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IntroductionHeadache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce.Material and methodsWe searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8–18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted.ResultsOut of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9–14%], 8% for migraine without aura (MwoA) [95%CI: 5–12%], 3% for migraine with aura (MwA) [95%CI:2–4%] and 17% for tension-type headache (TTH) [95% CI: 12–23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53–70%], with prevalence in females and males of 38% [95% CI: 16–66%] and 27% [95% CI: 11–53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking.ConclusionWe found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.

BackgroundHeadache disorders are a global public health concern affecting diverse populations. This review examines headache service organizations in low-, middle-, and high-income countries. It addresses global challenges in pharmacological headache treatment, with a focus on safety, tolerability, reproductive and child health, and outlines disparities in accessing innovative treatments worldwide.Main bodyOrganized headache services are essential due to the wide prevalence and varying severity of headache disorders. The tiered headache service model is globally recognized, although its implementation varies based on financial and workforce considerations. Headache burden affects well-being, causing disability, economic challenges, and work limitations, irrespective of location or income. All nations still require improved diagnosis and treatment, and the majority of countries face obstacles including limited access, awareness, economic barriers, and inadequate health policies. Provided adequate internet availability, telemedicine could help improve health equity by expanding access to headache care, since it can offer patients access to services without lengthy waiting times or extensive travel and can provide healthcare unavailable in underserved areas due to staff shortages.Numerous health disparities restrict global access to many headache medications, especially impacting individuals historically excluded from randomized controlled trials, such as those with cardiovascular and cerebrovascular conditions, as well as pregnant women. Furthermore, despite advancements in researching migraine treatments for young patients, the options for treatment remain limited.Access to headache treatment relies on factors like medication availability, approval, financial coverage, and healthcare provider expertise. Inadequate public awareness leads to neglect by policymakers and undertreatment by patients and healthcare providers. Global access discrepancies are exacerbated by the introduction of novel disease-specific medications, particularly impacting Asian, African, and Latin American nations excluded from clinical trials. While North America and Europe experience broad availability of migraine treatments, the majority of countries worldwide lack access to these therapies.ConclusionsHealthcare disparities, treatment access, and medication availability are concerning issues in headache medicine. Variations in national healthcare systems impact headache management, and costly innovative drugs are widening these gaps. Healthcare practitioners and experts should acknowledge these challenges and work towards minimizing access barriers for equitable global headache care in the future.

Combination treatments for migraine prophylaxis present a promising approach to addressing the diverse and complex mechanisms underlying migraine. This review explores the potential of combining oral conventional prophylactics, onabotulinumtoxin A, monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway, and small molecule CGRP receptor antagonists (gepants). Among the most promising strategies, dual CGRP inhibition through mAbs and gepants may enhance efficacy by targeting both the CGRP peptide and its receptor, while the combination of onabotulinumtoxin A with CGRP treatments offers synergistic pain relief. Oral non-CGRP treatments, which are accessible and often prescribed for patients with comorbid conditions, provide an affordable and practical option in combination regimens. Despite the potential of these combinations, there is a lack of evidence to support their widespread inclusion in clinical guidelines. The high cost of certain combinations, such as onabotulinumtoxin A with a CGRP mAb or dual anti-CGRP mAbs, presents feasibility challenges. Further large-scale trials are needed to establish safe and effective combination protocols and solidify their role in clinical practice, particularly for treatment-resistant patients. Graphical Abstract

Background The burden and disability associated with headaches are conceptualized and measured differently at patients’ and populations’ levels. At the patients’ level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0–1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients’ disability which might inform future GBD definitions of DW for headache disorders. Methods We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females’ percentage in the sample, and age). We developed a 0–1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium. Results A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake. Conclusions Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

Part 2 explores the transformative potential of artificial intelligence (AI) in addressing the complexities of headache disorders through innovative approaches, including digital twin models, wearable healthcare technologies and biosensors, and AI-driven drug discovery. Digital twins, as dynamic digital representations of patients, offer opportunities for personalized headache management by integrating diverse datasets such as neuroimaging, multiomics, and wearable sensor data to advance headache research, optimize treatment, and enable virtual trials. In addition, AI-driven wearable devices equipped with next-generation biosensors combined with multi-agent chatbots could enable real-time physiological and biochemical monitoring, diagnosing, facilitating early headache attack forecasting and prevention, disease tracking, and personalized interventions. Furthermore, AI-driven advances in drug discovery leverage machine learning and generative AI to accelerate the identification of novel therapeutic targets and optimize treatment strategies for migraine and other headache disorders. Despite these advances, challenges such as data standardization, model explainability, and ethical considerations remain pivotal. Collaborative efforts between clinicians, biomedical and biotechnological engineers, AI scientists, legal representatives and bioethics experts are essential to overcoming these barriers and unlocking AI’s full potential in transforming headache research and healthcare. This is a call to action in proposing novel frameworks for integrating AI-based technologies into headache care. Graphical Abstract

