-
Clinical and Translational Science Jan 2024Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated... (Review)
Review
Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.
Topics: Adult; Humans; Translational Science, Biomedical; Calcitonin Gene-Related Peptide; Antibodies, Monoclonal; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds
PubMed: 38266063
DOI: 10.1111/cts.13707 -
Biomolecules Jan 2024Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in... (Review)
Review
Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this risk becomes even higher in patients suffering from chronic migraine or migraine with aura. This relationship is bidirectional, since depression also predicts an earlier/worse onset of migraine, increasing the risk of migraine chronicity and, consequently, requiring a higher healthcare expenditure compared to migraine alone. All these data suggest that migraine and depression may share overlapping biological mechanisms. Herein, this review explores this topic in further detail: firstly, by introducing the common epidemiological and risk factors for this comorbidity; secondly, by focusing on providing the cumulative evidence of common biological aspects, with a particular emphasis on the serotoninergic system, neuropeptides such as calcitonin-gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y and orexins, sexual hormones, and the immune system; lastly, by remarking on the future challenges required to elucidate the etiopathological mechanisms of migraine and depression and providing updated information regarding new key targets for the pharmacological treatment of these clinical entities.
Topics: Humans; Depression; Pituitary Adenylate Cyclase-Activating Polypeptide; Migraine Disorders; Calcitonin Gene-Related Peptide; Neuropeptide Y
PubMed: 38397400
DOI: 10.3390/biom14020163 -
The Journal of Headache and Pain Aug 2023Headache is one of the most common neurological symptoms. Many previous studies have indicated a relationship between primary headaches and alcohol. Drinking has been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Headache is one of the most common neurological symptoms. Many previous studies have indicated a relationship between primary headaches and alcohol. Drinking has been associated with increased risk of tension-type headache (TTH) and migraine. However, recently published studies have not confirmed this relationship. The existing literature is inconclusive; however, migraine patients avoid alcohol. Therefore, the primary objective was to provide a reliable assessment of alcohol intake in people with primary headaches; the secondary objective was to identify any potential relationship between alcohol consumption and headache risk.
METHODS
This study was based on PubMed, Embase and Web of Science database searches performed on 11 July 2023. This systematic review was registered in PROSPERO (CRD42023412926). Risk of bias for the included studies was assessed using the Joanna Briggs Institute critical appraisal tools. Meta-analyses were performed using Statistica software. The Risk Ratio (RR) was adopted as the measure of the final effect. Analyses were based on a dichotomous division of the respondents into "non-drinkers" and "drinkers" for headache patients and matched non-headache groups.
RESULTS
From a total of 1892 articles, 22 were included in the meta-analysis. The majority demonstrated a moderate or high risk of bias. The first part of the meta-analysis was performed on data obtained from 19 migraine studies with 126 173 participants. The risk of migraine in alcohol drinkers is approximately 1.5 times lower than in the group of non-drinkers (RR = 0.71; 95% CI: 0.57-0.89). The second part involved 9 TTH studies with 28 715 participants. No relationship was found between TTH diagnosis and alcohol consumption (RR = 1.09; 95% CI: 0.93-1.27). Two of the included cluster-headache articles had inconclusive results.
CONCLUSIONS
Alcohol consumption and migraine are inversely correlated. The exact mechanism behind this observation may indicate that migraine leads to alcohol-avoidance, rather than alcohol having any protective role against migraine. There was no relationship between TTH and drinking. However, further studies related to primary headaches and alcohol consumption with low risk of bias are required. Additionally, patients and physicians should consider the latest medical data, in order to avoid the myths about alcohol consumption and primary headaches.
Topics: Humans; Ethanol; Headache; Migraine Disorders; Tension-Type Headache; Cluster Headache
PubMed: 37612595
DOI: 10.1186/s10194-023-01653-7 -
The Journal of Headache and Pain Aug 2023Given the similar presentation of migraine aura and acute ischemic stroke, advancing patient age might change the characteristics of migraine with aura (MA) and be...
AIM
Given the similar presentation of migraine aura and acute ischemic stroke, advancing patient age might change the characteristics of migraine with aura (MA) and be clinically important. Clinical data, however, are limited. Experimental studies indicate a decrease in the magnitude of cortical spreading depression (CSD), the pathophysiological correlate of migraine aura, with advancing age. Our study aimed to assess the influence of age on the clinical features of MA.
METHODS
Three hundred and forty-three patients were interviewed using a structured questionnaire. The questions covered the headache characteristics and symptom types including the characteristics of the C-criterion, as defined by the International Classification of Headache Disorders 3 Edition. The association of age with MA characteristics was assessed.
