Cephalalgia[JOURNAL]
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200 papers
Addressing unmet needs in migraine: Real-world fremanezumab effectiveness in participants of the PEARL study with at least three prior preventive treatment failures.
Ashina M, Tassorelli C, Kokturk P … +2 more , Akcicek H, Pozo-Rosich P
Cephalalgia · 2025 Dec · PMID 41432610 · Publisher ↗
BackgroundThe Pan-European Real Life (PEARL) Phase 4 study evaluated real-world effectiveness and safety of fremanezumab for episodic migraine (EM) and chronic migraine (CM) prevention. This post-hoc analysis evaluated t...
BackgroundThe Pan-European Real Life (PEARL) Phase 4 study evaluated real-world effectiveness and safety of fremanezumab for episodic migraine (EM) and chronic migraine (CM) prevention. This post-hoc analysis evaluated the effectiveness of fremanezumab in participants with three or more non-migraine-specific preventive treatment failures, including onabotulinumtoxinA.MethodsBaseline daily headache diary data were compared with diary data following fremanezumab initiation. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days (MMD) during the six months after fremanezumab initiation. Secondary endpoints included mean change from baseline in MMD at Months 1-12 and health-related quality of life. Safety was assessed through adverse events.ResultsOf 451 participants, 398 with three or more previous preventive treatment failures were included in the effectiveness analyses (EM, 40.2%; CM, 59.8%). Of the 290 participants with data available, the 50% responder rate was 53.8% (EM, 67.0%; CM, 46.5%) during the six months after fremanezumab initiation. The safety profile was consistent with previous findings.ConclusionsThis post-hoc analysis supports the effectiveness and safety of fremanezumab for migraine prevention in patients with three or more prior preventive treatment failures. These findings are consistent with those from a randomized controlled trial (RCT) in a similar population, illustrating the transferability of RCT data to real-world clinical practice.Trial registrationencepp.eu: EUPAS35111.
Indirect crosstalk between signalling pathways activated by CGRP and Piezo1 in human iPSC-derived endothelial cells relevant to migraine.
Gkouzioti V, Abdollahzadeh A, van den Hil F … +4 more , Orlova V, Giniatullin R, van den Maagdenberg AMJM, Frimat JP
Cephalalgia · 2025 Dec · PMID 41410740 · Publisher ↗
BackgroundIt is becoming increasingly evident that the vasculature is implicated in migraine pathophysiology. Calcitonin gene-related peptide (CGRP) acts as one of the key migraine mediators through various mechanisms th...
BackgroundIt is becoming increasingly evident that the vasculature is implicated in migraine pathophysiology. Calcitonin gene-related peptide (CGRP) acts as one of the key migraine mediators through various mechanisms that includes endothelium-mediated cerebral vessel vasodilation. Endothelial cells express mechanosensitive Piezo1 channels and have been suggested to play a role in migraine pathophysiology. However, the crosstalk between these two migraine-related signalling pathways remains unclear.MethodsWe measured intracellular calcium (Ca) in human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs), after exposure to Yoda1, a specific Piezo1 channel agonist, with and without CGRP. In addition, we investigated the effects of CGRP and Yoda1 on cellular remodelling by staining for focal adhesion (FA) protein paxillin using immunocytochemistry.ResultsOur data suggest that a one-hour sensitization of hiPSC-ECs with CGRP followed by application of Yoda1 leads to a higher intracellular Ca level compared to when Yoda1 and CGRP are acutely applied separately or combined, suggesting at least indirect crosstalk between the two signalling pathways in the vascular system. CGRP receptor antagonist BIBN4096 significantly reduced the intracellular Ca² level under this sensitization protocol, confirming effective CGRP pathway blockade. The results also show that a one-hour sensitization of CGRP and Piezo1 activation affects cellular remodelling as evidenced by an increased number and area size of paxillin FA points per cell in hiPSC-ECs.ConclusionsWe have generated a human cell assay based on iPSC-derived endothelial cells and provided some evidence for crosstalk between mechanosensitive Piezo1 channels and CGRP in our hiPSC-EC system, which shows the potential for modelling of vascular implications relevant to migraine.
Introducing the four dimensions 4D migraine scale: A composite score proposal evaluating migraine severity and treatment efficacy.
Pasqualetti P, Altamura C, Fofi L … +7 more , Iannone LF, Marcosano M, Bellini G, Romozzi M, Cevoli S, Manzoni GC, Vernieri F
Cephalalgia · 2025 Dec · PMID 41410272 · Publisher ↗
BackgroundDifferent parameters are currently used to evaluate migraine frequency and disability. We aimed to formulate a composite scale including the most relevant clinical measures to better evaluate the burden of migr...
