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Journal of Neurology Jul 2023Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system... (Review)
Review
Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system areas and networks. A growing increase in the understanding of migraine pathophysiology in recent years has facilitated translation of that knowledge into novel treatments, which are currently becoming available to patients in many parts of the world and are substantially changing the clinical approach to the disease. In the first part of this review, we will provide an up to date overview of migraine pathophysiology by analyzing the anatomy and function of the main regions involved in the disease, focusing on how these give rise to the plethora of symptoms characterizing the attacks and overall disease. The second part of the paper will discuss the novel therapeutic agents that have emerged for the treatment of migraine, including molecules targeting calcitonin gene-related peptide (gepants and monoclonal antibodies), serotonin 5-HT receptor agonists (ditans) and non-invasive neuromodulation, as well as providing a brief overview of new evidence for classic migraine treatments.
Topics: Humans; Migraine Disorders; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Receptors, Calcitonin Gene-Related Peptide; Migraine with Aura
PubMed: 37029836
DOI: 10.1007/s00415-023-11706-1 -
The Journal of Headache and Pain Jul 2023Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3 edition of the International... (Review)
Review
Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3 edition of the International Classification of Headache Disorders. Migraine is identified by specific features such as being more prevalent in females, being aggravated by physical activity, certain genetic factors, having photophobia, phonophobia, nausea, vomiting, or aura, and responding to specific drugs. Nonetheless, TTH and migraine share some common characteristics, such as onset occurring in the 20 s, and being triggered by psychological factors like stress, moderate pain severity, and mild nausea in chronic TTH. Both conditions involve the trigeminovascular system in their pathophysiology. However, distinguishing between TTH and migraine in clinical practice, research, and epidemiological studies can be challenging, as there is a lack of specific diagnostic tests and biomarkers. Moreover, both conditions may coexist, further complicating the diagnostic process. This review aims to explore the similarities and differences in the pathophysiology, epidemiology, burden and disability, comorbidities, and responses to pharmacological and non-pharmacological treatments of TTH and migraine. The review also discusses future research directions to address the diagnostic challenges and improve the understanding and management of these conditions.
Topics: Female; Humans; Tension-Type Headache; Migraine Disorders; Headache; Headache Disorders; Nausea
PubMed: 37474899
DOI: 10.1186/s10194-023-01614-0 -
The Journal of Headache and Pain Jun 2023Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal... (Review)
Review
BACKGROUND
Migraine 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.
FINDINGS
We 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 PAC antibody have been tested for migraine treatment, albeit with ambiguous results.
CONCLUSION
While 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.
Topics: Humans; Adrenomedullin; Calcitonin Gene-Related Peptide; Headache Disorders; Islet Amyloid Polypeptide; Migraine Disorders; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Calcitonin Gene-Related Peptide
PubMed: 37370051
DOI: 10.1186/s10194-023-01567-4 -
Medicine Jul 2023Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later...
Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later to be due to decreased acetylcholine release. The 1970s were marked by studies of cellular mechanisms aided by use of neutralizing antibodies as pharmacologic tools: BoNT/A disappeared from accessibility to neutralizing antibodies within minutes, although it took several hours for onset of muscle weakness. The multi-step mechanism was experimentally confirmed and is now recognized to consist broadly of binding to nerve terminals, internalization, and lysis or cleavage of a protein (SNAP-25: synaptosomal associated protein-25 kDa) that is part of the SNARE (Soluble NSF Attachment protein REceptor) complex needed for synaptic vesicle docking and fusion. Clinical use of the BoNT/A product onabotulinumtoxinA was based on its ability to reduce muscle contractions via inhibition of acetylcholine from motor terminals. Sensory mechanisms of onabotulinumtoxinA have now been identified, supporting its successful treatment of chronic migraine and urgency in overactive bladder. Exploration into migraine mechanisms led to anatomical studies documenting pain fibers that send axons through sutures of the skull to outside the head-a potential route by which extracranial injections could affect intracranial processes. Several clinical studies have also identified benefits of onabotulinumtoxinA in major depression, which have been attributed to central responses induced by feedback from facial muscle and skin movement. Overall, the history of BoNT/A is distinguished by basic science studies that stimulated clinical use and, conversely, clinical observations that spurred basic research into novel mechanisms of action.