RESULTS
The median age was 29 (IQR 28-52) and 235 of the 343 patients were women (69%). Individual symptoms of the C-criterion such as gradual aura spreading over longer than 5 min (P < 0.001), two or more aura symptoms occurring in succession (P = 0.005), duration of at least one MA symptom for longer than 60 min (P = 0.004), and associated headache (P = 0.01) were more frequent in younger patients. The number of symptoms including the C-characteristics decreased with increasing age (P < 0.001). Patients with sensory (P < 0.001), motor (P = 0.004) and speech disturbance (P = 0.02) were younger, and older patients with headache had less photophobia (P = 0.04) and phonophobia (P = 0.03). Sensitivity analyses yielded similar results.
CONCLUSION
The frequency of typical characteristics of migraine aura and migraine headache including photophobia and phonophobia decreases with advancing patient age. This might have potentially difficult implications for the diagnosis of MA in the elderly.
Topics: Humans; Female; Aged; Adult; Male; Migraine with Aura; Ischemic Stroke; Hyperacusis; Photophobia; Migraine Disorders; Epilepsy; Headache
PubMed: 37528414
DOI: 10.1186/s10194-023-01642-w -
The Journal of Headache and Pain Aug 2023The premonitory phase, or prodrome, of migraine, provides valuable opportunities to study attack initiation and for treating the attack before headache starts. Much that... (Review)
Review
BACKGROUND
The premonitory phase, or prodrome, of migraine, provides valuable opportunities to study attack initiation and for treating the attack before headache starts. Much that has been learned about this phase in recent times has come from the outcomes of functional imaging studies. This review will summarise these studies to date and use their results to provide some feasible insights into migraine neurobiology.
MAIN BODY
The ability to scan repeatedly a patient without radiation and with non-invasive imaging modalities, as well as the recognition that human experimental migraine provocation compounds, such as nitroglycerin (NTG) and pituitary adenylate cyclase activating polypeptide (PACAP), can trigger typical premonitory symptoms (PS) and migraine-like headache in patients with migraine, have allowed feasible and reproducible imaging of the premonitory phase using NTG. Some studies have used serial scanning of patients with migraine to image the migraine cycle, including the 'pre-ictal' phase, defined by timing to headache onset rather than symptom phenotype. Direct observation and functional neuroimaging of triggered PS have also revealed compatible neural substrates for PS in the absence of headache. Various imaging methods including resting state functional MRI (rsfMRI), arterial spin labelling (ASL), positron emission tomography (PET) and diffusion tensor imaging (DTI) have been used. The results of imaging the spontaneous and triggered premonitory phase have been largely consistent and support a theory of central migraine attack initiation involving brain areas such as the hypothalamus, midbrain and limbic system. Early dysfunctional pain, sensory, limbic and homeostatic processing via monoaminergic and peptidergic neurotransmission likely manifests in the heterogeneous PS phenotype.
CONCLUSION
Advances in human migraine research, including the use of functional imaging techniques lacking radiation or radio-isotope exposure, have led to an exciting opportunity to study the premonitory phase using repeated measures imaging designs. These studies have provided novel insights into attack initiation, migraine neurochemistry and therapeutic targets. Emerging migraine-specific therapies, such as those targeting calcitonin gene-related peptide (CGRP), are showing promise acutely when taken during premonitory phase to reduce symptoms and prevent subsequent headache. Therapeutic research in this area using PS for headache onset prediction and early treatment is likely to grow in the future.
Topics: Humans; Diffusion Tensor Imaging; Migraine Disorders; Brain; Headache; Neuroimaging; Pituitary Adenylate Cyclase-Activating Polypeptide; Nitroglycerin
PubMed: 37563570
DOI: 10.1186/s10194-023-01617-x -
The Journal of Headache and Pain Jul 2023Insights into the burden, needs and treatment of migraine from internet-based surveys in diverse real-world migraine populations are needed, especially at a time when... (Review)
Review
BACKGROUND
Insights into the burden, needs and treatment of migraine from internet-based surveys in diverse real-world migraine populations are needed, especially at a time when novel preventive migraine medications are becoming part of the therapeutic armamentarium. The objectives of this analysis are to describe traditional preventive (orals and onabotulinum toxin A) treatment patterns in the OVERCOME (EU) study migraine cohort, as well as treatment patterns and patient satisfaction with current treatment in a subgroup of respondents eligible for migraine preventive medication.
METHODS
The cross-sectional non-interventional OVERCOME (EU) study was conducted (October 2020-February 2021) via an online survey among adults (aged ≥ 18 years) resident in Germany or Spain. Participants, registered in existing online panels, who were willing to provide consent were considered. The migraine cohort included participants reporting headache/migraine in the past year, identified based on a validated migraine diagnostic questionnaire and/or self-reported physician diagnosis. A subgroup of survey respondents defined as eligible for migraine preventive medication at the point in time the cross-sectional survey was taken was also analysed. Variables assessed included sociodemographic and migraine-related clinical characteristics, preventive (traditional and calcitonin gene-related peptide monoclonal antibodies) treatment patterns and patient satisfaction with current treatment. Results are descriptive only.
