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.

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.

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.

Xenobiotic Exposure and Migraine-Associated Signaling: A Multimethod Experimental Study Exploring Cellular Assays in Combination with Ex Vivo and In Vivo Mouse Models.

BACKGROUND: Mechanisms for how environmental chemicals might influence pain has received little attention. Epidemiological studies suggest that environmental factors such as pollutants might play a role in migraine prevalence. Potential targets for pollutants are the transient receptor potential (TRP) channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which on activation release pain-inducing neuropeptide calcitonin gene-related peptide (CGRP). OBJECTIVE: In this study, we aimed to examine the hypothesis that environmental pollutants via TRP channel signaling and subsequent CGRP release trigger migraine signaling and pain. METHODS: A calcium imaging-based screen of environmental chemicals was used to investigate activation of migraine pain-associated TRP channels TRPA1 and TRPV1. Based on this screen, whole-cell patch clamp and in silico docking were performed for the pesticide pentachlorophenol (PCP) as proof of concept. Subsequently, PCP-mediated release of CGRP and vasodilatory responses of cerebral arteries were investigated. Finally, we tested whether PCP could induce a TRPA1-dependent induction of cutaneous hypersensitivity in vivo in mice as a model of migraine-like pain. RESULTS: A total of 16 out of the 52 screened environmental chemicals activated TRPA1 at 10 or 100µM. None of the investigated compounds activated TRPV1. Using PCP as a model of chemical interaction with TRPA1, in silico molecular modeling suggested that PCP is stabilized in a lipid-binding pocket of TRPA1 in comparison with TRPV1. In vitro, ex vivo, and in vivo experiments showed that PCP induced calcium influx in neurons and resulted in a TRPA1-dependent CGRP release from the brainstem and dilation of cerebral arteries. In a mouse model of migraine-like pain, PCP induced a TRPA1-dependent increased pain response (Ntotal=144). DISCUSSION: Here we show that multiple environmental pollutants interact with the TRPA1-CGRP migraine pain pathway. The data provide valuable insights into how environmental chemicals can interact with neurobiology and provide a potential mechanism for putative increases in migraine prevalence over the last decades. https://doi.org/10.1289/EHP12413.

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.

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.

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.

Diagnosis of Migrainous Infarction: A Case Report and Analysis of Previously Published Cases.

Migrainous infarction (MI) is a rare disorder. The precise diagnostic criteria for this diagnosis have been available in the International Classification of Headache Disorders (ICHD) since 1988, but many cases do not fulfil these criteria. This paper describes a good example of MI and analyzes previously published case reports. We report a very special case of MI in an 18-year-old woman who had a recurrent episode of migraine with a similar aura with numbness of the right arm and speech disturbances which had an unusually long duration (>120 min). On admission to the headache centre "Europe-Asia", she complained of slowness of speech and problems with choice of words. An MRI showed acute lacunar infarcts in the left parietal subcortical area. Ischemic infarcts were localized in a relevant area on the left side and the aura symptoms were right-sided. The patient, therefore, fulfilled the ICHD-3 diagnostic criteria for "Migrainous infarction". An analysis of 35 previously published articles with case reports about MI showed that 22 did not meet the diagnostic criteria of the ICHD for migrainous infarction. Using all this, we developed diagnostic recommendations for migrainous infarction which can help to improve the quality of diagnosis when used together with the diagnostic criteria of the ICHD for migrainous infarction.

The ATP sensitive potassium channel (KATP) is a novel target for migraine drug development.

Migraine is one of the leading causes of disability worldwide, affecting work and social life. It has been estimated that sales of migraine medicines will reach 12.9 billion USD in 2027. To reduce social impact, migraine treatments must improve, and the ATP-sensitive potassium (KATP) channel is a promising target because of the growing evidence of its implications in the pathogenesis of migraine. Strong human data show that opening of the KATP channel using levcromakalim is the most potent headache and migraine trigger ever tested as it induces headache in almost all healthy subjects and migraine attacks in 100% of migraine sufferers. This review will address the basics of the KATP channel together with clinical and preclinical data on migraine implications. We argue that KATP channel blocking, especially the Kir6.1/SUR2B subtype, may be a target for migraine drug development, however translational issues remain. There are no human data on the closure of the KATP channel, although blocking the channel is effective in animal models of migraine. We believe there is a good likelihood that an antagonist of the Kir6.1/SUR2B subtype of the KATP channel will be effective in the treatment of migraine. The side effects of such a blocker may be an issue for clinical use, but the risk is likely only moderate. Future clinical trials of a selective Kir6.1/SUR2B blocker will answer these questions.

Multi-omic analyses of triptan-treated migraine attacks gives insight into molecular mechanisms.

Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.

Pharmacological Profiling of KATP Channel Modulators: An Outlook for New Treatment Opportunities for Migraine.

