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Flavia Lo Castro,1 Simona Guerzoni,1 Lanfranco Pellesi2 1Medical Toxicology, Headache and Drug Abuse Research Center, Department of Specialized Medicine, AOU Policlinico di Modena, Modena, Italy; 2Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Lanfranco PellesiDanish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkTel +45 53 80 30 56Email lanfranco.pellesi@gmail.comAbstract: 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-HT1F receptor, while ubrogepant and rimegepant antagonize the calcitonin gene-related peptide receptor. All three medications are now prescribed in a real-world setting, and an adequate level of knowledge is the starting point for rational use. In this rapid systematic review, we have established what is known about lasmiditan, ubrogepant and rimegepant, highlighting the most relevant safety aspects available from published studies and speculating about their risk of MOH.Keywords: CGRP, headache, migraine, MOH, triptans

Lanfranco Pellesi,1 Roberto De Icco,2,3 Mohammad Al-Mahdi Al-Karagholi,1 Messoud Ashina1,4 1Danish Headache Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Headache Science Center, IRCCS Mondino Foundation, Pavia, Italy; 3Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; 4Danish Headache Knowledge Center, Rigshospitalet Glostrup, Glostrup, DenmarkCorrespondence: Lanfranco PellesiDanish Headache Center, Faculty of Health and Medical Sciences, University of Copenhagen, Vagtelvej 61, Copenhagen 2000, DenmarkTel +393409383056Email lanfranco.pellesi@gmail.comAbstract: 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. While efficacy endpoints were not met in the chronic subtype, galcanezumab reduced the weekly frequency of attacks in patients with episodic cluster headaches. In both studies, the antibody was well tolerated. This review summarizes and critically reviews the available data regarding the rationale behind targeting the calcitonin gene-related peptide with galcanezumab for the prevention of cluster headache.Keywords: cluster headache, calcitonin gene-related peptide, CGRP, antibody, LY2951742

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., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: LP has been employed by Lundbeck in the past two years. DGA has received honoraria for lectures and presentations from AbbVie/Allergan, Eli Lilly, Teva, Lundbeck, and Novartis and has participated in clinical trials as the principal investigator for Pfizer, BioHaven, and Lundbeck. DGA has also received honoraria from the World Health Organization as a subject matter expert. RM reports personal fees from AbbVie, Eli Lilly, Lundbeck, Pfizer, Teva, and Biomedia, outside the submitted work. IP serves as Head of Imaging Section of SN Comprehensive Clinical Medicine. BR reports research grants from Lundbeck, Novartis, the German Research Foundation, the German Migraine and Headache Society, and Else Kröner-Fresenius Stiftung, as well as personal fees from AbbVie/Allergan, Lilly, Lundbeck, Novartis, Perfood, and Teva. RR has received travel grants and/or honoraria from Allergan/AbbVie, Lilly, Lundbeck, Novartis, Pfizer, and Teva. WW serves as Section Editor of SN Comprehensive Clinical Medicine. All authors serve as junior editors of The Journal of Headache and Pain., (© 2024. The Author(s).)

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., Areas Covered: This review provides a brief review of the current uses, common adverse events, and potential areas of future clinical innovation attributed to rimegepant and atogepant. A database search for the term 'Rimegepant OR Atogepant' was completed, yielding 240 individual results. Following multiple rounds of assessment that aimed to determine relevance of each individual result, 42 studies were included in the synthesis of this review., Expert Opinion: Rimegepant and atogepant are exciting medications that demonstrate significant clinical innovation within the field of migraine therapy. While current indications are clear, data is lacking regarding the future expanded roles of these medications. Current areas of potential therapeutic innovation for rimegepant and atogepant include the pediatric population, in pregnancy and breastfeeding, in cluster headache and post-traumatic headache, and in patients that previously discontinued calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) therapy.

Background and Aim: Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features., Main Results: The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities., Conclusions: Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires., (© 2024. The Author(s).)

Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A's ability to target multiple pain pathways may make it a more promising candidate.

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. These include the challenge of defining high-risk periods, the potential for overmedication, and the risk of medication overuse headache (MOH). The current evidence on MOH with gepants is inconclusive, and recommendations on dosing may be insufficient. Additionally, the long-term safety of calcitonin gene-related peptide (CGRP) antagonists remains uncertain, especially regarding cardiovascular and other systemic effects. The commentary emphasizes the need for caution and thorough investigation into the long-term risks and benefits of situational prevention with rimegepant before widespread adoption., (© 2024. The Author(s).)

