they have one or two migrainous parents. The features of nitroglycerin-induced delayed headache suggest an analogy with the phenomenon of overreaction, a painful and exaggerated response (in latency, intensity and duration) to a stimulus, that is the most typical aspect of central pain. In nitroglycerin-induced delayed headache, which shows close similarities to the spontaneous attack of migraine, the trigger stimulus could be the moderate immediate headache which is probably correlated with the vasodilation provoked by nitroglycerin.     

Frequency of headache is related to sensitization: a population study

Central sensitization is thought to play an important role in the chronification of tension-type headache and in the maintenance and exacerbation of the migraine attack. It has, however, almost exclusively been studied in highly selected patients from headache clinics. The aim of the present study was to evaluate pain perception in primary headaches in the general population. Stimulus-response functions for pressure versus pain, tenderness and pressure pain thresholds were studied in a random sample of 523 adults from the general population. All results were controlled for the effects of age and gender. The area under the stimulus-response function was increased in chronic- and frequent episodic tension-type headache compared with subjects without headache (p<0.001, p<0.001) and in chronic tension-type headache compared with migraine (p=0.01). Increasing slope (p<0.0001) and displacement towards lower pressures was found in the following order: no headache, migraine, frequent episodic tension-type headache, chronic tension-type headache. The displacement of the stimulus-response function was closely associated with frequency of headache. Finally, the stimulus-response function tended to be qualitatively altered in patients with frequent headache. The findings demonstrate, for the first time in a population-based study, a close relation between altered pain perception and chronification of headache, which most likely can be explained by central sensitization.     

Pathophysiological mechanisms of tension-type headache: a review of epidemiological and experimental studies

In this present thesis I have discussed the epidemiology and possible pathophysiological mechanisms of tension-type headache. A population-based study of 1000 subjects randomly selected from a general population, two clinical studies, and a method study of EMG recordings, were conducted. Tension-type headache was the most prevalent form of headache, with a life-time prevalence of 78% in a general adult population. Thirty percent were affected more than 14 days per year and 3% were chronically affected, i.e. had headache at least every other day. Females were more frequently affected than males, and young subjects more frequently affected than older subjects. Females were more sensitive to mechanical pressure pain and revealed more tenderness from pericranial muscles and tendon insertions than males, and young subjects were more pain-sensitive than older subjects. Significantly higher tenderness in pericranial muscles was found in subjects with tension-type headache compared to migraineurs and to subjects without any experience of headache. Tenderness increased significantly with increasing frequency of tension-type headache in both males and females, whereas no such relation was found for mechanical pain thresholds. The applied EMG methodology was fairly reliable and nonpainful, but due to intersubject variability paired studies should be preferred. Subjects with chronic tension-type headache had slightly increased EMG levels during resting conditions and decreased levels during maximal voluntary contraction compared with headache-free subjects, indicating insufficient relaxation at rest and impaired recruitment at maximal activity. In a subsequent clinical, controlled study, the effect of 30 min of sustained tooth clenching was studied. Within 24 h, 69% of patients and 17% of controls developed a tension-type headache. Shortly after clenching, tenderness was increased in the group who subsequently developed headache, whereas tenderness was stable in the group of patients who remained headache-free, indicating that tenderness might be a causative factor of the headache. Likewise, psychophysical and EMG parameters were studied in 28 patients with tension-type headache, both during and outside of a spontaneous episode of tension-type headache. It was concluded that a peripheral mechanism of tension-type headache is most likely in the episodic subform, whereas a secondary, segmental central sensitization and/or an impaired supraspinal modulation of incoming stimuli seems to be involved in subjects with chronic tension-type headache. Prolonged nociceptive stimuli from myofascial tissue may be of importance for the conversion of episodic into chronic tension-type headache. The author emphasizes that tension-type headache is a multifactorial disorder with several concurrent pathophysiological mechanisms, and that extracranial myofascial nociception may constitute only one of them. The present thesis supplements the understanding of the balance between peripheral and central components in tension-type headache, and thereby, hopefully, leads us to a better prevention and treatment of the most prevalent type of headache.     

