The International Classification of Headache Disorders: History and future perspectives.

PURPOSE: The International Classification of Headache Disorders (ICHD) is universally accepted and forms the basis of headache management and clinical, experimental and pharmacological headache research. The present review summarizes the history of the three different editions of the classification, concentrating on aspects of general interest that are still valid today. METHODS: The article is based on the memory of the chairperson of three editions of the International Classification and on his notes in the work copies and published scientific classification studies. RESULTS: Many of the crucial issues in headache classification are discussed in the review of the different editions. Some have been resolved and some remain unresolved. The 11th edition of the World Health Organization's International Classification of Diseases (ICD) has been developed in close contact with the International Headache Society classification committee and is in fact an abbreviated version of ICHD-3. The principles of the ICHD have also been used by the International Association for Study of Pain in developing a pain classification now included in ICD-11. The many points of discussion of each of the three editions are still relevant for headache experts and all those who care for headache patients. CONCLUSION: Headache classification is a living and developing discipline of research. Here, the gradual expansion and refinement of the classification through 3 different editions are discussed with a view to present day relevance.

Mechanisms of GTN-induced migraine: Role of NOS isoforms, sGC and peroxynitrite in a migraine relevant mouse model.

BACKGROUND: Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon. METHODS: Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an in vivo mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (Ntotal = 312). RESULTS: Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase. CONCLUSIONS: Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.

Molecular nociceptive mechanisms in migraine: The migraine cascade.

OBJECTIVE: This review will explore the categorization of migraine-provoking molecules, their cellular actions, site of action and potential drug targets based on the migraine cascade model. METHODS: Personal experience and literature. RESULTS: Migraine impacts over 1 billion people worldwide but is underfunded in research. Recent progress, particularly through the human and animal provocation model, has deepened our understanding of its mechanisms. This model have identified endogenous neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) that induces controlled migraine-like attacks leading to significant discoveries of their role in migraine. This knowledge led to the development of CGRP-inhibiting drugs; a groundbreaking migraine treatment now accessible globally. Also a PACAP-inhibiting drug was effective in a recent phase II trial. Notably, rodent studies have shed light on pain pathways and the mechanisms of various migraine-inducing substances identifying novel drug targets. This is primarily done by using selective inhibitors that target specific signaling pathways of the known migraine triggers leading to the hypothesized cellular cascade model of migraine. CONCLUSION: The model of migraine presents numerous opportunities for innovative drug development. The future of new migraine treatments is limited only by the investment from pharmaceutical companies.

No association between migraine and HLA alleles in a cohort of 13,210 individuals with migraine from the Danish Blood Donor Study.

OBJECTIVE: To determine the association between human leukocyte antigen (HLA) alleles and migraine, migraine subtypes, and sex-specific factors. BACKGROUND: It has long been hypothesized that inflammation contributes to migraine pathophysiology. This study examined the association between migraine and alleles in the HLA system, a key player in immune response and genetic diversity. METHODS: We performed a case-control study and included 13,210 individuals with migraine and 86,738 controls. All participants were part of the Danish Blood Donor Study Genomic Cohort. Participants were genotyped and 111 HLA alleles on 15 HLA genes were imputed. We examined the association between HLA alleles and migraine subtypes, considering sex-specific differences. RESULTS: We found no association between HLA alleles and migraine, neither overall, nor in the sex-specific analysis. In the migraine subtype analysis, three HLA alleles were associated with migraine without aura; however, these associations could not be replicated in an independent Icelandic cohort (2191 individuals with migraine without aura and 278,858 controls). Furthermore, we found no association between HLA alleles and migraine with aura or chronic migraine. CONCLUSION: We found no evidence of an association between the HLA system and migraine, suggesting that genetic factors related to the HLA system do not play a significant role in migraine susceptibility.

Provocation of attacks to discover migraine signaling mechanisms and new drug targets: early history and future perspectives - a narrative review.