BackgroundDifferent parameters are currently used to evaluate migraine frequency and disability. We aimed to formulate a composite scale including the most relevant clinical measures to better evaluate the burden of migraine.MethodsTo create the composite four dimensions 4D migraine scale, we selected the most commonly used outcome measures: monthly migraine days (MMDs), number of monthly acute medications (MAMs), pain intensity (by Numerical Rating Score, NRS) and Migraine Disability Assessment (MIDAS) Score. Each parameter was categorized in different levels: five for MMDs, seven for MAMs, five for NRS and six for MIDAS to cover the entire empirical range of each variable. First, the relative weight of each level per parameter was rated by 197 migraine patients and 118 headache experts using Conjoint Analysis. Secondly, we applied the 4D migraine score to a sample of patients treated with galcanezumab. We assessed its concurrent validity for the scale's single parameters and the Head Impact Test HIT-6, an external patient-reported outcome measure.ResultsThere was a substantial agreement between clinicians and patients about the weight of each parameter in terms of Relative Importance (RI). For both categories, MMDs were the most relevant attribute (RI: 34% for clinicians, 32% for patients) and pain intensity NRS the least important (RI: 14% vs 13%). Though marginally, MIDAS was more important than MAMs for patients (29% vs. 26%), while for clinicians the relevance of these two attributes was almost equal (26% and 27%). In terms of the utility assigned to each level, strong agreement was confirmed between clinicians and patients. According to the utilities implicitly attributed by participants to the chosen representative levels of the four parameters, four different statistical models were derived, allowing to compute utilities from all possible values of MMDs, MAMs, NRS and MIDAS and finally a unique 4D migraine score for every possible patient, ranging from 0 (without migraine) to 100 (with the most severe migraine). The 4D score was valid in terms of sensitivity to changes and showed concurrent validity with respect to HIT-6.ConclusionThe 4D migraine scale, based on the preference weights of both clinicians and patients, could be useful to fully quantify the migraine burden and the efficacy of a treatment.
The burden of high-frequency episodic migraine and chronic migraine in the population-based PopHEAD study.
Engstrand H, Argren MB, Zwart JA … +2 more , Tronvik E, Winsvold BS
Cephalalgia · 2025 Dec · PMID 41406073 · Publisher ↗
AimThe diagnostic criteria for chronic migraine, which are based on the total number of monthly headache days, are the subject of ongoing debate. The present study aimed to investigate and compare the burden of disease a...
AimThe diagnostic criteria for chronic migraine, which are based on the total number of monthly headache days, are the subject of ongoing debate. The present study aimed to investigate and compare the burden of disease and quality of life between high-frequency episodic migraine and chronic migraine, using data from the large population-based PopHEAD study.MethodsPopHEAD is a population-based cross-sectional study in the Norwegian county of Vestfold and Telemark performed in 2023. Among 28,753 randomly selected adults (aged 18-70 years) invited to complete an electronic questionnaire, 8265 (28.7%) participants responded. The questionnaire was a modified version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation questionnaire, and migraine was classified using a diagnostic algorithm that has been validated by telephone interview in this population. High-frequency episodic migraine was classified according to newly proposed criteria, and chronic migraine according to International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria. Using linear regression for continuous variables and logistic regression for binary outcomes, we compared the disease burden and quality of life between participants classified with high-frequency episodic migraine and those with chronic migraine. The analysis was conducted in two steps: a primary analysis adjusted for age and sex, as well as a second analysis with an additional adjustment for monthly migraine days.ResultsOf the 8265 responders, 225 had high-frequency episodic migraine and 349 had chronic migraine. Compared to the high-frequency episodic migraine group, the chronic migraine group had more monthly migraine days (17.9 vs. 9.7, < 0.001) and headache days (20.8 vs. 9.9, < 0.001). The chronic migraine group also used more acute medication ( < 0.001). In analyses adjusted for age and sex, participants with chronic migraine reported greater disease burden across almost all measures, including work and social impairment, and had a lower quality of life ( < 0.01). With additional adjustment for monthly migraine days, no significant differences in disease burden were found between the two groups, except from days missed from household work ( = 0.03).ConclusionsThe higher disease burden observed in chronic migraine compared to high-frequency episodic migraine was fully explained by the higher number of monthly migraine days in the chronic migraine group. Our findings support previous suggestions to simplify the ICHD-3 criteria for chronic migraine by basing it solely on the number of monthly migraine days.
Estrogen exposure from modern contraceptives and vascular risk in women with migraine: A nationwide electronic medical record database study.
Ihara K, Pike CW, Hui G … +5 more , Gombar S, Jackson ML, Callahan A, Tietjen GE, Chiang CC
Cephalalgia · 2025 Dec · PMID 41406065 · Publisher ↗
BackgroundMany guidelines list migraine with aura (MwA) as a contraindication to estrogen-containing combined hormonal contraceptives (CHCs) due to vascular risks. However, current evidence is based on small sample studi...