Recurrent headache and migraine as a public health problem--a population-based study in Sweden

OBJECTIVE: To study the prevalence of recurrent headache and/or self-considered migraine (RH/M) and its association with self-rated health, other symptoms, and use of health care and medication in the general population. METHODS: The study comprised a random population sample of 43,770 men and women aged 18 to 79 years covering an area of 58 municipalities in Sweden. The data were obtained using a postal survey questionnaire during March to May 2000. The overall response rate was 65%. RESULTS: The overall prevalence of self-reported RH/M was 10% among men and 23% among women. RH was more common (15%) than migraine (4%). The prevalence of RH was highest in the younger age groups (18 to 34 years) and decreased with increasing age. The prevalence of migraine was highest (6%) among 35 to 49 years old. Subjects with RH/M had poorer self-rated health compared to subjects with no reported headache independent of age. Poor self-rated health was most common among subjects with both RH and M. Musculoskeletal pain and psychosomatic symptoms were more common among those with RH/M. The association between RH/M and poor self-rated health was partly explained by these symptoms. Those with RH/M utilized more health care at all levels than those with no RH/M. In addition, subjects with RH/M reported two to three times more often that they had been in need of medical care but not sought it. About two-thirds of the subjects with RH/M had used analgesic during the last 2 weeks compared with less than one-third among subjects with no RH/M. CONCLUSION: RH/M constitutes a substantial public health problem that mainly affects young and middle aged adults. It is associated with poor self-rated health, musculoskeletal and psychosomatic symptoms, increased use of health care and medication as well as unmet needs of health care.     

上尖牙拔髓术中阿替卡因与利多卡因局部麻醉效果比较

目的：比较阿替卡因与利多卡因在上尖牙拔髓术中的局部麻醉效果。方法：共纳入94例患者,共102颗需在局部麻醉下进行根管治疗的活髓上尖牙。所有患者随机分为阿替卡因组和利多卡因组,分别用阿替卡因或利多卡因进行粘膜下浸润麻醉。对两组患者在麻醉注射时、拔髓时的疼痛程度以及麻醉持续时间进行分析比较。结果：阿替卡因组局部浸润麻醉时注射疼痛明显小于利多卡因组,拔髓时疼痛程度明显小于利多卡因组,两组差异有统计学意义（P〈0.05）;阿替卡因组麻醉维持时间显著长于利多卡因组（P〈0.05）。结论：阿替卡因局部渗透力强,起效快,维持时间长,效果明显优于利多卡因。     

Increased muscle pain sensitivity in patients with tension-type headache

Nociceptive mechanisms in tension-type headache are poorly understood. The aim was to investigate the pain sensitivity of pericranial muscles and a limb muscle in patients with tension-type headache. Experimental muscle pain was induced by standardized infusions of 0.5 ml of 1 M hypertonic saline into two craniofacial muscles (anterior temporalis (TPA) and masseter (MAS)) and a limb muscle (anterior tibial (TA)) in 24 frequent episodic tension-type headache patients (FETTH), 22 chronic tension-type headache patients (CTTH) and 26 age and gender matched healthy subjects. Headache patients were examined twice, both on days with and on days without headache. The pressure pain thresholds (PPTs) were determined before and after infusions. The subjects continuously reported intensity of saline-induced pain on an electronic visual analogue scale (VAS) and the perceived area of pain was drawn on anatomical maps. Headache patients demonstrated significantly lower PPTs, higher saline-evoked VAS pain scores and greater pain areas than healthy subjects at all the tested muscle sites (P<0.05). There was a significant gender difference for the PPTs in all three groups of participants (P<0.05) and for VAS pain scores in the CTTH patients (P<0.05). There was no difference in pain sensitivity between FETTH and CTTH or between patients with or without headache. In conclusion, the present study demonstrates the presence of generalized pain hypersensitivity both in FETTH and CTTH compared to controls which is unrelated to actual headache status and extends to include responses to longer-lasting stimuli which are clinically highly relevant. Gender differences in deep pain sensitivity seem to be a consistent finding both in healthy controls and patients with tension-type headache.     