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., Methods: A systematic literature search was conducted on PubMed and Embase (Ovid) databases using the search terms "GLP-1" and "pain". Animal and human studies published in English language were included. Abstracts, reviews, and articles on other disorders than "pain" were excluded., Results: The search strategy identified 833 hits, of which 42 studies were included in the final review. The studies were categorized into four groups: inflammatory pain and osteoarthritis, headaches, neuropathic pain and diabetic neuropathy, and visceral pain and irritable bowel syndrome. GLP-1 receptor (GLP-1R) agonists, like liraglutide, have shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory and neuropathic pain. GLP-1 is involved in migraine mechanisms and GLP-1R agonists are beneficial in individuals with idiopathic intracranial hypertension. Additionally, GLP-1R agonists reduce visceral hypersensitivity and ameliorate symptoms in patients with irritable bowel syndrome., Conclusions: The therapeutic scope of GLP-1R agonists is expanding beyond traditional metabolic targets, highlighting its potential for headache and pain disorders. Engineering bimodal molecules that integrate GLP-1R agonism with specific pain-related mechanisms may offer innovative therapeutic options., (© 2024. The Author(s).)

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., Methods: An exploratory questionnaire-based survey took place online between November 2022 and June 2023. Participants were recruited through advertisements shared on social media accounts (e.g., Facebook and Instagram) and seasonal newsletters of three Danish patient associations. In addition, posters and flyers in headache and pain centers at Danish hospitals and private neurological, pain, and physiotherapeutic clinics were utilized., Results: A total of 314 adults with migraine with and/or without aura completed the survey. Among the respondents, 236 individuals (75.2%) regularly used triptans to treat their migraines. Compared with non-triptan users, individuals using triptans were characterized by significantly more foods and/or drinks triggering migraine (74.2% vs. 56.4%, p = 0.005). Alcoholic beverages and most specifically red wine were overreported as migraine triggers by triptan users (48.3% vs. 21.8%, p < 0.001). In the week preceding the survey, red wine was significantly less consumed by triptan users than non-triptan users (92.4% vs. 76.9%, p < 0.001)., Conclusions: Patients who regularly consume triptans report red wine most frequently as a migraine trigger. Triptan users are characterized by a lower consumption of red wine than non-triptan users, suggesting that a regular triptan intake may promote an increased sensitivity to red wine-induced migraine., (© 2024 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

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., Areas Covered: The key milestones in its development, including preclinical achievements, phase I, II, and III clinical trials, and regulatory approvals are reviewed. Additionally, clinical efficacy, safety profile, and tolerability of atogepant are discussed. The literature review is based on a comprehensive search of English peer-reviewed articles from various electronic databases, including PubMed and ClinicalTrials.gov., Expert Opinion: The development of atogepant represents a significant breakthrough in migraine prevention, particularly due to its improved safety profile that reduces the risk of liver injury, which was a major limitation of first-generation gepants. Drug-drug interaction studies with atogepant highlight the necessity for more inclusive study populations. Given that migraine disproportionately affects females, future clinical development programs should include diverse patient demographics to ensure the findings are generalizable to all individuals suffering from migraine.

Abstract: 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. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a K ATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo ( P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo ( P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo ( P = 0.037). These findings demonstrate that K ATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of K ATP channel inhibitors as therapeutic agents for cluster headaches., (Copyright © 2023 International Association for the Study of Pain.)

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., Areas Covered: We focused on conventional treatments, emerging therapies, and novel compounds in clinical development, including therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic therapies, and other options. English peer-reviewed articles were searched in PubMed, Scopus, and ClinicalTrials.gov electronic databases., Expert Opinion: Several novel treatment options for migraine have become available in recent years. Emerging pharmacological therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic interventions, and other emerging treatment modalities, may prove to be valuable for the treatment of migraine. Further research, clinical trials, and substantiated evidence are necessary to validate the efficacy, safety, and long-term outcomes of these therapeutic options.