Background: The Migraine in Poland study is a cross-sectional survey that assesses symptomatology, consulting, diagnosis, treatment and impact of migraine in Poland. Objectives: The purpose of this article is to define patterns of care for migraine in Polish patients. Methods: The survey was conducted from August 2021 to June 2022. Participants were recruited through various channels, targeting mostly persons suffering from headaches. The web survey included questions allowing for diagnosis according to the International Classification of Headache Disorders. A detailed questionnaire evaluated healthcare system utilization, history of diagnosis, as well as the use of acute or preventive treatment, including non-pharmacological methods. Results: In total, 3225 individuals aged 13–80 (mean age 38.9) responded to the questionnaire (87.1% were women). Migraine without aura (MwoA) diagnosis was confirmed in 1679 (52.7%) of subjects, and 1571 (93.6%) of them consulted a medical professional for their headaches in the past. Among those who consulted for headache, 91% reported having received a medical diagnosis of migraine. 92.5% of MwoA participants declared the current use of some form of treatment. Non-steroidal anti-inflammatory drugs and acetaminophen were the most frequently used acute medications (n = 1318, 78.5%) followed by combination analgesics, especially those containing codeine (n = 991, 59%). Triptans/ergots were used by 57.1%. A total of 22.8% of subjects used acute treatment with a frequency indicating medication-overuse. Prophylactic treatment was at some point used by 35.68%, while 11.49% were currently on preventive medications. The most frequently prescribed preventives were iprazochrome (8.99%), followed by flunarizine (8.10%) and topiramate (5.90%). A total of 23.28% subjects used nutraceuticals for migraine prevention (most frequently magnesium). Conclusion: Despite high consultation and diagnosis rates among Polish patients with migraine, there is a need for improving standards of care, especially in regard to choice of treatment. There is also a need to raise public awareness of the dangers of codeine-based medications (available over-the-counter in Poland). Plain language summary Consulting, diagnosis and treatment patterns in migraine: results from the Migraine in Poland study The Migraine in Poland study is a cross-sectional survey that assesses symptomatology, consulting, diagnosis, treatment, and impact of migraine in Poland. The purpose of this paper is to define patterns of care for migraine in Polish patients. The survey was conducted from August 2021 to June 2022. Participants were recruited through various channels, targeting mostly persons suffering from headaches. The web survey included questions allowing for diagnosis according to the International Classification of Headache Disorders. A detailed questionnaire evaluated healthcare system utilization, history of diagnosis, as well as the use of acute or preventive treatment, including non-pharmacological methods. 3225 individuals aged 13 to 80 (mean age 38.9) responded to the questionnaire (87.1% were women). Migraine without aura (MwoA) diagnosis was confirmed in 1679 (52.7%) of subjects, and 1571 (93.6%) of them consulted a medical professional for their headaches in the past. Among those who consulted for headache 91% reported having received a medical diagnosis of migraine. 92.5% of MwoA participants declared the current use of some form of treatment. Non-steroidal anti-inflammatory drugs and acetaminophen were the most frequently used acute medications (n=1318, 78.5%) followed by combination analgesics, especially those containing codeine (n=991, 59%). Triptans/ergots were used by 57.1%. 22.8% of subjects used acute treatment with a frequency indicating medication-overuse. Prophylactic treatment was at some point used by 35.68%, while 11.49% were currently on preventive medications. The most frequently prescribed preventives were iprazochrome (8.99%), followed by flunarizine (8.10%) and topiramate (5.90%). Despite high consultation and diagnosis rates among Polish patients with migraine there is a need for improving standards of care, especially in regard to choice of treatment. There is also a need to raise public awareness of the dangers of codeine-based medications.