BackgroundMany guidelines list migraine with aura (MwA) as a contraindication to estrogen-containing combined hormonal contraceptives (CHCs) due to vascular risks. However, current evidence is based on small sample studies with potential influence by confounding factors. Additionally, few studies have examined the vascular risk associated with modern CHCs with lower dose estrogen, particularly in relation to aura status. The present study aims to investigate the vascular risk of modern CHCs in women with migraine with and without aura.MethodsWe used a de-identified electronic medical record database with 120 million patients across multiple health systems in the United States of America. We included female patients aged 18-45 years who received a migraine diagnosis code, had at least three office visits within three years, and were prescribed at least one migraine-specific medication within 6 months following the first outpatient visit. All data after 2010 were included. Patients with prior cardiovascular events were excluded. Our composite endpoint consisted of acute ischemic stroke, acute myocardial infarction, deep vein thrombosis/pulmonary embolism and intravenous thrombolytic administration. We stratified our analysis according to CHC exposure and aura status and compared the incidence of the endpoint with high-dimensional propensity score-matching between CHC users and non-users in (i) the overall cohort, (ii) MwA and (iii) migraine without aura (MwoA); between MwA and MwoA in (iv) patients prescribed CHCs; and in (v) those without CHC prescriptions.ResultsWe included 5535 patients who received CHC prescriptions and 21,520 who did not. 114 (2.06%) of CHC users and 547 (2.54%) of CHC non-users had at least one vascular event. With propensity score-matched comparison, the composite endpoint did not significantly differ between CHC and non-CHC in the overall migraine group, those with MwA and the MwoA group. In those prescribed CHC, MwA and MwoA did not differ in all the outcomes. For CHC non-users, MwA was associated with a higher incidence of acute ischemic stroke (hazard ratio = 2.45; 95% confidence interval = 1.58-3.78; < 0.001; = 6201 in each group) and the composite endpoint (hazard ratio = 1.34; 95% confidence interval = 1.08-1.67; = 0.008).ConclusionsOur real-world study showed that exposure to modern CHC was not associated with a significant increase in vascular risk in women aged 18-45 years with migraine, MwA or MwoA who have no prior cardiovascular events. However, in those who never received CHC, MwA was associated with higher vascular risks compared to MwoA. While limitations exist using large scale electronic medical record databases for analysis, our results suggest that carefully designed prospective studies should be conducted to reassess the vascular risk associated with CHC use in women with migraine, especially MwA.
The interplay between migraine, endometriosis and polycystic ovarian syndrome: A systematic review.
Gómez-Dabó L, Jordà-Baleri T, Losa-Puig H … +2 more , Caronna E, Pozo-Rosich P
Cephalalgia · 2025 Dec · PMID 41384854 · Publisher ↗
BackgroundMigraine and gynecological conditions, such as endometriosis (EDM) and polycystic ovarian syndrome (PCOS), are highly prevalent among females and appear to influence each other, with a potential shared pathophy...
BackgroundMigraine and gynecological conditions, such as endometriosis (EDM) and polycystic ovarian syndrome (PCOS), are highly prevalent among females and appear to influence each other, with a potential shared pathophysiological mechanism. Therefore, this study aims to provide a comprehensive summary of the current evidence regarding the relationship between migraine and EDM/PCOS from a clinical perspective.MethodsA systematic review was conducted using four databases (MEDLINE(Pubmed), EMBASE (Elsevier), Web of Science and Cochrane Library) along with searches in the grey literature. The protocol was registered prospectively on the PROSPERO platform (CRD42024628010). The primary search was performed on 4 December 2024. Eligible studies included observational studies that compared two or more groups of females with migraine, EDM and/or PCOS diagnosis. The modified Newcastle-Ottawa Scale was used to assess the quality of the included studies. Data extraction was performed and results systematically analyzed.ResultsFrom an initial 408 identified studies, a final selection of 15 was analyzed (14 focused on EDM and 1 on PCOS) with a total of 289,519 individuals included. All selected studies achieved a score of 6 or higher on the mNOS. When comparing females with and without EDM, the prevalence of migraine reached up to 44.7%, with females affected with EDM having up to a five-fold increased risk of developing migraine (adjusted odds ratio = 5.35, 95% confidence interval = 2.11-16.4). When comparing females with and without migraine, a higher prevalence and risk of EDM was observed, with rates reaching 53.4% and an adjusted odds ratio up to 10.5 (95% confidence interval = 2.2-51.4). Mixed findings were found regarding the influence of EDM on migraine characteristics, as well as the impact of migraine in EDM-related symptoms and disease severity. Females with migraine and EDM exhibited higher scores in disability assessment tools (Headache Impact Test-6, 30-item Endometriosis Health Profile), suggesting a greater disease burden. Due to the limited data, no conclusions could be drawn regarding a link between PCOS and migraine.ConclusionsAlthough further high-quality research is required to better understand the underlying mechanisms linking migraine, EDM and PCOS, the current evidence supports a significant association between migraine and endometriosis. PROSPERO Registration ID: CRD42024628010.
Post-traumatic headache phenotypes and clinical characteristics.
Cortel-LeBlanc A, Cortel-LeBlanc M, Webster RJ … +8 more , Chen K, Schytz HW, Jolliffe K, Dodd AB, Terekhov I, Dashti F, Zemek R, TRANSCENDENT Concussion Research Team
Cephalalgia · 2025 Dec · PMID 41370085 · Publisher ↗
Background/AimPost-traumatic headache often resembles migraine or tension-type headache, but distinct phenotype and clinical characteristics necessitate further delineation. We aimed to characterize the clinical phenotyp...