Topics: Humans; Botulinum Toxins, Type A; Acetylcholine; Urinary Bladder, Overactive; Migraine Disorders; Muscle Contraction
PubMed: 37499078
DOI: 10.1097/MD.0000000000032372 -
Journal of Neurology Dec 2023In individuals with migraine, attacks may increase in frequency, severity, or both. Preventing migraine progression has emerged as a treatment goal in headache... (Review)
Review
BACKGROUND
In individuals with migraine, attacks may increase in frequency, severity, or both. Preventing migraine progression has emerged as a treatment goal in headache subspecialty practice, but there may be less awareness in general neurology or primary care settings where most people with migraine who seek treatment consult. Herein, we review the definition of and risk factors for migraine progression and consider strategies that could reduce its risk.
METHODS
A group of headache expert healthcare professionals, clinicians, and researchers reviewed published evidence documenting factors associated with increased or decreased rates of migraine progression and established expert opinions for disease management recommendations. Strength of evidence was rated as good, moderate, or based solely on expert opinion, using modified criteria for causation developed by AB Hill.
RESULTS
Migraine progression is commonly operationally defined as the transition from ≤ 15 to ≥ 15 monthly headache days among people with migraine; however, this does not necessarily constitute a fundamental change in migraine biology and other definitions should be considered. Established and theoretical key risk factors for migraine progression were categorized into five domains: migraine disease characteristics, treatment-related factors, comorbidities, lifestyle/exogenous factors, and demographic factors. Within these domains, good evidence supports the following risk factors: poorly optimized acute headache treatment, cutaneous allodynia, acute medication overuse, selected psychiatric symptoms, extra-cephalic chronic pain conditions, metabolism-related comorbidities, sleep disturbances, respiratory conditions, former/current high caffeine intake, physical inactivity, financial constraints, tobacco use, and personal triggers as risk factors. Protective actions that may mitigate migraine progression are sparsely investigated in published literature; our discussion of these factors is primarily based on expert opinion.
CONCLUSIONS
Recognizing risk factors for migraine progression will allow healthcare providers to suggest protective actions against migraine progression (Supplementary Fig. 1). Intervention studies are needed to weight the risk factors and test the clinical benefit of hypothesized mitigation strategies that emerge from epidemiological evidence.
Topics: Humans; Migraine Disorders; Chronic Disease; Risk Factors; Headache; Disease Progression; Patient-Centered Care
PubMed: 37615752
DOI: 10.1007/s00415-023-11880-2 -
International Journal of Molecular... Jul 2023Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules... (Review)
Review
Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.
Topics: Humans; Animals; Migraine Disorders; Signal Transduction; Vasoactive Intestinal Peptide; Potassium Channels; Analgesics, Opioid
PubMed: 37569648
DOI: 10.3390/ijms241512268 -
The Journal of Headache and Pain Sep 2023Targeting 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... (Review)
Review
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.
Topics: Humans; Antibodies, Monoclonal; Calcitonin Gene-Related Peptide Receptor Antagonists; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide; Signal Transduction
PubMed: 37691118
DOI: 10.1186/s10194-023-01644-8 -
Nutrients Jul 2023Consumption of caffeine in the diet, both daily and occasional, has a significant biological effect on the nervous system. Caffeine, through various and not yet fully... (Review)
Review
Consumption of caffeine in the diet, both daily and occasional, has a significant biological effect on the nervous system. Caffeine, through various and not yet fully investigated mechanisms, affects headaches. This is especially noticeable in migraine. In other headaches such as hypnic headache, post-dural puncture headache and spontaneous intracranial hypotension, caffeine is an important therapeutic agent. In turn, abrupt discontinuation of chronically used caffeine can cause caffeine-withdrawal headache. Caffeine can both relieve and trigger headaches.
Topics: Humans; Caffeine; Headache; Migraine Disorders
PubMed: 37513588
DOI: 10.3390/nu15143170 -
Brain : a Journal of Neurology Oct 2023Migraine, especially chronic migraine, is highly debilitating and still lacks effective treatment. The persistent headache arises from activation and sensitization of...