RESULTS
Of the 20,756 participants in the migraine cohort, 78.5% sought professional medical care, 50.8% received a migraine diagnosis and only 17.7% had ever used preventive medication. Half (53.3%) of participants currently using preventives took their most recent medication for six months or less. Most patients (73.9%) classified as eligible for preventive medication (based on headache frequency and/or at least moderate disability due to migraine) reported not using traditional preventives and many of those who did (66.8%) were not satisfied with their current standard of care.
CONCLUSIONS
Our findings highlight the low proportion of people diagnosed with migraine despite a higher rate of consultation and suggest the need for better access to treatment for people with migraine and new preventive therapies with improved efficacy and safety profiles to improve adherence and patient satisfaction.
Topics: Adult; Humans; Cross-Sectional Studies; Patient Satisfaction; Migraine Disorders; Surveys and Questionnaires; Headache
PubMed: 37460942
DOI: 10.1186/s10194-023-01623-z -
Frontiers in Immunology 2024Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this...
BACKGROUND
Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes.
METHODS
We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations.
RESULTS
No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases.
CONCLUSION
The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.
Topics: Humans; Mendelian Randomization Analysis; Migraine Disorders; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Immune System Diseases; Genome-Wide Association Study; Linkage Disequilibrium; Risk Factors
PubMed: 38650934
DOI: 10.3389/fimmu.2024.1376698 -
Brain : a Journal of Neurology Dec 2023There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified... (Randomized Controlled Trial)
Randomized Controlled Trial
There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.
Topics: Humans; Receptors, Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide; Cilostazol; Migraine Disorders; Second Messenger Systems; Cyclic AMP
PubMed: 37540009
DOI: 10.1093/brain/awad261 -
The Journal of Headache and Pain Jul 2023Menstrual migraine is a subtype of migraine disease that is typically more disabling, longer-lasting, and more challenging to treat. The purpose of this network... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Menstrual migraine is a subtype of migraine disease that is typically more disabling, longer-lasting, and more challenging to treat. The purpose of this network meta-analysis (NMA) is to compare the relative efficacy of treatments for menstrual migraine.
METHODS
We systematically searched databases, including PubMed, EMBASE, and Cochrane, and included all eligible randomized controlled trials in the study. We conducted the statistical analysis using Stata version 14.0, based on the frequentist framework. We used the Cochrane Risk of Bias tool for randomized trials version 2 (RoB2) to assess the risk of bias of the included studies.
RESULTS
This network meta-analysis included 14 randomized controlled trials with 4601 patients. For short-term prophylaxis, frovatriptan 2.5 mg twice daily had the highest probability of effectiveness [OR = 1.87 (95% CI: 1.48 to 2.38)] compared to placebo. For acute treatment, the results showed that sumatriptan 100 mg [OR = 4.32 (95% CI: 2.95 to 6.34)] was the most effective treatment compared to placebo.
CONCLUSIONS
These findings suggest that frovatriptan 2.5 mg twice daily was best for short-term prevention, sumatriptan 100 mg were best for acute treatment. More high-quality randomized trials are required to determine the most effective treatment.
Topics: Humans; Sumatriptan; Network Meta-Analysis; Migraine Disorders; Tryptamines
PubMed: 37400775
DOI: 10.1186/s10194-023-01625-x -
European Journal of Medical Research Jan 2024Allergic rhinitis (AR) and migraine are among the most common public health problems worldwide. Observational studies on the correlation between AR and migraine have...
PURPOSE
Allergic rhinitis (AR) and migraine are among the most common public health problems worldwide. Observational studies on the correlation between AR and migraine have reported inconsistent results. This study aimed to investigate the causal relationship of AR with migraine and its subtypes, including migraine with aura (MA) and migraine without aura (MO).
METHODS
Bidirectional two-sample Mendelian randomization (MR) analysis was performed with publicly available summary-level statistics of large genome-wide association studies to estimate the possible causal effects. The inverse variance-weighted method was selected for primary analysis and was supplemented with the weighted median, weighted mode, and MR-Egger methods. The causal analysis using summary effect estimates (CAUSE) were further performed to verify the causality. Several sensitivity tests, including the leave-one-out, Cochran's Q, MR-Egger intercept, and MR-PRESSO tests, were performed to assess the robustness of the results.
RESULTS
AR did not exhibit a significant causal correlation with the elevated risk of any migraine (odd ratio (OR), 0.816; 95% confidence interval (CI), 0.511-1.302; P = 0.394), MA (OR, 0.690; 95% CI 0.298-1.593; P = 0.384), or MO (OR, 1.022; 95% CI 0.490-2.131; P = 0.954). Consistently, reverse MR analysis did not reveal causal effects of any migraine or its subtypes on AR. Almost all sensitivity analyses supported the robustness of the results.
CONCLUSIONS
This MR study did not reveal a clear causal association between AR and migraine risk. More research is warranted to reveal the complex association between AR and migraine.
Topics: Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Migraine Disorders; Rhinitis, Allergic; Dietary Supplements
PubMed: 38281051
DOI: 10.1186/s40001-024-01682-1