Background/AimPost-traumatic headache often resembles migraine or tension-type headache, but distinct phenotype and clinical characteristics necessitate further delineation. We aimed to characterize the clinical phenotype, headache patterns, associated features and comorbidities, medication patterns and functional impact of post-traumatic headache in an adult population following mild traumatic brain injury.MethodsThis is a cross-sectional analysis of a cohort of adults with post-traumatic headache after mild traumatic brain injury, by any mechanism, evaluated by a neurologist at an outpatient specialized concussion and headache center in Ontario, Canada between February 2021 and October 2023. Data were collected through standardized pre- and during-visit questionnaires. Descriptive statistics are presented.ResultsAmong 405 patients assessed by a neurologist for post-traumatic headache, median time since injury was 37 days (IQR: 13-126). Most patients reported headache 26 + days per month (292, 72.1%). Headache was continuous in 114 (28.1%), whereas in 215 (53.1%) it lasted hours to days. Headache location was unilateral in 174 (43.0%) and bilateral in 159 (39.3%). Headache quality was described as pulsating/throbbing in 260 (64.2%). The median severity was 7/10 (IQR 5-8). Aggravation by routine physical activity was reported in 287 (70.9%), nausea/vomiting in 279 (69.0%), photophobia in 358 (88.4%) and phonophobia in 337 (83.2%). There was no positional preference for 147 patients (36.3%), while 216 (53.3%) preferred lying down/reclined. Acute medication use frequency was reported as 3 + days per week in 218 (53.8%) and daily in 143 (35.3%). Within this cohort, 201 (49.6%) endorsed one or more psychiatric comorbidities. Only 66 (16.3%) had returned to full work/school attendance, while 169 (41.7%) were completely off usual occupational activities post-injury. One hundred seventy-eight (44.0%) reported pending litigation or insurance claims related to their injury, and/or having a work-related injury. Among the 183 (45.2%) who had undergone neuroimaging, 160 (87.9%) studies were reportedly normal, while there were 13 (7.1%) incidental findings and eight (4.3%) injury-related.DiscussionWhile select migraine features such as photophobia, phonophobia and worsening with routine physical activity are common in post-traumatic headache, there are also distinct features, including daily or near daily headache of long duration. The latter may suggest early sensitization in post-traumatic headache There is an associated high risk of medication overuse headache, given frequent administration of acute medications, as well as high rates of psychiatric comorbidities and functional impairment. Future studies should aim to further delineate the longitudinal clinical, pathophysiological, and treatment response differences between post-traumatic headache and primary migraine.
Evoked potential studies in migraine: A systematic review of neurophysiological patterns across migraine subtypes.
Ulutas S, Özçelik EU, Dabó LG … +7 more , Bolla F, Tepe N, Yambao P, Ling YH, Pan LH, Wang SJ, International Headache Academy of the International Headache Society (IHS-iHEAD)
Cephalalgia · 2025 Dec · PMID 41364425 · Publisher ↗
BackgroundEvoked potentials are widely used to investigate sensory and nociceptive processing abnormalities in migraine. However, electrophysiological distinctions between migraine subtypes remain insufficiently characte...
BackgroundEvoked potentials are widely used to investigate sensory and nociceptive processing abnormalities in migraine. However, electrophysiological distinctions between migraine subtypes remain insufficiently characterized in the literature. The aim was to systematically review and summarize neurophysiological abnormalities in evoked potential studies (visual, auditory, brainstem, somatosensory and laser) in migraine patients, with a particular focus on latency, amplitude, habituation and clinical correlations across subtypes and healthy controls.MethodsFollowing PRISMA guidelines, we searched PubMed, EMBASE and Web of Science for studies, terms included "Migraine Disorders," "Migraine," "Vestibular Diseases" and "Evoked Potentials", which were published from 2000 to 2024 were included. Risk of bias was assessed using a modified Newcastle-Ottawa Scale.ResultsIn total, 813 studies were screened, resulting in 55 studies meeting the inclusion criteria. Patients with migraine with aura demonstrated higher amplitudes and asymmetry of visual evoked potentials compared to those with migraine without aura. Habituation deficits were particularly evident across all types of evoked potentials. A few studies compared chronic and episodic migraine, reporting higher brainstem and somatosensory evoked potential amplitudes in chronic migraine.ConclusionsMigraine patients have a consistent habituation deficit on all evoked potential parameters. Migraine with aura and chronic migraine may have higher cortical excitability. Further research with larger sample sizes, standardized methodologies and an accurate comparison of migraine phases will enlighten our understanding of the migraine subtypes.Trial RegistrationPROSPERO ID: CRD42024502803.
Complex regional pain syndrome and migraine: Clinical relationships and possible common aetiology.
Drummond PD, Finch PM
Cephalalgia · 2025 Dec · PMID 41364424 · Publisher ↗
BackgroundMigraine headache and complex regional pain syndrome share mechanisms, such as neuroinflammation, central sensitization and loss of inhibitory pain controls, that could provoke or exacerbate symptoms in both di...
BackgroundMigraine headache and complex regional pain syndrome share mechanisms, such as neuroinflammation, central sensitization and loss of inhibitory pain controls, that could provoke or exacerbate symptoms in both disorders. In the present study, it was hypothesized that headaches would worsen after the onset of complex regional pain syndrome and that limb pain would be more severe in patients with co-morbid headaches than in patients who remained headache-free. Notably, complex regional pain syndrome is associated with ipsilateral cranial symptoms such as photophobia and forehead hyperalgesia. Whether shared mechanisms might drive these symptoms was also explored.MethodsEighty-eight patients with complex regional pain syndrome were asked about their previous and current headache experience. The spatial distribution of pain was quantified from pain drawings, and hyperalgesia to mechanical and thermal stimulation was assessed in the limbs and forehead. In addition, the visual discomfort threshold was measured separately for each eye.ResultsSixty-six percent of patients reported that headaches (primarily migraine) had developed or worsened after the onset of complex regional pain syndrome and 22 percent now had daily or near-daily headaches. Limb pain and hyperalgesia were greater in such cases than in those with stable headaches or who remained headache-free. Photophobia and forehead hyperalgesia were greater ipsilateral than contralateral to symptoms of complex regional pain syndrome in patients with stable or worsening headaches but were symmetrical in headache-free patients. In addition, photophobia was symmetrical in patients with recurrent tension-type headaches. Patients with worsening headaches were younger at the onset of complex regional pain syndrome than patients with stable headaches or who were headache-free, in line with greater vulnerability to migraine in younger than older adults. In a subgroup of patients, the pain of complex regional pain syndrome extended from the upper limb to the ipsilateral dorsal cervical region, a documented source of pain in migraine. However, headaches ipsilateral to complex regional pain syndrome also recurred in patients with lower limb pain, indicating involvement of other pain mechanisms.ConclusionsTogether, the findings indicate that headaches with features of migraine develop after the onset of complex regional pain syndrome. In turn, this is associated with ipsilateral cranial symptoms and heightened limb pain. We suggest that shared pathophysiology increases susceptibility to ipsilateral cranial symptoms and exacerbates pain in both disorders, potentially in a positive loop. Breaking this cycle might permit otherwise intractable symptoms and pain to subside.
