Influence of next-generation artificial intelligence on headache research, diagnosis and treatment: the junior editorial board members' vision - part 2.

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.

Combining treatments for migraine prophylaxis: the state-of-the-art.

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.

Rimegepant and atogepant: novel drugs providing innovative opportunities in the management of migraine.

Introduction: Rimegepant and atogepant, two innovative oral medications for the treatment of migraine, are gaining prominence in the treatment of migraine. However, outside of specialist headache centers, these novel medications remain subjectively underutilized. While multiple rationales exist describing their underutilization, a leading factor is the complexity and clinical flexibility attributed to the individual members of the gepant medication class.

Situational prevention in migraine: are we doing the right thing?

This commentary addresses the use of rimegepant for situational prevention in migraine management. While the approach of using prophylactic treatments during high-risk periods is not new, its application with rimegepant described by Lipton et al. raises ethical and clinical concerns.

Glucagon-like peptide-1 (GLP-1) receptor agonists for headache and pain disorders: a systematic review.

Background: Glucagon-like peptide-1 (GLP-1) plays a crucial role in metabolic disorders by enhancing insulin secretion, inhibiting glucagon release, and slowing gastric emptying, thereby improving glycemic control. In recent years, GLP-1 role in neuronal pathways has expanded its therapeutic potential. We aim to comprehensively evaluate the relevance of GLP-1 in headache and pain disorders.

The preclinical discovery and development of atogepant for migraine prophylaxis.

Introduction: Atogepant is a selective calcitonin gene-related peptide (CGRP) receptor antagonist that is utilized in adults for the prevention of episodic and chronic migraine. Cumulative findings support the involvement of CGRP in migraine pathophysiology, and atogepant functions by competitively antagonizing CGRP receptors, which results in the inhibition of trigeminovascular nociception. The mechanism of action addresses the cause of migraine pain, providing an effective preventive treatment option.

Pharmacological management of migraine: current strategies and future directions.

Introduction: Migraine is a complex neurological disorder that affects a significant portion of the global population. As traditional pharmacological approaches often fall short in alleviating symptoms, the development of innovative therapies has garnered significant interest. This text aims to summarize the current pharmacological options for managing migraine and to explore the potential impact of novel therapies.

Triptan treatment is associated with a higher number of red wine-induced migraine episodes: An exploratory questionnaire-based survey.

Aim: Diet, including foods and beverages, affects migraine. Conversely, the influence of migraine therapies on dietary habits is largely unknown. This study aimed at investigating the effects of triptan intake on foods and drinks consumed by adults with migraine with and/or without aura.

Targeting the PACAP-38 pathway is an emerging therapeutic strategy for migraine prevention.

Introduction: The pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) has emerged as a key mediator of migraine pathogenesis. PACAP-38 and its receptors are predominantly distributed in arteries, sensory and parasympathetic neurons of the trigeminovascular system. Phase 2 trials have tested human monoclonal antibodies designed to bind and inhibit PACAP-38 and the pituitary adenylate cyclase-activating polypeptide type I (PAC) receptor for migraine prevention.

Induction of cluster headache after opening of adenosine triphosphate-sensitive potassium channels: a randomized clinical trial.

Activation of adenosine triphosphate-sensitive potassium (K ATP ) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present.

The human NTG model of migraine in drug discovery and development.

Introduction: Various triggers can originate a migraine attack. In healthy volunteers and patients with migraine, the nitroglycerin (NTG) provocation model induces a headache that resembles migraine in pain characteristics and vascular manifestations. This headache is reversible and treatable in monitored conditions, providing an opportunity to test novel antimigraine medications in early clinical development.

Plasma levels of VIP are not elevated during PACAP- and VIP-induced cluster headache attacks: an exploratory study.

Background: Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) provoked cluster headache attacks in individuals with episodic cluster headache during their active phase and individuals with chronic cluster headache. In this study, we investigated whether infusions of PACAP and VIP caused alterations in plasma levels of VIP and their potential contribution to induced cluster headache attacks.

Methods: Participants received either PACAP or VIP infusion for 20 min on 2 separate days with an interval of at least 7 days in between.

Plasma Levels of CGRP During a 2-h Infusion of VIP in Healthy Volunteers and Patients With Migraine: An Exploratory Study.

Introduction: The activation of perivascular fibers and the consequent release of vasoactive peptides, including the vasoactive intestinal polypeptide (VIP), play a role in migraine pathogenesis. A 2-h infusion of VIP provoked migraine, but the mechanisms remain unknown. We investigated whether 2-h infusion of VIP caused alterations in plasma levels of the calcitonin gene-related peptide (CGRP) and whether any changes might be related to the induced migraine attacks.

Clinical Evidence of Cannabinoids in Migraine: A Narrative Review.

The endocannabinoid system (ECS) influences many biological functions, and hence, its pharmacological modulation may be useful for several disorders, such as migraine. Preclinical studies have demonstrated that the ECS is involved in the modulation of trigeminal excitability. Additionally, clinical data have suggested that an endocannabinoid deficiency is associated with migraine.

Safety and Risk of Medication Overuse Headache in Lasmiditan and Second-Generation Gepants: A Rapid Review.

The treatment of migraine is often complicated by insufficient headache relief, a miscellany of side effects and the risk of developing Medication Overuse Headache (MOH). Novel acute therapies have been recently developed and are now in the early post-marketing phase. Lasmiditan is a highly selective serotonin receptor agonist that binds to the 5-HT receptor, while ubrogepant and rimegepant antagonize the calcitonin gene-related peptide receptor.

PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation.

Background: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation.

Methods: All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min.

Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial.

Importance: Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP.

Objective: To determine whether a 2-hour infusion of VIP would provoke migraine attacks.

A systematic review, meta-analysis and meta-regression evaluating the adverse reactions to erenumab in the preventive treatment of migraine.

: Erenumab has recently been approved as a pharmacological treatment for the prevention of migraine. However, the incidence estimates of adverse drug reactions (ADRs) were not consistent among studies. Consequently, pooled measures of the incidences of ADRs that accounts for inter-study heterogeneity are desirable.

Reducing Episodic Cluster Headaches: Focus on Galcanezumab.

The involvement of calcitonin gene-related peptide in migraine and cluster headache has led to the recent development of new therapies. Galcanezumab, a novel monoclonal antibody targeting the calcitonin gene-related peptide, is approved for the migraine prevention and has recently been tested for the prevention of cluster headache. Two clinical trials have been conducted to investigate the efficacy and safety of galcanezumab in episodic cluster headache and chronic cluster headache.