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 1 ) receptor for migraine prevention., Areas Covered: This review focuses on the significance of the PACAP-38 pathway as a target in migraine prevention. English peer-reviewed articles were searched in PubMed, Scopus and ClinicalTrials.gov electronic databases., Expert Opinion: A PAC 1 receptor monoclonal antibody was not effective for preventing migraine in a proof-of-concept trial, paving the way for alternative strategies to be considered. Lu AG09222 is a humanized monoclonal antibody targeting PACAP-38 that was effective in preventing physiological responses of PACAP38 and reducing monthly migraine days in individuals with migraine. Further studies are necessary to elucidate the clinical utility, long-term safety and cost-effectiveness of therapies targeting the PACAP pathway.

Competing Interests: The author has been employed at Lundbeck in the past two years.

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., Areas Covered: This perspective covers the main characteristics and applications of the human NTG model of migraine with effective and ineffective antimigraine therapies., Expert Opinion: The NTG model represents a potential de-risking strategy to test novel hypotheses for antimigraine mechanisms in humans. Considering previous studies conducted with effective and ineffective antimigraine therapies, the sensitivity of the model was 71% while the specificity was 100%. The probability that following an analgesic effect, that compound would truly be efficacious in individuals with migraine was 100%. Following a negative result, the probability that such compound would truly be ineffective in patients with individuals was 33%. A clinical trial testing the analgesic properties of novel compounds after a sublingual and/or intravenous NTG challenge in migraine patients may support a subsequent phase 2 trial for the treatment of migraine.

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. Blood collection was performed at T 0 , T 20 , T 30 , and T 90 . Plasma levels of VIP were measured using a validated radioimmunoassay method., Results: Blood samples were collected from participants with episodic cluster headache in the active phase (eCHA, n = 14), remission (eCHR, n = 15), and from participants with chronic cluster headache (cCH, n = 15). Baseline levels of VIP did not differ among the three groups ( p = 0.1161). During PACAP infusion, mixed-effects analysis revealed a significant increase in plasma levels of VIP in eCHA ( p = 0.0300) and eCHR ( p = 0.0058) but not in cCH ( p = 0.2930). We found no difference in the increase of plasma VIP levels between patients who developed PACAP38- or VIP-induced attacks., Conclusion: Cluster headache attacks induced by PACAP38 or VIP infusion are not associated with changes in plasma levels of VIP. Further studies are needed to investigate the role of VIP and the parasympathetic system in cluster headache., Clinical Trial Registration: The parent study is registered at ClinicalTrials.gov (NCT03814226)., Competing Interests: MA reported receiving personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals during the conduct of the study. MA reported serving as Associate Editor of Cephalalgia, Associate Editor of The Journal of Headache and Pain, and Associate Editor of Brain. AS and LP are currently employed at Lundbeck. The opinions expressed in this manuscript are solely their own and do not express the views or opinions of Lundbeck. RJ reported fees from lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan and that she has been or is investigator in clinical trials with Eli-Lilly, Novartis and Lundbeck. She is also director of Danish Headache Center, Lifting The Global Burden of Headache and director of Master of Headache Disorders at University of Copenhagen. She has received research funding from the University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation, and Tryg Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Deligianni, Pellesi, Chaudhry, Haulund Vollesen, Snoer, Hannibal, Jensen and Ashina.)

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. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T 0 ), at the end of the infusion (T 20 ), 10 min after the infusion (T 30 ), and 70 min after the infusion (T 90 )., Results: Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide ( p  = 0.7074), tryptase ( p  = 0.6673), or histamine ( p  = 0.4792) remained unchanged during provoked attacks compared to attack-free patients., Conclusion: Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation. Trial Registration : The study is registered at ClinicalTrials.gov (NCT03814226).