IntroductionMigraine prophylactic therapy has changed over recent years with the development and approval of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway. As new therapies emerged, leading headache societies have been providing guidelines on the initiation and escalation of such therapies. However, there is a lack of robust evidence looking at the duration of successful prophylaxis and the effects of therapy discontinuation. In this narrative review we explore both the biological and clinical rationale for prophylactic therapy discontinuation to provide a basis for clinical decision-making.MethodsThree different literature search strategies were conducted for this narrative review. These include i) stopping rules in comorbidities of migraine in which overlapping preventives are prescribed, notably depression and epilepsy; ii) stopping rules of oral treatment and botox; iii) stopping rules of antibodies targeting the CGRP (receptor). Keywords were utilized in the following databases: Embase, Medline ALL, Web of Science Core collection, Cochran Central Register of Controlled Trials, and Google Scholar.DiscussionReasons to guide decision-making in stopping prophylactic migraine therapies include adverse events, efficacy failure, drug holiday following long-term administration, and patient-specific reasons. Certain guidelines contain both positive and negative stopping rules. Following withdrawal of migraine prophylaxis, migraine burden may return to pre-treatment level, remain unchanged, or lie somewhere in-between. The current suggestion to discontinue CGRP(-receptor) targeted mAbs after 6 to 12 months is based on expert opinion, as opposed to robust scientific evidence. Current guidelines advise the clinician to assess the success of CGRP(-receptor) targeted mAbs after three months. Based on excellent tolerability data and the absence of scientific data, we propose if no other reasons apply, to stop the use of mAbs when the number of migraine days decreases to four or fewer migraine days per month.There is a higher likelihood of developing side effects with oral migraine preventatives, and so we suggest stopping these drugs according to the national guidelines if they are well tolerated.ConclusionTranslational and basic studies are warranted to investigate the long-term effects of a preventive drug after its discontinuation, starting from what is known about the biology of migraine. In addition, observational studies and, eventually, clinical trials focusing on the effect of discontinuation of migraine prophylactic therapies, are essential to substantiate evidence-based recommendations on stopping rules for both oral preventives and CGRP(-receptor) targeted therapies in migraine.

Background Calcitonin gene related peptide (CGRP) pathway targeting therapies have proven efficacy, safety and tolerability. However, CGRP is also involved in immune responses, and reports of an increased risk of infection have emerged. This meta-analysis aims to verify whether CGRP-targeting therapies show evidence of increasing infection risk. Methods A systematic review was conducted according to PRISMA-Harms guidelines. A PubMed and Embase search result selection and extraction was performed. Risk of bias, sensitivity analysis, and fixed/random effects network meta-analyses were conducted for incidence of infectious adverse events in the studied populations with subsequent effect size assessment. An additional infectious serious adverse event search was performed in double-blind and open-label studies. Results The search and selection process yielded 37 randomized placebo-controlled trials. 22,518 patients (77.3% women) treated with erenumab, fremanezumab, galcanezumab, eptinezumab, atogepant and rimegepant participated in these studies. Preventive CGRP-targeting therapies appear to increase the infection relative risk (RR = 1.08 [1.01; 1.14], p  = 0.016, Number Needed to Harm [NNH] = 287). However, in individual analyses only galcanezumab and eptinezumab showed an increase in risk of infections: galcanezumab at clinically used doses (RR 1.13 [1.02; 1.25], p  = 0.024, NNH = 77); eptinezumab at higher doses (RR 1.23 [1.04; 1.45], p  = 0.015, NNH = 24). Fremanezumab was associated with fewest infectious SAEs ( n  = 3 in 3 studies), while erenumab showed the highest incidence of these events ( n  = 36 in 11 studies). Conclusions CGRP has multiple and often potentially opposing effects on the immune system. In effect, preventive CGRP pathway antagonists (especially eptinezumab and galcanezumab) possibly only mildly increase the risk of infections. However, it is unlikely to affect most migraine patients considering relatively high NNH, low effect size and few infectious SAEs reported so far. The result of CGRP-targeting therapies potentially depends on the type of pathogen and patient’s immune status. Consequently, in immunocompromised patients or at public health levels the increased infection risk may have more pronounced effect.

BackgroundMigraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine.FindingsWe covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far.Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results.ConclusionWhile current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

Migraine is a complex neurological disorder with diverse clinical phenotypes and a multifaceted pathophysiology, which poses substantial challenges for accurate diagnosis, subtype differentiation, and biomarker discovery. Machine learning (ML) techniques have emerged as promising tools for classifying migraine patients and uncovering the underlying neurobiological mechanisms that differentiate migraine types and subtypes. This systematic review identifies current ML classification models for migraine types and subtypes, evaluating the quality, reproducibility, and clinical utility of published studies. The findings demonstrate that current ML models, particularly support vector machines and linear discriminant analysis, can accurately classify migraine patients based on structural and functional neuroimaging features with accuracies ranging from 75 to 98%. However, quality assessment revealed significant methodological heterogeneity across studies, including inconsistent reporting of model performance, insufficient patient phenotyping, small and imbalanced datasets, and limited external validation. These limitations hinder the global generalizability and reproducibility of these studies. We propose a roadmap for future research emphasizing well-characterized clinical subgrouping, standardized data acquisition and feature engineering protocols, transparency in model development and reporting, and collaborative multicentric designs to enable large-scale validation. Furthermore, this review stresses the importance of incorporating real-world phenotypic data, such as treatment response, comorbidities, and digital phenotyping metrics, to enrich ML models and support the transition toward precision medicine in migraine care. Ultimately, this review highlights the urgent need for methodological rigor in migraine ML classification studies to bridge the gap between experimental success and clinical applicability. Graphical Abstract