miR-382-5p and miR-34a in migraine: Expression in monocytes and a post-hoc exploratory comparison with expression in peripheral blood mononuclear cells.
Greco R, Bighiani F, Demartini C … +17 more , Zanaboni A, Francavilla M, Facchetti S, Sproviero D, Vaghi G, Allena M, Martinelli D, Corrado M, Guaschino E, Ghiotto N, Bottiroli S, Cammarota F, Antoniazzi A, Grillo V, Sances G, Tassorelli C, De Icco R
Cephalalgia · 2025 Dec · PMID 41342643 · Publisher ↗
BackgroundEmerging evidence highlights the role of microRNAs (miRNAs) in epigenetic mechanisms related to migraine pain. The expression of miR-382-5p and miR-34a is higher in serum and peripheral blood mononuclear cells...
BackgroundEmerging evidence highlights the role of microRNAs (miRNAs) in epigenetic mechanisms related to migraine pain. The expression of miR-382-5p and miR-34a is higher in serum and peripheral blood mononuclear cells of people with migraine, but limited data is available regarding their possible alteration in other cell subtypes. Several lines of evidence support a monocyte dysfunction in migraine pathophysiology. To gain deeper insights into cell-specific miRNAs expression in migraine individuals with different disease severity, this study aims to determine the expression levels of miR-34a and miR-382-5p in monocytes.MethodsThis cross-sectional, controlled study included 47 participants with episodic migraine (EM, 72.3% females, 41.4 ± 10.7 years), 32 with chronic migraine with medication overuse (CM-MO, 81.3% females, 46.1 ± 10.9 years) and 30 healthy controls (HCs, 66.7% females, 42.9 ± 14.8 years). We assessed interictal monocyte-specific miR-382-5p and miR-34a expression by qRT-PCR, normalizing the expression with U6 RNA (relative quantification - RQ).ResultsmiR-382-5p monocytic expression was higher in EM (4.21 ± 1.41 RQ) and CM-MO (6.80 ± 4.37 RQ) when compared to HCs (2.02 ± 0.64 RQ) ( = 0.005 for all comparisons). miR-34a monocytic expression was higher in EM (4.50 ± 1.62 RQ) and CM-MO (6.47 ± 1.87 RQ) when compared to HCs (1.94 ± 0.81 RQ, = 0.005 for all comparisons). Expression of miR-382-5p and miR-34a were higher in CM-MO when compared to EM ( = 0.005 for both comparisons). After adjusting for age, sex, ongoing preventive medications, presence of anxiety or depressive symptoms, and smoking habit, a logistic regression model confirmed the differences in the monocytic expression of miR-34a and miR-382-5p between EM and CM-MO participants.ConclusionsOur findings underscore the relevance of miR-34a and miR-382-5p in migraine pathophysiology, as evidenced by their altered expression in monocytes from migraine participants compared to HCs. These miRNAs were also associated with disease severity, being higher in CM-MO when compared to EM individuals.Trial RegistrationThe study protocol was registered at ClinicalTrials.gov (NCT05891808).
Medication-overuse headache hospitalisations in Australia, 2009-2024: A national study of a preventable condition.
Assefa DZ, Xia T, Stark RJ … +1 more , Nielsen S
Cephalalgia · 2025 Dec · PMID 41342639 · Publisher ↗
BackgroundTo examine national trends in medication-overuse headache (MOH) hospitalisation rates, length of hospital stays, and patient demographics in Australia in the context of evolving access to medications implicated...
BackgroundTo examine national trends in medication-overuse headache (MOH) hospitalisation rates, length of hospital stays, and patient demographics in Australia in the context of evolving access to medications implicated in MOH.MethodsA retrospective analysis of national hospital admissions data from the Australian Institute of Health and Welfare (AIHW), focusing on cases with a principal diagnosis of MOH from 2009 to 2024. MOH hospitalisation rates per 100,000 population and length of hospital stay were analysed over time and stratified by age group and sex.ResultsA total of 2480 MOH cases were identified over 16 years, including 1661 (67%) females and 954 (38.5%) individuals aged > 60 years. Overall MOH-related hospitalisation rates declined (IRR: 0.97; 95% CI: 0.96-0.98), as did the average length of stay per admission (-0.035 days/year; p = 0.036). Females were more likely to be admitted (IRR: 1.95; 95% CI: 1.79-2.12), as were older patients (IRR: 8.08; 95% CI: 6.77-9.65); however, longer stays were observed only among older patients (mean [SD]: 2.74 [0.48] vs. 2.21 [0.37] days; p = 0.005).ConclusionThis trend, occurring alongside rising migraine-related hospitalisations, the phasing out of ergotamine, and increased triptan use, may be partially attributed to the 2018 codeine rescheduling. Future studies using detailed prescription data are warranted to assess the long-term impact of medication policy changes on MOH trends.