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., Materials and Methods: We enrolled individuals with episodic migraine without aura and healthy participants to randomly receive a 2-h infusion of either VIP (8 pmol/kg/min) or placebo (sterile saline) in two randomized, placebo-controlled crossover trials. We collected clinical data and measured plasma levels of VIP and CGRP at fixed time points: at baseline (T 0 ) and every 30 min until 180 min (T 180 ) after the start of the infusion., Results: Blood samples were collected from patients with migraine ( n = 19) and healthy individuals ( n = 12). During VIP infusion, mixed effects analysis revealed a significant increase in plasma CGRP ( p = 0.027) at T 30 (vs. T 180 , adjusted p- value = 0.039) and T 60 (vs. T 180 , adjusted p -value = 0.027) in patients with migraine. We found no increase in plasma CGRP during VIP-induced migraine attacks ( p = 0.219). In healthy individuals, there was no increase in plasma CGRP during VIP ( p = 0.205) or placebo ( p = 0.428) days., Discussion: Plasma CGRP was elevated in patients with migraine during a prolonged infusion of VIP, but these alterations were not associated with VIP-induced migraine attacks. Given the exploratory design of our study, further investigations are needed to clarify the role of CGRP in VIP-induced migraine., Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03989817 and NCT04260035., Competing Interests: MA reported receiving personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva Pharmaceuticals during the conduct of the study. MA reported serving as Associate Editor of Cephalalgia, The Journal of Headache and Pain and Brain. FA is principal investigator for a phase IV trial for Teva. FA has received personal fees for lecturing and/or participating in advisory boards for Teva, Novartis, Eli Lilly and Lundbeck. CL reported being full employee at Roche Holding AG and shareholder of Novartis International AG. JS reported being full-time employee and shareholder of Novartis International AG. MA-K reported being an invited speaker for Novartis and receiving fees from ElectroCore. JH reported receiving fees from the Danish Biotechnology Center for Cellular Communication. CL and JS were employed by Novartis Pharma AG. This study received funding from Novartis Pharma AG. The funder had the following involvement with the study: support for study design and critical revision of the manuscript., (Copyright © 2022 Pellesi, Al-Karagholi, De Icco, Chaudhry, Lopez, Snellman, Hannibal, Amin and Ashina.)

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. Given these data, phytocannabinoids, as well as synthetic cannabinoids, have been tried as migraine treatments. In this narrative review, the current clinical evidence of potential ECS involvement in migraine pathogenesis is summarized. Furthermore, studies exploring the clinical effects of phytocannabinoids and synthetic cannabinoids on migraine patients are reviewed.

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., Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month., Interventions: Patients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days., Main Outcomes and Measures: The primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo., Results: Twenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P < .001). The VIP-induced migraine attacks mimicked patients' spontaneous attacks. The area under the curve (AUC) of headache intensity scores (0-12 hours), as well as the AUC of the superficial temporal artery diameter (0-180 minute) were significantly greater after VIP compared with placebo (AUC0-12h, P = .003; AUC0-180min, P < .001)., Conclusions and Relevance: A 2-hour infusion of VIP caused migraine attacks, suggesting an important role of VIP in migraine pathophysiology. VIP and its receptors could be potential targets for novel migraine drugs., Trial Registration: ClinicalTrials.gov Identifier: NCT04260035.

Background : 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. In addition, little is known on the factors leading to such heterogeneity. Research design and methods : Clinical trials evaluating the occurrence of ADRs related to erenumab in migraine patients were searched with Ovid MEDLINE until April 2020. Random intercept models were used to estimate the pooled incidence of the ADRs reported at least in 5 different study populations. To examine whether specific factors correlated with the pooled incidence, we performed random-effects meta-regression. Results : Of 138 retrieved references, 8 clinical trials were included in the meta-analysis. We observed a significant heterogeneity of the incidence estimates of back pain, influenza, nasopharyngitis, and upper respiratory tract infection (URTI). Most of the observed heterogeneity is ascribed to treatment duration for back pain ( p = 0.045), influenza ( p < 0.001) and URTI ( p < 0.001), and significantly attributed to Body Mass Index (BMI) for nasopharyngitis ( p < 0.001). Conclusions : Back pain, influenza, nasopharyngitis and URTI showed a significant heterogeneity of incidence estimates.

Background: In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified., Methods: In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo., Results: The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo ( p  < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher ( p  = 0.003) on the VIP day compared to the placebo day. The difference in headache intensity scores was more evident in the post-infusion period (120-200 min, p  = 0.034) and in the post-hospital phase (4-12 h, p  = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo ( p  = 0.033)., Conclusion: Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03989817).

