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Although clinically distinguishable, migraine and cluster headache share prominent features such as unilateral pain, common pharmacological triggers such glyceryl trinitrate, histamine, calcitonin gene-related peptide (CGRP) and response to triptans and neuromodulation. Recent data also suggest efficacy of anti CGRP monoclonal antibodies in both migraine and cluster headache. While exact mechanisms behind both disorders remain to be fully understood, the trigeminovascular system represents one possible common pathophysiological pathway and network of both disorders. Here, we review past and current literature shedding light on similarities and differences in phenotype, heritability, pathophysiology, imaging findings and treatment options of migraine and cluster headache. A continued focus on their shared pathophysiological pathways may be important in paving future treatment avenues that could benefit both migraine and cluster headache patients.

The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT 1B and 5-HT 1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine. The effect on cranial vasculature is relevant, because all specific anti-migraine drugs and migraine pharmacological triggers may act in perivascular space. This review reports the effects of triptans and CGRP blocking molecules on cranial vasculature in humans, focusing on their specific relevance to migraine treatment.

Headache is among the most frequent symptoms persisting or newly developing after coronavirus disease 2019 (COVID-19) as part of the so-called long COVID syndrome. The knowledge on long COVID headache is still limited, however growing evidence is defining the features of this novel condition, in particular regarding clinical characteristics, some pathophysiological mechanisms and first treatment recommendations. Long COVID headache can present in the form of worsening of a preexisting primary headache, or, more specifically, in the form of a new (intermittent or daily) headache starting during the acute infection or after a delay. It often presents together with other long COVID symptoms, most frequently with hyposmia. It can manifest with a migrainous or, more frequently, with a tension-type-like phenotype. Persistent activation of the immune system and trigeminovascular activation are thought to play a role. As there are virtually no treatment studies, treatment currently is largely guided by the existing guidelines for primary headaches with the corresponding phenotype. The present report, a collaborative work of the international group of the Junior Editorial Board of The Journal of Headache and Pain aims to summarize the most recent evidence about long COVID headache and suggests approaches to the diagnosis and treatment of this disorder.

Artificial intelligence (AI) is revolutionizing the field of biomedical research and treatment, leveraging machine learning (ML) and advanced algorithms to analyze extensive health and medical data more efficiently. In headache disorders, particularly migraine, AI has shown promising potential in various applications, such as understanding disease mechanisms and predicting patient responses to therapies. Implementing next-generation AI in headache research and treatment could transform the field by providing precision treatments and augmenting clinical practice, thereby improving patient and public health outcomes and reducing clinician workload. AI-powered tools, such as large language models, could facilitate automated clinical notes and faster identification of effective drug combinations in headache patients, reducing cognitive burdens and physician burnout. AI diagnostic models also could enhance diagnostic accuracy for non-headache specialists, making headache management more accessible in general medical practice. Furthermore, virtual health assistants, digital applications, and wearable devices are pivotal in migraine management, enabling symptom tracking, trigger identification, and preventive measures. AI tools also could offer stress management and pain relief solutions to headache patients through digital applications. However, considerations such as technology literacy, compatibility, privacy, and regulatory standards must be adequately addressed. Overall, AI-driven advancements in headache management hold significant potential for enhancing patient care, clinical practice and research, which should encourage the headache community to adopt AI innovations. Graphical Abstract