INTRODUCTION: The development of several experimental migraine provocation models has significantly contributed to an understanding of the signaling mechanisms of migraine. The early history of this development and a view to the future are presented as viewed by the inventor of the models. METHODS: Extensive knowledge of the literature was supplemented by scrutiny of reference lists. RESULTS: Early studies used methodologies that were not blinded. They suggested that histamine and nitroglycerin (Glyceryl trinitrate, GTN) could induce headache and perhaps migraine. The development of a double blind, placebo-controlled model, and the use of explicit diagnostic criteria for induced migraine was a major step forward. GTN, donor of nitric oxide (NO), induced headache in people with- and without migraine as well as delayed migraine attacks in those with migraine. Calcitonin gene-related peptide (CGRP) did the same, supporting the development of CGRP antagonists now widely used in patients. Likewise, pituitary adenylate cyclase activating peptide (PACAP) provoked headache and migraine. Recently a PACAP antibody has shown anti migraine activity in a phase 2 trial. Increase of second messengers activated by NO, CGRP and PACAP effectively induced migraine. The experimental models have also been used in other types of headaches and have been combined with imaging and biochemical studies. They have also been used for drug testing and in genetic studies. CONCLUSION: Conclusion. Human migraine provocation models have informed about signaling mechanisms of migraine leading to new drugs and drug targets. Future use of these models in imaging-, biochemistry- and genetic studies as well as in the further study of animal models is promising.

VPAC1 and VPAC2 receptors mediate tactile hindpaw hypersensitivity and carotid artery dilatation induced by PACAP38 in a migraine relevant mouse model.

BACKGROUND: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.

The World Health Organization Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders and the headache revolution: from headache burden to a global action plan for headache disorders.

The World Health Organization (WHO) Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders was developed by WHO to address the worldwide challenges and gaps in provision of care and services for people with epilepsy and other neurological disorders and to ensure a comprehensive, coordinated response across sectors to the burden of neurologic diseases and to promote brain health across life-course. Headache disorders constitute the second most burdensome of all neurological diseases after stroke, but the first if young and midlife adults are taken into account. Despite the availability of a range of treatments, disability associated with headache disorders, and with migraine, remains very high. In addition, there are inequalities between high-income and low and middle income countries in access to medical care. In line with several brain health initiatives following the WHOiGAP resolution, herein we tailor the main pillars of the action plan to headache disorders: (1) raising policy prioritization and strengthen governance; (2) providing effective, timely and responsive diagnosis, treatment and care; (3) implementing strategies for promotion and prevention; (4) fostering research and innovation and strengthen information systems. Specific targets for future policy actions are proposed. The Global Action Plan triggered a revolution in neurology, not only by increasing public awareness of brain disorders and brain health but also by boosting the number of neurologists in training, raising research funding and making neurology a public health priority for policy makers. Reducing the burden of headache disorders will not only improve the quality of life and wellbeing of people with headache but also reduce the burden of neurological disorders increasing global brain health and, thus, global population health.

Role of PACAP in migraine: An alternative to CGRP?

Migraine is a widespread and debilitating neurological condition affecting more than a billion people worldwide. Thus, more effective migraine therapies are highly needed. In the last decade, two endogenous neuropeptides, calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP), were identified to be implicated in migraine. Recently, introduction of monoclonal antibodies (mAbs) blocking the CGRP is the most important advance in migraine therapy for decades. However, 40% of patients are unresponsive to these new drugs. We believe that PACAP may be involved in these patients. Like CGRP, PACAP is located to sensory nerve fibers, it dilates cranial arteries, it causes migraine when infused into patients and it is a peptide that lends itself to antibody therapy. Also, recent studies suggest that the PACAP pathway is independent of the CGRP pathway. Understanding the signaling pathways of PACAP may therefore lead to identification of novel therapeutic targets of particular interest in patients unresponsive to anti-CGRP therapy. Accordingly, neutralizing mAb to PACAP is currently in clinical phase II development. The aim of the present review is, therefore, to give a thorough account of the existing data on PACAP, its receptors and its relation to migraine.

The Global Campaign Against Headache and its future relation to IHS and WHO.

BACKGROUND: Preparations for the Global Campaign Against Headache done jointly with WHO started almost 25 years ago. It was officially incorporated 18 years ago. It is the story of a few dedicated individuals who, together with the World Health Organization, generated epidemiological data all over the world and made use of these data to gradually increase the position of headache disorders, until migraine became number two among all causes of years lost to disability. It is also the story of impressive development of scientific tools, their validation and use in low-income countries. METHODS: Models of care for headache patients were developed that are adaptable and hence can be implemented in future throughout the world. RESULTS: The last phase of the campaign shall use the impressive data set generated to cause real improvement in the healthcare for people with headache throughout the world. The recent World Health Organization initiative: Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders invites international organizations to collaborate, and headache is mentioned. CONCLUSION: This calls for the International Headache Society and all its national members and all other organizations involved in headache to work together with Lifting the Burden, the organization in charge of the Global Campaign Against Headache.