Purpose of the Study: The pathophysiological mechanism of medication overuse headache is uncertain; no distinctive markers have been described right now. The aim of this study was to conduct proteomic analyses on serum samples from patients with medication overuse headache and healthy individuals. Specifically, mono- (SDS-PAGE) and two-dimensional gel electrophoresis (2-DE) followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to evaluate changes in serum proteins., Main Findings: By SDS-PAGE, four over-expressed bands were revealed in patients, compared to controls. 2-DE combined with LC-MS/MS analysis allowed confirmation of some proteins preliminarily detected by SDS-PAGE: Hemopexin, alpha-1-acid glycoprotein 1, apolipoprotein A4 and haptoglobin. Moreover, other differential proteins were isolated, mostly increased in MOH patients: Alpha-1-antitrypsin, immunoglobulin heavy constant alpha 1, retinol binding protein and transthyretin. Only one protein, immunoglobulin kappa constant, was decreased in the patients' group., Conclusions: The investigation of the serum proteome can offer a better understanding about biological mechanisms underlying medication overuse headache. Specifically, medication overuse headache shares some serum biochemical markers with chronic pain conditions. Further studies might uncover the relevance of these proteins in medication overuse headache.

Objective: To narratively review the pathophysiological rationale of dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A in treatment-resistant chronic migraine prevention., Background: For the prevention of chronic migraine, several pharmacological therapies are available, including oral medications, botulinum toxin type A, and the newly approved monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. However, monotherapy does not yield benefits in some affected individuals, which raises the question of whether dual therapy with monoclonal antibodies and botulinum toxin type A hold promise in patients with treatment-resistant chronic migraine., Method: We searched MEDLINE for articles published from database inception to December 31st, 2019. Publications were largely selected from the past 10 years but commonly referenced and highly regarded older publications were not excluded., Results: Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab - an antibody targeting the calcitonin gene-related peptide - mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers., Conclusion: There is currently only indirect preclinical evidence to support a rationale for dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A for chronic migraine prevention. Rigorous studies evaluating clinical efficacy, safety, and cost-effectiveness are needed., (© 2020 American Headache Society.)

Background: The notion that smoking cannabis may damage the respiratory tract has been introduced in recent years but there is still a paucity of studies on this subject. The aim of this study was to investigate the relationship between cannabis smoking, pneumothorax and bullous lung disease in a population of operated patients., Methods and Findings: We performed a retrospective study on patients operated on for spontaneous pneumothorax. Patients were divided into three groups according to their smoking habit: cannabis smokers, only-tobacco smokers and nonsmokers. Cannabis lifetime exposure was expressed in dose-years (1d/y = 1 gram of cannabis/week for one year). Clinical, radiological and perioperative variables were collected. The variables were analyzed to find associations with smoking habit. The impact of the amount of cannabis consumption was also investigated by ROC curves analysis. Of 112 patients, 39 smoked cannabis, 23 smoked only tobacco and 50 were nonsmokers. Median cannabis consumption was 28 dose/years, median tobacco consumption was 6 pack/years. Cannabis smokers presented with more severe chronic respiratory symptoms and bullous lung disease and with a higher incidence of tension pneumothorax than both tobacco smokers and nonsmokers. Cannabis smokers also developed a larger pneumothorax, experienced prolonged postoperative stay and demonstrated a higher incidence of pneumothorax recurrence after the operation than nonsmokers did. The risk of occurrence of chronic respiratory symptoms and bullous lung disease in cannabis smokers was dose-related., Conclusions: Cannabis smoking seems to increase the risk of suffering from respiratory complaints and can have detrimental effects on lung parenchyma, in a dose-dependent manner. Cannabis smoking also negatively affected the outcome of patients operated for spontaneous pneumothorax. A history of cannabis abuse should always be taken in patients with pneumothorax. There may be need for a specific treatment for pneumothorax in cannabis smokers., Competing Interests: The Authors have declared that no competing interests exist

Background: Nummular headache (NH) is a rare headache disorder characterized by a small, circumscribed painful area of the scalp. The description of many cases in the last years has supported its re-classification as a primary headache from the International Headache Society, moving it from its previous placement in the Appendix of the International Criteria of Headache Disorders., Methods: Data were collected from a retro-prospective observational study about rare headaches promoted by the RegistRare Network, a collaborative group of seven Italian Headache Centres. According to the gender-biased profile of certain primary headaches, we have looked further NH patients from a gender perspective., Results: Nineteen NH patients (11 men, 8 women) have been enrolled in the study. Headache onset was at 39 years and preceded approximately 8 years the diagnosis. No clinically evident differences between men and women have been found, including treatment prescriptions and headache resolution. Of note, the mean time from the onset of NH to the first visit in a Headache Centre was longer in men, compared with women (13.5 vs. 0.9 years). NH attacks were efficaciously treated with nonsteroidal anti-inflammatory drugs in 60% of patients receiving treatment. Headache prophylaxis with pregabalin and amitriptyline has been reported as effective in 40% and 67% of the treated patients, respectively., Conclusions: NH is a primary headache clinically heterogeneous in terms of temporal patterns and pain characteristics. Further research is needed to investigate the existence of male and female phenotypes, by clarifying whether it may be relevant for therapeutic purposes.