Migraine is a highly disabling pain disorder with huge socioeconomic and personal costs. It is genetically heterogenous leading to variability in response to current treatments and frequent lack of response. Thus, new treatment strategies are needed. A combination of preclinical and clinical data indicate that ATP-sensitive potassium (KATP) channel inhibitors could be novel and highly effective drugs in the treatment of migraine. The subtype Kir6.1/SUR2B is of particular interest and inhibitors specific for this cranio-vascular KATP channel subtype may qualify as future migraine drugs. Historically, different technologies and methods have been undertaken to characterize KATP channel modulators and, therefore, a head-to-head comparison of potency and selectivity between the different KATP subtypes is difficult to assess. Here, we characterize available KATP channel activators and inhibitors in fluorescence-based thallium-flux assays using HEK293 cells stably expressing human Kir6.1/SUR2B, Kir6.2/SUR1, and Kir6.2/SUR2A KATP channels. Among the openers tested, levcromakalim, Y-26763, pinacidil, P-1075, ZM226600, ZD0947, and A-278637 showed preference for the KATP channel subtype Kir6.1/SUR2B, whereas BMS-191095, NN414, and VU0071306 demonstrated preferred activation of the Kir6.2/SUR1 subtype. In the group of KATP channel blockers, only Rosiglitazone and PNU-37783A showed selective inhibition of the Kir6.1/SUR2B subtype. PNU-37783A was stopped in clinical development and Rosiglitazone has a low potency for the vascular KATP channel subtype. Therefore, development of novel selective KATP channel blockers, having a benign side effect profile, are needed to clinically prove inhibition of Kir6.1/SUR2B as an effective migraine treatment.

DanMAC5: a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals.

OBJECTIVES: Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https://identifiers.org/ega. DATASET: EGAD00001009756 ) and in a dedicated browser, DanMAC5 (available at www.danmac5.dk ). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation. DATA DESCRIPTION: Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high-quality summary level dataset of sequence variants.

Population-Based Characterization of Menstrual Migraine and Proposed Diagnostic Criteria.

Importance: There is a need for better recognition and more extensive research into menstrual migraine (MM) in the general population, and a revision of the diagnostic criteria for MM is warranted to move the field forward. Increased understanding of MM is crucial for improving clinical care, diagnosis, and therapy for MM. Objectives: To assess the clinical characteristics of MM, including severity and treatment response, and to propose new diagnostic criteria for pure MM and menstrually related migraine. Design, Setting, and Participants: This is a case-control study of Danish individuals with migraine. All individuals completed a 105-item validated diagnostic migraine questionnaire, sent via the Danish electronic mailing system (e-Boks) between May and August 2020, allowing diagnosis of pure MM and menstrually related migraine by the International Classification of Headache Disorders, Third Edition (ICHD-3). Data analysis was performed from September 2021 to November 2022. Exposure: Diagnosis of migraine. Main Outcomes and Measures: Clinical characteristics of women with MM and women with nonmenstrual migraine (non-MM) were compared using the ICHD-3 diagnostic criteria. A simulation of the risk of randomly misclassifying MM was based on number of migraine attacks during 3 menstrual cycles (3 × 28 days), and simulation analyses were performed using 100 000 permutations of random migraine attacks in migraine patients. Results: A total of 12 618 individuals, including 9184 women, with migraine participated in the study. Among the women with migraine, the prevalence of MM was 16.6% (1532 women), and the prevalence of non-MM was 45.9% (4216 women). The mean (SD) age was 38.7 (8.7) years for women with MM and 37.0 (9.2) years for women with non-MM. Of the 1532 women with MM, 410 (26.8%) fulfilled ICHD-3 diagnostic criteria for pure MM, 1037 (67.7%) fulfilled ICHD-3 diagnostic criteria for menstrually related migraine, and 152 (9.9%) fulfilled proposed diagnostic criteria for rare pure MM. MM was associated with a higher frequency of migraine-accompanying symptoms (odds ratio [OR], 1.98; 95% CI, 1.71-2.29), more frequent (OR, 7.21; 95% CI, 5.77-9.03) and more severe (OR, 1.17; 95% CI, 1.13-1.21) migraine attacks, lower frequency of nonmigraine headache (OR, 0.31; 95% CI, 0.18-0.49), an overall greater response to treatment with triptans (OR, 1.66; 95% CI, 1.24-2.24), better improvement of migraine attacks during late pregnancy (OR, 5.10; 95% CI, 2.17-14.00), and faster reappearance of migraine attacks post partum (OR, 3.19; 95% CI, 2.40-4.25). Hormonal contraceptive-related MM was associated with a higher prevalence of migraine without aura than migraine related to spontaneous menstruation (OR, 1.82; 95% CI, 1.62-2.06). Otherwise, no differences between hormonal and spontaneous MM were observed. The risk of random diagnostic misclassification of ICHD-3 menstrually related migraine in women with high frequency episodic migraine was 43%. This risk was reduced to 3% when applying the proposed criteria for menstrually related migraine. Conclusions and Relevance: In this case-control study, MM in the general population had clinical characteristics that were quantitively different from those of non-MM. Detailed descriptive data and suggested improved diagnostic criteria for pure MM and menstrually related migraine were provided.

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.

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.

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.

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.

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.