Proposed general diagnostic criteria for secondary headaches.

BACKGROUND: The distinction between a pre-existing primary headache and a secondary headache at the onset of a disorder is important and has not been taken into account in the International Classification of Headache Disorders-3. This study aimed to improve the general diagnostic criteria for secondary headaches using results of our previous studies. MATERIALS AND METHODS: We analyzed characteristics of headaches including their changes in intensity, duration, frequency, localization and side, development of new accompanying symptoms, and therapeutic response at the onset of transient ischemic attacks (TIA) (n = 120, mean age 56.1, 55% females) and ischemic stroke (n = 550, mean age 63.1, 56% females) compared to the control group (n = 192, mean age 58.7, 64% females). RESULTS: Headache of a new type occurred in 8.4% of ischemic stroke patients and 5% of TIA patients on the day of admission but did not occur at all in the control group. Pre-existing headache with a change of at least one characteristic occurred significantly more often in stroke (5.4%) and TIA (7.5%) than in the control group (1%) (p = 0.01 and p = 0.003 respectively). CONCLUSION: The presence of a new type of headache and a pre-existing headache with altered characteristics in close temporal relation to a disorder indicates causality. Based on these data we propose revised general diagnostic criteria for secondary headaches.

Evaluation of the ICHD-3 diagnostic criteria for cardiac cephalalgia and new proposal.

BACKGROUND: The current International Classification of Headache Disorders, 3rd edition (ICHD-3) diagnostic criteria for cardiac cephalalgia were established according to previous case reports and the opinion of experts. We aimed to assess the ICHD-3 diagnostic criteria for cardiac cephalalgia. METHODS: We conducted a series of cases study and evaluated these criteria in 54 patients with cardiac cephalalgia. Next, we assessed whether the ICHD-3 diagnostic criteria B, C and D for migraine without aura were fulfilled by these patients. RESULTS: ICHD-3 criteria A, B, C1, C2 and D for cardiac cephalalgia were met by 100% of patients, whereas criterion C3 was fulfilled by 81.5%. The least frequently fulfilled sub-criterion was C3b (accompanied by nausea) (18.5%). Moreover, we found that ICHD-3 criteria B, C and D for migraine without aura were met by a low proportion of patients: 11.1%, 46.3% and 25.9%, respectively, and no patient fulfilled the three criteria simultaneously. CONCLUSION: Based on our results, we propose revised diagnostic criteria for cardiac cephalalgia. We suggest removing criterion C3 and C4. We also suggest removing the word "migraine-like" from its description.

Prevalence, clinical characteristics and associated factors of cardiac cephalalgia: A prospective study.

BACKGROUND: The prevalence of cardiac cephalalgia is unknown and there is limited information about its clinical features. We aimed to assess the prevalence of cardiac cephalalgia, its clinical characteristics and associated factors. METHODS: We conducted a prospective study of patients with suspected acute coronary syndrome admitted to the Cardiology Service at Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain, over a one-year period. We interviewed patients within the first 24 hours of admission using a standardized case-report form to assess the presence of headache in relation to the acute coronary syndrome and its characteristics. RESULTS: We included 438 patients, 381 with confirmed myocardial ischemia. Prevalence of cardiac cephalalgia was 14.2% (n = 54). The most common features were frontal location, pressing quality and moderate intensity. Pain referred to the jaws (aOR 2.61; 95% CI 1.33-5.12; p = 0.005), palpitations (aOR 3.65; 95% CI 1.57-8.50; p = 0.003) and circumflex coronary artery as the culprit artery for the myocardial ischemia (aOR 3.8; 95% CI 1.07-13.74; p = 0.021) were related to cardiac whereas history of hypertension was inversely associated (aOR 0.37: 95% CI 0.18-0.74; p = 0.005). CONCLUSION: The prevalence of cardiac cephalalgia was 14.2%. Our study provides valuable information about cardiac cephalalgia characteristics that suggest revision of current diagnostic criteria.

From fragmentation to collaboration in European brain research: The early history of the European Brain Council (EBC), an organization that changed our perspective of advocacy.