Background: Medication Overuse Headache (MOH) is a prevalent and disabling disorder resulting from the overuse of analgesic drugs, triptans or other acute headache medications. In previous proteomic studies, several proteins have been found at high concentrations in the urine of MOH patients and in the serum of rats with neuropathic pain. The aim of this study was to compare the serum levels of lipocalin-type Prostaglandin D2 synthase (L-PGDS), Vitamin D-binding protein (VDBP), apolipoprotein E (APOE) and apolipoprotein A1 (APOA1) in MOH patients and healthy individuals, further exploring their relationship with cutaneous pain thresholds (CPTs) in the territories innervated by the trigeminal nerve., Methods: Sixty-nine MOH patients and 42 age- and sex-matched healthy volunteers were enrolled in the study. Von Frey-like filaments were applied to the skin territories innervated by the trigeminal nerve, to determine the CPTs. L-PGDS, VDBP, APOE and APOA1 were quantified in the serum by Enzyme-linked Immunosorbent Assay (ELISA). Clinical and laboratory data were collected. Comparisons between MOH patients and healthy individuals were performed using independent t test or χ 2 test. To correlate serum proteins with CPTs, Pearson correlation coefficient or Spearman's rank correlation coefficient were used., Results: CPTs were lower among MOH patients. L-PGDS, VDBP and APOE had significantly different serum concentrations between groups (p < 0.01), but no correlation was found with CPTs. APOA1 serum concentrations did not differ between patients and healthy individuals., Conclusions: L-PGDS, VDBP and APOE had abnormal serum levels in MOH patients, confirming their alteration in some conditions of chronic headache and neuropathic pain. However, they had no relationship with CPTs. The in-depth study of serum proteins represents a promising approach for a better understanding of MOH, as well as the detection of candidate biomarkers for chronic headache or the risks associated with overuse medications.

Background: Daily cannabis assumption is currently associated with several physical and mental health problems, however in the past it was prescribed for a multitude of symptoms, including vomiting, abdominal pain and diarrhea. Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders., Case Presentation: We retrospectively analysed the efficacy and safety of a CB1-receptor agonist administered in six patients with refractory chronic diarrhea, between April 2008 and July 2016. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. Most of the benefits persisted through the three-month follow-up. Only one patient interrupted the treatment after one month, due to severe fatigue and mental confusion; the symptoms disappeared in the follow-up period., Conclusions: These findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.

Introduction: Recommended medications for the acute treatment of migraine encompass triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics. While it is true that triptans have been the first successful mechanism-driven treatment in the field, recently, new targets involved in migraine pathogenesis have emerged and new drug classes have been studied for migraine attack therapy. Areas covered: Pharmacodynamics and pharmacokinetics of the new acute treatments of migraine (i.e. ditans, gepants, and glutamate receptor antagonists), considering also marketed drugs in new formulations and administration routes. Expert opinion: Research on the administration routes of marketed drugs was performed in order to improve, in accordance with basic pharmacokinetics parameters, the speed of action of these medications. Similar to the triptans, the new acute treatments are migraine-specific medications, acting on the trigeminovascular system, albeit with different mechanisms. Although available data do not conclusively indicate the superiority of a class over the others, the pharmacodynamics explains the peculiar tolerability and safety profile of different drug classes emerging from clinical trials. Further studies are needed to investigate the possibility of combining different drug classes to optimize the clinical response and the potential role of the novel drugs in medication-overuse headache.