Background Migraine represents the third leading cause of disability-adjusted life years among young females worldwide, responsible for physical and emotional distress along with reduced social functioning. The matter is further complicated by resistance and even refractoriness to the available treatments. Indeed, despite the several therapeutic strategies, remarkably improved by the development of the novel, specific drugs directed towards calcitonin-gene related peptide (CGRP) signalling, 40% patients, also undergoing anti-CGRP therapy, are still difficult-to-treat. The potential role of environmental factors and epigenetic modifications in the pathogenesis of migraine and in the responsiveness to treatments still remains poorly investigated. Moreover, the expression of a wide panel of serum microRNAs was recently related to frequency and features of migraine attacks. Thus, the aim of the present study is to analyze the possible epigenetic mechanisms at the root of differences in migraine features and response to treatments. Methods Eligibility criteria, search strategy and information sources are established a priori. PubMed, Scopus and Web of Science were inspected for studies published from database inception to the date of last search on October 2nd, 2025. Results A few studies so far support the role of DNA methylation in migraine chronification, indicating that these stable but reversible epigenetic modifications may influence the process of progression and transformation from episodic to chronic migraine. Altered DNA methylation sites were linked to genes involved in synaptic plasticity and estrogen receptor signaling. Up-regulation of circulating miRNAs was reduced following treatment with gepants. Within this complex figure, the role of the transient receptor potential (TRP) vanilloid 1 (TRPV1) in the trigeminal ganglia deserves deep investigation, including the prediction of response to first-line therapies such as triptans. Likewise, TRP ankyrin 1 (TRPA1) expression is subjected to pain-induced epigenetic modifications. DNA methylation and the modulation of histone deacetylase activity are implicated in the mechanisms of action of currently used preventative drugs, such as valproic acid and topiramate, and could serve as biomarkers of drug response. Finally, the role of miRNAs as potential biomarker for predicting the response to novel monoclonal antibodies, such as erenumab, has emerged in recent studies. Conclusions The role of epigenetic modifications of genes involved in the CGRP pathway, synaptic plasticity and TRPV1, TRPA1 and estrogen receptor signaling in migraine is emerging. Therefore, a deeper understanding of the impact of epigenetics in migraine pathophysiology and neuropharmacology is needed to revert chronification and personalize medicine in the field of migraine, improving efficacy and safety of treatments and widening the therapeutic armamentarium.

Background Understanding the mechanisms of pathological brain network activity and the efficacy of therapies requires testing hypothesis in vivo, where brain circuitry remains preserved. Therefore, animal models are a key tool in the study of primary neurological disorders such as migraine, stroke and epilepsy. These models not only have advanced our understanding of the underlying neurobiology of these disorders but have also provided novel pharmacological targets and insights on shared pathophysiological processes such as spreading depolarizations (SD). SD, the electrographic correlate of migraine with aura, are transient waves of near-complete neuroglial depolarization associated with transmembrane ionic and water shifts. Body Many studies investigating the impact of SD in preclinical models have done so in the presence of anesthesia. However, the use of anesthesia is a well-known confounding factor that not only influences SD threshold or frequency but also SD-evoked hemodynamic responses as common anesthetics affect cerebral blood flow and neurovascular coupling, limiting translation. Therefore, here we discuss research methods that have recently been developed or refined to allow the study of SD in awake rodents with a focus on migraine with aura. We discuss advantages, limitations and also efforts made to transition towards minimally-invasive procedures. Methods include optogenetic approaches to induce SD, multisite high-fidelity DC-coupled electrophysiological recordings, and measurements of neurovascular signals detected at both mesoscopic/macroscopic (e.g., fluorescent reporters, functional ultrasound system) and microscopic levels (e.g., two-photon microscopy, miniscopes). Additionally, we discuss continuous wireless telemetry recordings to detect spontaneous SD frequency over weeks to months in freely moving animals. Conclusion Implementation of these methods in awake brain will close the translational gap and improve the relevance of preclinical animal models.

Background Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of ( S )- isometheptene and ( R )-isometheptene, and the pharmacological profile of the more potent enantiomer. Methods The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, ( S )-isometheptene or ( R )-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results Compared to ( R )-isometheptene, ( S )-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to ( S )-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to ( S )-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to ( S )-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions The different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for ( S )-isometheptene (a tyramine-like action and a direct stimulation of α 1 -adrenoceptors); and (ii) exclusively a tyramine like action for ( R )-isometheptene. Thus, ( R )-isometheptene may represent a superior therapeutic benefit as an antimigraine agent.

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

Targeting CGRP has proved to be efficacious, tolerable, and safe to treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing the general pharmacology of the different types of treatments currently available, which target directly or indirectly the CGRP receptor or its ligand. Moreover, the latest evidence regarding the selectivity and site of action of CGRP small molecule antagonists (gepants) and monoclonal antibodies is critically discussed. Finally, the reasons behind non-responders to anti-CGRP drugs and rationale for combining and/or switching between these therapies are addressed.