The regional outreach programme of the International Headache Society: A WHO-IGAP oriented programme to improve access to care for headache patients in sub-Saharan Africa.
Martinelli D, Tassorelli C
Cephalalgia · 2025 Dec · PMID 41335012 · Publisher ↗
Abstract loading — click title to view on PubMed.
Combination preventive therapy with onabotulinumtoxinA and atogepant for chronic migraine: A 24-week, prospective, real-world evaluation (SYNERGY study).
Iannone LF, Romozzi M, Russo A … +8 more , Finkelstein I, Seabi D, Ahlden A, Aamodt AH, Caronna E, Pozo-Rosich P, Tronvik EA, Sundal C
Cephalalgia · 2025 Dec · PMID 41329703 · Publisher ↗
BackgroundChronic migraine (CM) is highly disabling, and many patients fail to respond to monotherapy with approved preventive treatments. OnabotulinumtoxinA (BoNTA) and atogepant act on distinct but complementary target...
BackgroundChronic migraine (CM) is highly disabling, and many patients fail to respond to monotherapy with approved preventive treatments. OnabotulinumtoxinA (BoNTA) and atogepant act on distinct but complementary targets within the trigeminovascular system and may exert additive or synergistic effects when used together. Real-world data on their combination remain scarce.MethodsWe prospectively analyzed adult patients with CM who had received at least three prior BoNTA cycles and initiated atogepant 60 mg/day for a minimum of 24 weeks as add on to BoNTA. Co-primary outcomes were changes in monthly migraine days (MMDs) and ≥50% response rate at 24 weeks. Secondary outcomes included disability, medication use, tolerability and subgroup comparisons by prior monoclonal antibodies exposure.ResultsAmong 101 patients, 82 completed 24 weeks of co-treatment. Mean MMDs decreased by 6.5 days ( < 0.001) and 45.1% of patients achieved a ≥50% reduction. Acute medication days decreased by 6.0 ( < 0.001) and Headache Impact Test-6 scores improved significantly (mean change: -4.0; < 0.001). Patient's Global Impression of Change scores indicated moderate-to-great improvement. Anti-calcitonin gene-related peptide naïve patients experienced larger reductions in MMDs (-7.75 vs. -5.87) and disability scores compared to non-naïve patients. Multivariable analysis identified only baseline acute medication use as predictor of response. Adverse events were mild and consistent with known safety profiles for both drugs separately; no novel safety concerns emerged.ConclusionsThe addition of atogepant to BoNTA might be effective and well tolerated in real-world setting, including CM patients previously exposed to multiple preventives. Prospective controlled trials and health-economic evaluations are warranted to validate these observations and inform future clinical guidelines.
Greater occipital nerve block for the treatment of migraine: An umbrella review, systematic review, and meta-analysis.
Atraszkiewicz D, Ünal E, Bassett P … +2 more , Morell-Ducos F, Bahra A
Cephalalgia · 2025 Dec · PMID 41329694 · Publisher ↗
BackgroundGreater occipital nerve block (GONB) has become an established treatment for migraine. Though numerous systematic reviews and randomised control trials (RCTs) are cited as supporting evidence, the quality and c...
BackgroundGreater occipital nerve block (GONB) has become an established treatment for migraine. Though numerous systematic reviews and randomised control trials (RCTs) are cited as supporting evidence, the quality and consistency of this data remains unclear.MethodsAn umbrella review of systematic reviews investigating GONB for migraine was conducted. Additionally, an independent systematic review and meta-analysis of relevant RCTs was performed in accordance with PRISMA guidelines. Both evaluated MEDLINE ('PubMed'), Embase, and CENTRAL databases.ResultsNine relevant systematic reviews were identified; all had significant limitations and/or contained methodological errors. The reviews had been cited 256 times. None were eligible for statistical analysis.Sixteen RCTs (930 patients) and seven RCTs (401 patients) were included for qualitative and quantitative analyses respectively. Studies were heterogeneous in their methodologies. No serious adverse effects were identified. With moderate certainty, local anaesthetic (LA) GONB reduces headache severity in acute migraine attacks at 30 min (-2.08; < 0.001). With low certainty, weekly bilateral LA GONB injections reduce headache severity (-1.33; < 0.001) and monthly headache days (-4.46; < 0.001) at one month for chronic migraine. Sustained benefits of GONB remain unclear. Data was insufficient to analyse the efficacy of steroid GONB, LA-steroid GONB, nor unilateral GONB for chronic migraine, and GONB - of any type - for episodic migraine.ConclusionsThere is limited RCT evidence supporting GONB for the treatment of migraine. Existing systematic reviews should be interpreted with caution. RCTs with homogeneous methodologies are required to evaluate GONB in the management of disability in migraine.Trial RegistrationPROSPERO registration ID: CRD42024595492.
Persistent idiopathic facial pain: Integrating headache neurology insights into interdisciplinary guidelines.
Robblee J
Cephalalgia · 2025 Dec · PMID 41328518 · Publisher ↗
Abstract loading — click title to view on PubMed.
Management of persistent idiopathic facial pain (PIFP) - An international Delphi study.