Phantom eye: features and prevalence. The predisposing role of headache

We prospectively evaluated the frequency, time-course and predisposing factors of phantom eye syndrome in 53 patients who underwent surgical eye amputation to cure ocular cancer. Before surgery, patients were classified as Group 1 (n=25) if they had no history of headache or Group II (n=28) if they were headache sufferers. Three clinical patterns were distinguished: phantom pain, non-painful phantom phenomena and photopsias. Their symptoms developed 7 days to 6 months after surgery, with peak incidence after 6 months (photopsia 43%; phantom pain 28%; non-painful phantom phenomena 62%). Phantom eye syndrome was more common in headache sufferers than in non-headache subjects. Headache sufferers were more prone to phantom pain, but more so to non-painful phenomena and photopsias. These findings are in accord with our previous results indicating that prima y headache sufferers are prone to phantom tooth pain.     

The Role of Personality in the Etiology of Chronic Headache

SYNOPSIS
Whether a neurotic personality is a precursor to or a consequence of the experience of living with chronic pain has been a topic of much heated debate in the psychosomatic research literature. To investigate this question, 151 chronic headache sufferers from three headache types (migraine, tension, combined), matched on age and gender, were divided into three equal groups on the basis of their percentage of life with headache. Each headache sufferer was administered a comprehensive battery of psychological tests. ANCOVAs, using age as the covariate and diagnosis and %-life groupings as the between subjects factors, were then performed on the clinical scale data. Results indicated no significant differences greater than that expected by chance among the %-life groups, indicating that the percentage of life one spends with head pain has no differential effect on a number of psychological test measures. One interpretation of the above results is that the characterological personality traits so often found in headache sufferers are not a result of the pain experience but in fact were present before the pain problem started.     

Catastrophizing and pain-coping in young adults: associations with depressive symptoms and headache pain.

Cognitive and behavioral pain-coping strategies, particularly catastrophizing, are important determinants of the pain experience. Most studies of pain-coping are performed in samples of treatment-seeking patients with longstanding pain complaints. Individual differences in pain-coping styles may also significantly affect day-to-day pain and quality of life in nonclinical samples, though this has rarely been investigated. In particular, headache pain is common in the general population, and little is known about how pain-related coping affects pain and quality of life among headache sufferers from a nonclinical setting. In this study, 202 generally healthy subjects were divided into 2 groups, those who reported problem headaches and pain-free control subjects. Reports of pain-related catastrophizing and the use of active pain-coping strategies did not differ between the groups, but differential associations between pain-coping strategies and emotional functioning were observed. Specifically, within the headache group only, those reporting higher levels of pain catastrophizing and lower levels of active pain-coping showed the highest level of depressive symptoms. Further, higher catastrophizing was associated with greater headache pain and pain-related interference. These findings suggest that catastrophizing has little influence on emotional functioning in those without ongoing pain complaints and highlight the importance of coping in modulating the consequences of pain on day-to-day functioning, even in samples from nonclinical settings. Moreover, these findings indirectly suggest that interventions that increase adaptive coping and decrease catastrophizing may help to buffer some of the deleterious functional consequences of headache pain. PERSPECTIVE: This study adds to a growing literature that conceptualizes catastrophizing as a diathesis, or risk factor, for deleterious pain-related consequences. These data suggest that catastrophizing may require the presence of a pain condition before its detrimental effects are exerted.     