BACKGROUND: The European Academy of Neurology (EAN) is a member of the European Brain Council (EBC), a coalition of neurologists, psychiatrists, neurosurgeons, neuroscientists, patient organizations and industry with an interest in the brain and its diseases. It was founded by the present author. Here, its formation, early history and the results of its advocacy are described. METHOD: Eyewitness report and relevant literature were considered. RESULTS: After a long and difficult inception, the European Brain Council (EBC) brought all major players with an interest in the brain and its diseases to work closely together. Important data on the cost of brain diseases, lack of funding and fantastic research possibilities were generated and effectively used in advocacy. During the early years of the collaborative effort, the funding of brain research increased from €85 million in framework program (FP) 5 to €260 million in FP6 and to more than €2000 million in FP7. CONCLUSION: The EBC has been extremely successful. It is essential that advocacy in the European Union continues to be united so that those involved in brain research are able to speak with one voice to policy makers. An even bigger task, still insufficiently pursued, is for national brain councils to achieve prioritization of brain research in their national political agenda to bring about improved provision of care to those living with a brain disease.

European Federation of Neurological Societies: parent to the European Academy of Neurology.

BACKGROUND AND PURPOSE: The European Academy of Neurology (EAN) is a vigorous organization of great importance for all neurologists and for our patients. But how did neurology get organized at the European level? That is the topic of this article. METHODS: Most important sources are memories and documents of the author, who was a moving force in developing the European Federation of Neurological Societies (EFNS), one of the two parents of the EAN. RESULTS: All European national neurological societies and the World Federation of Neurology were involved in a difficult political interaction resulting in the EFNS. Organizational and administrative development was the initial task. Scientific panels led by a scientific committee, teaching courses for young neurologists, teaching courses in middle and eastern Europe and successful congresses were developed. The purchase of headquarters as well as the creation of a fully owned scientific journal (European Journal of Neurology) were important and financially beneficial. The EFNS also promoted the formation of the European Brain Council and of the patient organization European Federation of Neurological Associations. All these elements have continued after fusion with the European Neurological Society to form the EAN. CONCLUSION: The very successful development of the EFNS has largely been carried on into the EAN.

Sex differences in clinical characteristics of migraine and its burden: a population-based study.

BACKGROUND AND PURPOSE: Understanding migraine in a sex-specific manner is crucial for improving clinical care, diagnosis and therapy for both females and males. Here, data on sex differences are provided in the presentation of migraine in a large European-based population cohort, which is representative of the general population. METHODS: A population-based study of 62,672 Danish blood donors (both present and previous donors), of whom 12,658 had migraine, was performed. All participants completed a 105-item diagnostic migraine questionnaire sent via an electronic mailing system (e-Boks) between May 2020 and August 2020. The questionnaire allowed for correct diagnosis of migraine according to the International Classification of Headache Disorders, third edition. RESULTS: The migraine questionnaire was in-cohort validated and had a positive predictive value of 97% for any migraine, a specificity of 93% and a sensitivity of 93%. There were 9184 females (mean age 45.1 years) and 3434 males (mean age 48.0 years). The 3-month prevalence of migraine without aura was 11% in females and 3.59% in males. The 3-month prevalence of migraine with aura was 1.72% in females and 1.58% in males. In females, the age-related 3-month prevalence of migraine without aura increased markedly during childbearing age. In males, migraine both with and without aura showed less age variation. Females had a higher frequency of migraine attacks (odds ratio [OR] 1.22) but a lower frequency of non-migraine headaches (OR = 0.35). Females also had a greater intensity of pain, more unilateral and pulsatile pain, and exacerbation by physical activity (OR = 1.40-1.49) as well as more associated symptoms (OR = 1.26-1.98). Females carried 79% of the total migraine disease burden, which was almost exclusively driven by migraine without aura (77%), whilst there was no sex difference in the disease burden of migraine with aura. CONCLUSION: Females have more severe disease, resulting in a much higher migraine disease burden than indicated by prevalence alone.

The PACAP pathway is independent of CGRP in mouse models of migraine: possible new drug target?