Lindfors E, Alstergren P, Benoliel R … +16 more , Conti P, Durham J, Goulet JP, Komiyama O, List T, May A, Mitsikostas DD, Nixdorf DR, Pigg M, Renton T, Skagerberg G, Svensson P, Treede RD, Türp JC, Zakrzewska JM, Gordh T
Cephalalgia · 2025 Dec · PMID 41328507 · Publisher ↗
Background/AimPersistent idiopathic facial pain (PIFP) is a rare condition with a lifetime prevalence of approximately 0.03%. It is characterized by persistent daily facial pain without identifiable cause and presents di...
Background/AimPersistent idiopathic facial pain (PIFP) is a rare condition with a lifetime prevalence of approximately 0.03%. It is characterized by persistent daily facial pain without identifiable cause and presents diagnostic and therapeutic challenges due to unknown pathophysiology, symptom overlap with other painful disorders, and limited evidence-based treatments. The aim of this Delphi study was to establish international consensus-derived guidelines for the management of patients with PIFP.MethodsA three-round Delphi study was conducted with 16 international pain experts, each with ≥10 years of clinical experience in pain management and extensive peer-reviewed publications. The first round involved open-ended questions, and the qualitative data were analyzed using systematic text condensation, resulting in a quantitative questionnaire with 42 statements. Subsequent rounds employed Likert-scale responses to these statements. Consensus was defined as ≥80% agreement or disagreement. In addition, if 11-12 (68-75 percent) out of the 16 experts agreed or disagreed, consensus was not reached, but a majority was considered to have a particular opinion.ResultsConsensus was reached in 35 out of the 42 statements (83%), emphasizing multidisciplinary collaboration and avoidance of invasive procedures in the treatment of PIFP. In an additional three statements (7%) a majority of the experts agreed with each other. In four statements (10%), no consensus or majority was reached. Pharmacological treatments, including tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids, may be considered; however, opioids should generally be avoided in the treatment of PIFP. Patient education and behavioral therapies are important interventions, and the most important measure of therapeutic success is improved quality of lifeConclusionThe present Delphi study has established internationally derived consensus guidelines and recommendations for the evaluation and comprehensive management of patients with PIFP. This is a first step in gathering knowledge for future evidence-based guidelines and more specific treatment recommendations. These international expert consensus guidelines recommend a multi- or interdisciplinary approach in managing PIFP, avoiding invasive interventions and prioritizing patient-centered outcomes.
Biodistribution of atogepant and rimegepant in mouse peripheral and central structures of relevance to migraine pathogenesis.
Pistolesi A, De Cesaris F, Buonvicino D … +1 more , Chiarugi A
Cephalalgia · 2025 Nov · PMID 41313225 · Publisher ↗
BackgroundSecond and third generation gepants have been recently approved for migraine therapy. They represent the first drugs that are able to work as both preventatives and symptomatics of the migraine attack. Their ab...
BackgroundSecond and third generation gepants have been recently approved for migraine therapy. They represent the first drugs that are able to work as both preventatives and symptomatics of the migraine attack. Their ability to counteract calcitonin gene-related peptide signaling has been convincingly shown, but where they act to exert the therapeutic effects remains unsolved. Although the low brain/plasma ratio suggests peripheral antimigraine activity of gepants, recent preclinical and clinical lines of evidence hint that these compounds may also act centrally.MethodsBy means of mass spectrometry analysis, we have measured the biodistribution of atogepant and rimegepant in plasma, dura mater, trigeminal ganglion (TG), parietal brain cortex and hypothalamus of mice. The biodistribution of oxazepam has been also determined as that of a prototypical brain permeant drug. Animals received interspecies (human-to-mouse) converted doses. Drugs were administered orally, as single or repeated (seven days) dosing. Atogepant was also administered as a single oral or intranasal dose matching (mg/kg) that adopted in migraine patients.ResultsUpon administration of interspecies converted oral doses, we found that atogepant reached similar in plasma and TG after three hours, that then rapidly decreased at six and 12 hours. Of note, atogepant contents in the parietal brain cortex linearly increased up to six hours (reaching a brain/plasma concentration ratio of 5.6) and substantially decreased at 12 hours. Tissue contents of rimegepant were lower than those of atogepant, although the drug reached in the brain analogues to those found in the TG. Three hours after dosing, we also found the highest accumulation of atogepant and rimegepant in the dura, with substantial accumulation even in the hypothalamus where drug contents equaled those present in the TG. Of note, when atogepant was administered orally or intranasally at a dose corresponding to that adopted in patients, it also reached brain contents comparable to those found in the TG. However, a preferred delivery of atogepant to the TG was obtained with the intranasal route. At variance with oxazepam, the two gepants did not accumulate in the TG or parietal brain cortex upon a seven day oral treatment.ConclusionsThe data obtained in the present study indicate substantial and transient permeation of the mouse brain by gepants.
Corticosteroid-dependent increased expression of CGRP and its receptor subunits within the rodent trigeminal ganglion does not prompt cephalic allodynia.
Pistolesi A, Tuniz S, Lapucci A … +6 more , Molli A, De Cesaris F, Landini L, Nassini R, Buonvicino D, Chiarugi A
Cephalalgia · 2025 Nov · PMID 41308054 · Publisher ↗
BackgroundCalcitonin gene-related peptide (CGRP) has a causative role in migraine pathogenesis but its effects on trigeminal afferents are still unclear. Corticosteroids represent a very useful tool in headache therapy w...