Migraine, especially chronic migraine, is highly debilitating and still lacks effective treatment. The persistent headache arises from activation and sensitization of primary afferent neurons in the trigeminovascular pathway, but the underlying mechanisms remain incompletely understood. Animal studies indicate that signalling through chemokine C-C motif ligand 2 (CCL2) and C-C motif chemokine receptor 2 (CCR2) mediates the development of chronic pain after tissue or nerve injury. Some migraine patients had elevated CCL2 levels in CSF or cranial periosteum. However, whether the CCL2-CCR2 signalling pathway contributes to chronic migraine is not clear. Here, we modelled chronic headache with repeated administration of nitroglycerin (NTG, a reliable migraine trigger in migraineurs) and found that both Ccl2 and Ccr2 mRNA were upregulated in dura and trigeminal ganglion (TG) tissues that are implicated in migraine pathophysiology. In Ccl2 and Ccr2 global knockout mice, repeated NTG administration did not evoke acute or persistent facial skin hypersensitivity as in wild-type mice. Intraperitoneal injection of CCL2 neutralizing antibodies inhibited chronic headache-related behaviours induced by repeated NTG administration and repetitive restraint stress, suggesting that the peripheral CCL2-CCR2 signalling mediates headache chronification. We found that CCL2 was mainly expressed in TG neurons and cells associated with dura blood vessels, whereas CCR2 was expressed in subsets of macrophages and T cells in TG and dura but not in TG neurons under both control and disease states. Deletion of Ccr2 gene in primary afferent neurons did not alter NTG-induced sensitization, but eliminating CCR2 expression in either T cells or myeloid cells abolished NTG-induced behaviours, indicating that both CCL2-CCR2 signalling in T cells and macrophages are required to establish chronic headache-related sensitization. At cellular level, repeated NTG administration increased the number of TG neurons that responded to calcitonin-gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP) as well as the production of CGRP in wild-type but not Ccr2 global knockout mice. Lastly, co-administration of CCL2 and CGRP neutralizing antibodies was more effective in reversing NTG-induced behaviours than individual antibodies. Taken together, these results suggest that migraine triggers activate CCL2-CCR2 signalling in macrophages and T cells. This consequently enhances both CGRP and PACAP signalling in TG neurons, ultimately leading to persistent neuronal sensitization underlying chronic headache. Our work not only identifies the peripheral CCL2 and CCR2 as potential targets for chronic migraine therapy, but also provides proof-of-concept that inhibition of both peripheral CGRP and CCL2-CCR2 signalling is more effective than targeting either pathway alone.
Topics: Animals; Mice; Calcitonin Gene-Related Peptide; Chemokine CCL2; Headache; Mice, Knockout; Migraine Disorders; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, CCR2; Receptors, Chemokine
PubMed: 37284790
DOI: 10.1093/brain/awad191 -
The Journal of Headache and Pain Sep 2023Intranasal agents may be ideal for the treatment of migraine patients. Many new acute intranasal-specific therapies have been developed, but few of them have been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intranasal agents may be ideal for the treatment of migraine patients. Many new acute intranasal-specific therapies have been developed, but few of them have been directly compared. The aim of this network meta-analysis (NMA) was to compare the efficacy and safety of various intranasal agents for the treatment of acute migraine in adult patients.
METHODS
The Cochrane Register of Controlled Trials, Embase, and PubMed were searched from inception to 15 August 2023. Randomized controlled trials (RCTs) using intranasal agents (no restrictions on dose, formulation, dosing regimen or timing of the first dose) to treat adult patients with acute migraine were included. The primary efficacy endpoint was pain freedom at 2 h, and the primary safety endpoint was adverse events (AEs). The analysis process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS
Nineteen studies (21 RCTs, 9738 participants) were included. Compared to the placebo, 5 mg of zolmitriptan using a conventional liquid nasal spray device was the most effective for pain freedom at 2 h [odds ratio (OR): 4.67, 95% confidence interval (CI): 3.43 to 6.43] and 24 h (OR: 5.49, 95% CI: 3.58 to 8.42) among all the interventions. Butorphanol nasal spray 1 mg was the most effective (OR: 8.62, 95% CI: 1.11 to 66.92) for pain freedom at 1 h, but with low-quality evidence. DFN-02 presented the highest freedom from nausea (OR: 4.95, 95% CI: 1.29 to 19.01) and phonophobia (OR: 5.36, 95% CI: 1.67 to 17.22) at 2 h, albeit with lower odds of achieving complete pain freedom. ROX-828 showed the highest improvement in freedom from photophobia at 2 h (OR: 4.03, 95% CI: 1.66 to 9.81). Dihydroergotamine nasal spray was significantly associated with the highest risk of AEs (OR: 9.65, 95% CI: 4.39 to 21.22) and was not recommended for routine use. Zavegepant nasal spray demonstrated the lowest risk of AEs (OR: 2.04, 95% CI: 1.37 to 3.03). The results of sensitivity analyses for the primary endpoints (pain freedom at 2 h and AEs) were generally consistent with those of the base case model.
CONCLUSIONS
Compared with other new intranasal-specific therapies in treating migraine attacks, zolmitriptan nasal spray 5 mg was the most effective agent for pain freedom at 2 h. Zavegepant nasal spray 10 mg had the fewest adverse side effects.
Topics: Adult; Humans; Nasal Sprays; Network Meta-Analysis; Migraine Disorders; Oxazolidinones
PubMed: 37723470
DOI: 10.1186/s10194-023-01662-6