Calcitonin gene-related peptide (CGRP)-antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target. To understand differences in CGRP- and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based on multiple stimulations and subsequent measurement of tactile sensitivity response with von Frey filaments. Genetically modified mice lacking either functional CGRP receptors (Ramp1 knockout) or TRPA1 channels (Trpa1 knockout) were used together with CGRP-targeting antibodies and chemical inhibitors in wild-type mice (ntotal = 299). Ex vivo myograph studies were used to measure dilatory responses to CGRP and PACAP-38 in mouse carotid arteries. PACAP-38 provoked significant hypersensitivity and dilated the carotid arteries independently of CGRP. In contrast, glyceryl trinitrate-induced hypersensitivity is dependent on CGRP. Contrary to previous results with the migraine-inducing substances glyceryl trinitrate, cilostazol and levcromakalim, PACAP-38-induced hypersensitivity worked only partially through inhibition of ATP-sensitive potassium channels. Using multiple migraine-relevant models, these findings establish the PACAP-38 pathway as distinct from other migraine provoking pathways such as CGRP and glyceryl trinitrate. PACAP antagonism may therefore be a novel therapeutic target of particular interest in patients unresponsive to CGRP-antagonizing drugs.

Rethinking headache as a global public health case model for reaching the SDG 3 HEALTH by 2030.

The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a "headache-tailored" perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations' health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally.

Multi-omics to predict changes during cold pressor test.

BACKGROUND: The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. We hypothesize, that performing multi-omic analyses during CPT gives the opportunity to home in on molecular mechanisms involved. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken. RNA-Sequencing, steroid profiling and untargeted metabolomics were performed. Each 'omic level was analyzed separately at both single-feature and systems-level (principal component [PCA] and partial least squares [PLS] regression analysis) and all 'omic levels were combined using an integrative multi-omics approach, all using the paired-sample design. RESULTS: We showed that PCA was not able to discriminate time points, while PLS did significantly distinguish time points using metabolomics and/or transcriptomic data, but not using conventional physiological measures. Transcriptomic and metabolomic data revealed at feature-, systems- and integrative- level biologically relevant processes involved during CPT, e.g. lipid metabolism and stress response. CONCLUSION: Multi-omics strategies have a great potential in pain research, both at feature- and systems- level. Therefore, they should be exploited in intervention studies, such as pain provocation tests, to gain knowledge on the biological mechanisms involved in complex traits.

Personal view: Modelling pain mechanisms of migraine without aura.

INTRODUCTION: This review aims to model migraine nociception. METHODS: Personal experience and litterature. RESULTS: Genetic and environmental factors in combination decide whether a person suffers from migraine. Endogenous and/or exogenous factors precipitate the individual attacks. Nociception takes place around blood vessels. There is a growing understanding of the molecular pathophysiological mechanisms of migraine from human provocation studies. Rodent models of migraine are necessary to understand the complex interrelation between the many putatively involved molecules and tissues but their relevance for human migraine is uncertain. The crucial element in migraine nociception is a unit consisting of endothelial cells, vascular smooth muscle cells, perivascular nerve fibers (trigeminal, parasympathetic and sympathetic) and mast cells. Attacks may start outside the brain by humoral or neurogenic activity releasing nociceptive substances around blood vessels. They may also (perhaps more often) start by the brain generating efferent activity in autonomic and somatic nerves. CONCLUSION: Human and rodent studies can quickly uncover the "mystery of migraine".

Headache provocation by nitric oxide in men who have never experienced a headache.

INTRODUCTION: In the general population 4% have never experienced a headache. Freedom from headache could be due to distinctive protective mechanisms or a lack of environmental risk factors for headache. Isosorbide-5-mononitrate is an organic nitrate which in the body is metabolised to nitric oxide. The nitric oxide pathway plays a crucial role in the primary headaches. We hypothesized that people who are free from headache are protected by distinctive mechanisms in the nitric oxide pathway. METHODS: We performed an observer blinded case-control study using nitric oxide to provoke a headache. 32 headache free male participants and 26 randomly selected male controls received 60 mg Isosorbide-5-mononitrate orally on the study day. Participants fill out a headache diary with headache intensity and characteristics until 12 hours after administration of Isosorbide-5-mononitrate. Primary endpoint were areas under the curve of headache intensity score. RESULTS: All 58 participants completed the study. There was no significant difference in headache incidence, headache intensity score or migraine-like attack between headache free participants and controls. CONCLUSION: We show that men who have never experienced a headache develop a headache when provoked with Isosorbide-5-mononitrate. This indicates that freedom from headache in men is not related to the nitric oxide pathway which is involved in the primary headache disorders.