EDTA-dependent pseudothrombocytopaenia: a 12-month epidemiological study

The phenomenon of in vitro platelet clumping and consequent pseudothrombocytopaenia in the presence of EDTA has been studied in 33,623 subjects referring to a general hospital in a 1-year period. The observed frequency was 0.13%. EDTA-dependent pseudothrombocytopaenia (PTP) was suspected when a routine blood counting by the Coulter S-Plus IV/D showed a peculiar leucocyte histogram and pseudoleucocytosis. Confirmation was obtained by the manual count and by the finding of platelet aggregates in a stained blood smear. EDTA-dependent PTP was diagnosed when the platelet number and the morphological examination of blood anticoagulated with sodium citrate from the same patient were normal. EDTA-dependent PTP was found in 23 subjects aged from 19 to 79 years (0.068% of the study population): 17 were patients suffering from miscellaneous diseases, while six were apparently healthy. As a rule, platelet clumping was evident within 60 minutes from blood collection, but a longer latency (2-3 h) was observed in a few cases. EDTA-dependent PTP is a rare, but misleading phenomenon, the recognition of which is important in order to avoid expensive and potentially harmful procedures.     

The insulin tolerance test and ovine corticotrophin-releasing-hormone test in episodic cluster headache II: comparison with low back pain patients

Hypothalamic involvement has been invoked to explain the periodicity of the cluster periods and rhythmicity of the pain attacks in cluster headache. To explore this hypothesis the ovine corticotrophin-releasing hormone (o-CRH) and the insulin tolerance test were administered to a group of episodic cluster headache sufferers during both cluster period and remission. A group of low back pain patients and healthy subjects comprised the control populations. For the o-CRH test, 7 healthy subjects, 7 low back pain patients, 6 cluster headache patients in remission, and 12 in cluster period were studied. Five healthy subjects, 7 low back pain patients, 6 cluster headache patients in remission, and 9 in cluster period were administered the insulin tolerance test. Significantly increased basal cortisol levels were found in cluster headache patients in both illness phases ( p < 0.0001), but not in low back pain patients. Significantly reduced cortisol response to the o-CRH test was observed in cluster headache patients in both phases compared to healthy controls ( p < 0.02.). A blunted ACTH and cortisol response ( p < 0.0001 and p < 0.003 respectively) to the insulin tolerance test was present in cluster headache patients in both phases of the illness compared to healthy subjects and low back pain patients. On the contrary, the ACTH surge after insulin induced hypoglycemia was significantly increased in the low back pain patient group ( p = 0.02). These results suggest that the altered hypothalamic-pituitary-adrenal axis responsiveness in cluster headache patients is not a consequence of the pain, and point to a central, probably hypothalamic derangement in this pathology.     

Increased prevalence of tension-type headache over a 12-year period is related to increased pain sensitivity. A population study

We recently reported an increase in prevalence and frequency of tension-type headache (TTH) over a 12-year period in the young Danish population. The aim of the present study was to analyse whether this increase was related to increased pain sensitivity. The study was a cross-sectional replicate of a large Danish population study. It compared 113 subjects aged 25-36 years in 2001, with 221 comparable subjects in 1989. Tenderness was considerably higher in 2001 than in 1989. When stratified according to presence of headache, the increase in tenderness was clinically and statistically significant only in women with frequent TTH. The pressure pain threshold was significantly lower in 2001 compared with 1989 in women with frequent TTH. The increase in tenderness in the population may predict an even higher prevalence of TTH in future. The changes support the hypothesis of central sensitization in TTH.     

A randomized controlled trial of tai chi for tension headaches

This study examined whether a traditional low-impact mind–bodyexercise, Tai Chi, affects health-related quality-of-life (HRQOL)and headache impact in an adult population suffering from tension-typeheadaches. Forty-seven participants were randomly assigned toeither a 15 week intervention program of Tai Chi instructionor a wait-list control group. HRQOL (SF-36v2) and headache status(HIT-6^TM) were obtained at baseline and at 5, 10 and 15 weekspost-baseline during the intervention period. Statisticallysignificant (P < 0.05) improvements in favor of the interventionwere present for the HIT score and the SF-36 pain, energy/fatigue,social functioning, emotional well-being and mental health summaryscores. A 15 week intervention of Tai Chi practice was effectivein reducing headache impact and also effective in improvingperceptions of some aspects of physical and mental health.     