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting., Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version., Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity., Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Purpose: The recent release of a medical cannabis strain has given a new impulse for the study of cannabis in Italy. The National Health Service advises to consume medical cannabis by vaporizing, in decoction or oil form. This is the first study that explores the pharmacokinetics and tolerability of a single oral dose of cannabis as decoction (200 ml) or in olive oil (1 ml), as a first step to improve the prescriptive recommendations., Methods: This is a single-center, open-label, two-period crossover study designed to assess the pharmacokinetics and tolerability of oral cannabis administered to 13 patients with medication overuse headache (MOH). A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was conducted for the quantification of THC, CBD, 11-OH-THC, THC-COOH, THC-COOH-glucuronide, THCA-A, and CBDA. Blood pressure, heart rate, and a short list of symptoms by numerical rating scale (NRS) were assessed., Results: Decoctions of cannabis showed high variability in cannabinoids content, compared to cannabis oil. For both preparations, THCA-A and CBDA were the most widely absorbed cannabinoids, while THC and CBD were less absorbed. The most important differences concern the bioavailability of THC, higher in oil (AUC 0-24 7.44, 95% CI 5.19, 9.68) than in decoction (AUC 0-24 3.34, 95% CI 2.07, 4.60), and the bioavailability of CBDA. No serious adverse events were reported., Conclusions: Cannabis decoction and cannabis oil showed different pharmacokinetic properties, as well as distinct consequences on patients. This study was performed in a limited number of patients; future studies should be performed to investigate the clinical efficacy in larger populations.

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.

Drug interactions are one of the most common causes of side effects in polypharmacy. Alcoholics are a category of patients at high risk of pharmacological interactions, due to the presence of comorbidities, the concomitant intake of several medications and the pharmacokinetic and pharmacodynamic interferences of ethanol. However, the data available on this issue are limited. These reasons often frighten clinicians when prescribing appropriate pharmacological therapies for alcohol use disorder (AUD), where less than 15% of patients receive an appropriate treatment in the most severe forms. The data available in literature regarding the relevant drug-drug interactions of the medications currently approved in United States and in some European countries for the treatment of AUD (benzodiazepines, acamprosate, baclofen, disulfiram, nalmefene, naltrexone and sodium oxybate) are reviewed here. The class of benzodiazepines and disulfiram are involved in numerous pharmacological interactions, while they are not conspicuous for acamprosate. The other drugs are relatively safe for pharmacological interactions, excluding the opioid withdrawal syndrome caused by the combination of nalmefene or naltrexone with an opiate medication. The information obtained is designed to help clinicians in understanding and managing the pharmacological interactions in AUDs, especially in patients under multi-drug treatment, in order to reduce the risk of a negative interaction and to improve the treatment outcomes., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background Rare primary headaches are mainly included in Chapters 3, Trigeminal autonomic cephalalgias, and 4, Other primary headache disorders, Part One of the International Classification of Headache Disorders 3rd edition. Epidemiological data are scarce, mostly emerging from case series or small studies, with the exception of cluster headache. In order to overcome the knowledge gap about rare primary headaches, the RegistRare Network was launched in 2017 to promote research in the field. Methods A retrospective cohort study including patients who, from April 30, 2014 to May 1, 2017, visited seven Italian tertiary Headache Centres, was undertaken to estimate in that clinical setting prevalence and incidence of headaches included in Chapters 3 and 4, Part One of the International Classification of Headache Disorders 3rd edition. Prevalent headache is defined as a headache recorded within the study timeframe, regardless of when the diagnosis was made. Incident headache is defined as a headache diagnosed for the first time in the patient during the study period. Results Twenty thousand and eighty-three patients visited the participating centres, and 822 (4.1%) prevalent cases, of which 461 (2.3%) were incident cases, were registered. Headaches listed in Chapter 3 affected 668 patients, representing 81.3% of the total number of prevalent cases. Headaches listed in Chapter 4 affected 154 patients and represent 18.7% of the total number of prevalent cases. Cluster headaches represent the most frequently diagnosed rare headaches (70.4%). For 13 entities out of 20, no cases were registered in more than 50% (n ≥ 4) of the centres, and for 14 entities more than 50% of diagnoses were incident. Conclusions This large, multicentre study gives the first wide-ranging snapshot of the burden in clinical practice of rare headaches and confirms that cooperative networks are necessary to study rare headaches, as their prevalence is often very low. The launch of a disease registry by the RegistRare Network will favour research in this neglected population of headache patients. Trial registration NCT03416114.