BackgroundCalcitonin gene-related peptide (CGRP) has a causative role in migraine pathogenesis but its effects on trigeminal afferents are still unclear. Corticosteroids represent a very useful tool in headache therapy with an unknown mechanism of action. Despite the widespread effects of corticosteroids on gene transcription, whether they regulate CGRP expression within the trigeminovascular system remains to be investigated.MethodsThe effects of dexamethasone on expression of CGRP and its receptor subunits receptor activity-modifying protein (RAMP1) and calcitonin receptor-like receptor (CLR) have been evaluated in rat thyroid parafollicular CA77 and human neuroblastoma SHSY-5Y cell cultures, as well as in isolated human peripheral blood mononuclear cells. The effects of dexamethasone on the rat and human CGRP promoter were also evaluated. , rats and mice were treated with betamethasone (320 µg/kg for 10 days) to investigate whether the drug altered the expression of CGRP, RAMP1 and CLR in the trigeminal ganglion (TG). We also evaluated the effect of betamethasone on CGRP mRNA stability and release from the mouse TG, as well as on mouse spontaneous or nitroglycerin-induced cephalic allodynia.ResultsWe report that dexamethasone triggered transcriptional activation of the rat and human CGRP gene, also increasing transcript levels of RAMP1 but not of CLR in cultured cells. These effects were paralleled in the TG of rats and mice challenged with betamethasone, with mice also showing increased expression levels of CLR. Of note, although a 13-fold increase of the CGRP releasable pool occurred in the TG of betamethasone-treated mice, the animals were not sensitized to cephalic allodynia.ConclusionsIn keeping with the emerging immunosuppressing effects of CGRP, corticosteroids increase its expression in rat and human cell lines, as well as in rodent TG. Evidence that a substantial increase of releasable CGRP in the TG does not reduce orofacial pain thresholds suggests that basal release of endogenous CGRP differs from its exogenous administration in terms of trigeminal afferent sensitization.
The promise of artificial intelligence and machine learning for migraine treatment outcome prediction: A narrative review.
Pardo K, Schwedt TJ, Cutrer FM … +1 more , Chiang CC
Cephalalgia · 2025 Nov · PMID 41269887 · Publisher ↗
BackgroundMigraine is a highly prevalent neurological disorder with many treatment options, both pharmacological and non-pharmacological. Artificial intelligence (AI) has great potential to optimize treatment selection s...
BackgroundMigraine is a highly prevalent neurological disorder with many treatment options, both pharmacological and non-pharmacological. Artificial intelligence (AI) has great potential to optimize treatment selection strategies for individual patients. This review provides an overview of AI models and the techniques used to predict migraine treatment outcomes.MethodsWe conducted a literature search in PubMed and examined studies that reported employing AI models to predict migraine preventive and acute treatment outcomes. We also explored incorporating AI/machine learning to enhance personalized migraine treatment strategies, including forecasting migraine attacks. Additionally, we summarized future research directions, including incorporating multimodality data, using AI frameworks for the discovery of novel treatment targets, and advancing the field with innovative AI techniques such as digital twins, conversational AI and virtual AI agents.ResultsStudies have employed ML and deep learning on a combination of clinical features and imaging data to predict acute or preventive migraine treatment outcomes with reported success. Continued model optimization, validation, and prospective assessment of the clinical utility of deploying ML models in real-world settings are crucial.ConclusionsWhile AI has demonstrated success in predicting migraine treatment responses, future research incorporating novel AI techniques and diverse data sources could pave the way to advance personalized migraine treatment.
Migraine management during pregnancy, breastfeeding and in women planning pregnancy.
Ornello R, Maassen van den Brink A, Puledda F … +11 more , Sandoe CH, Iannone LF, Pelzer N, Lee MJ, Haghdoost F, Gomez-Dabo L, Pozo-Rosich P, Monteith TS, Tassorelli C, Terwindt GM, Sacco S
Cephalalgia · 2025 Nov · PMID 41263702 · Publisher ↗
Migraine is a common neurological disorder that predominantly affects women during their reproductive years, presenting unique challenges in the context of pregnancy, breastfeeding, and pregnancy planning. In the present...
Migraine is a common neurological disorder that predominantly affects women during their reproductive years, presenting unique challenges in the context of pregnancy, breastfeeding, and pregnancy planning. In the present review, we intend to summarize those challenges and propose possible solutions. Women with migraine, particularly those with aura, face an increased risk of pregnancy-related complications, including preeclampsia, stroke, and preterm birth, highlighting the need for careful monitoring throughout gestation. When migraine persists during pregnancy, management should prioritize non-pharmacological approaches, with a strong emphasis on lifestyle modifications and behavioral therapies. In some settings, non-invasive neuromodulation may also be a reasonable option. However, disabling migraine should not be left untreated and may require pharmacological management. Pharmacological treatments should be chosen primarily based on safety considerations, as many migraine medications are not suitable for use during pregnancy. Given the limited safety data available for several treatments, shared decision-making between patients and healthcare providers is essential. During breastfeeding, medication selection should focus on minimizing infant exposure while ensuring effective migraine control for the mother. In women of childbearing potential, caution is needed when prescribing certain migraine treatments, as unplanned pregnancies can occur. Special considerations should also be given to those requiring preventive treatment while planning pregnancy. Given the complexities of migraine management in this population, an individualized approach is crucial to balancing maternal well-being with fetal and infant safety.
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