Do Certain Headache Syndromes Occur in "Pain-Prone" Patients?

SYNOPSIS
To clarify the actual components of headache syndromes and their possible association with other types of pain and psychological traits, 177 patients subject to severe intermittent headaches were studied. Data used were derived from (a) a de tailed headache questionnaire, (b) a second questionnaire concerning the occurrence of other pain and of feelings of good or ill health, (c) the Cornell Medical Index. A stepwise regression analysis was run for each headache characteristic using data from the pain questionnaire and the Cornell Medical Index as independent variables. Interesting associations of variables were (1) increased frequency of headache with male sex and increased duration of headache with female, (2) inability to carry on work load during headache, headache preceded by spots before the eyes, weakness of arm or leg preceding headache were all positively associated with history of fainting. Neither vomiting with headache, nor unilaterality of pain was associated with any other pain variables. Also of note was the fact that there was no evidence by testing of increased psychological disturbance in patients with back pain. The results suggest that the "tension headache-neurosis" concept is dubious, that autonomic instability as evidenced by fainting is indeed important in some headache syndromes, and that new headache syndromes need to be defined.     

Population-based validation of a German-language self-administered headache questionnaire

We validated a German-language self-administered headache questionnaire for migraine (M), tension-type headache (TTH) and trigeminal autonomic cephalalgia (TAC) in a general population sample of people with headache. Randomly selected subjects ( n  = 240) diagnosed by the questionnaire as M ( n  = 60), TTH ( n  = 60), a combination of M and TTH (M+TTH, n  = 60) and TAC ( n  = 60) were invited for examination by headache specialists. One hundred and ninety-three subjects (80%) were studied. Sensitivity and specificity for M were 0.85 and 0.85, for TTH 0.6 and 0.88, for M+TTH 0.82 and 0.87, respectively. Cohen's κ was 0.6 (95% confidence interval 0.50, 0.71). Of 45 patients with TAC according to the questionnaire, physicians diagnosed cluster headache in two patients only. We conclude: (i) the questionnaire can be used to diagnose M, TTH and M+TTH, but not TAC; (ii) screening questionnaires for epidemiological research should be validated in a general population sample but not in a tertiary headache clinic.     

Headache characteristics during the development of tolerance to nitrates: pathophysiological implications

Recent studies suggest that nitric oxide (NO) plays an important role in nitrate-induced headache and in spontaneous migraine attacks. Organic nitrates act as prodrugs for NO and headache is a predominant adverse effect of nitrates but often disappears during continuous treatment. Insight into tolerance to headache could lead to insight into vascular headache mechanisms in general. The specific aim of the present study was therefore to characterize the headache and accompanying symptoms during continuous nitrate administration until a state of tolerance to headache had developed. 5-isosorbide-mononitrate (5-ISMN) 30 mg three times daily was administered orally for 7 days in 11 healthy subjects in a double-blind, randomized placebo controlled cross-over design. Wash-out between periods was 14 days or more. Haemodynamic data from the present study were compared to the observed changes of headache over time. Headache during 5-ISMN was longer lasting and more severe compared to placebo (P<0.004). In 10 subjects the headache fulfilled the pain sub-criteria for migraine and in five subjects all diagnostic criteria for migraine without aura were fulfilled. Conversely, 20 min of intravenous infusion of glyceryl trinitrate caused a milder headache and no migraine. The present results therefore suggest that NO may elicit a migraine attack in many healthy subjects if a high enough dose is given for several hours. A close temporal association between the disappearance of headache and the attenuation of the 5-ISMN induced dilatation of the superficial temporal artery was observed. In contrast, tolerance in the middle cerebral artery already appeared after 24 h, which was earlier than the development of tolerance to headache. If vasodilatation is the cause of headache the results point to extracerebral arteries. However, cytotoxic and pain modulating central nervous system effects of NO, the time courses of which are unknown, may also play a role, involving both intra- and extracranial arteries.