Background: The burden and disability associated with headaches are conceptualized and measured differently at patients’ and populations’ levels. At the patients’ level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0–1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients’ disability which might inform future GBD definitions of DW for headache disorders. Methods: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females’ percentage in the sample, and age). We developed a 0–1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium. Results: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake. Conclusions: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

Background: Focusing on calcitonin gene-related peptide (CGRP) as a specific target has changed and improved migraine management. After the positive results of monoclonal antibodies directed to the CGRP pathway (anti-CGRP mAbs), randomized controlled trials also demonstrated the efficacy of gepants in migraine prevention. The present study aimed to assess the effectiveness of atogepant in preventing migraine after a 12-week treatment in clinical practice. Methods: Adult patients with a clinical indication for atogepant 60 mg daily were screened for participation in this multicentric prospective observational cohort study. At baseline (T0) and after 12 weeks (T3) since the first atogepant administration, monthly migraine days (MMDs), monthly headache days (MHDs) and monthly acute medications (MAMs) were assessed. The co-primary endpoints were the changes in MMDs from T0 to T3 and the percentage of T3 Responders (those with a reduction of MMDs ≥50%, i.e. 50% response rate (RR)). At T0 and T3, we also collected the Headache Impact Test (HIT-6), the Migraine Disability Assessment (MIDAS) questionnaire, the Migraine Treatment Optimization Questionnaire-6 (mTOQ-6), the Migraine-Specific Quality-of-Life Questionnaire (MSQ), the 12-item Allodynia Symptom Checklist (ASC-12) and the Migraine Interictal Burden Scale (MIBS-4). Results: One hundred and six patients (56/106 (52.8%) with chronic migraine (CM), 93/106 (87.7%) female, aged 50.6 ± 13.2 years) from 10 Italian centers completed the 12-week observation since the first atogepant tablet intake. From baseline to T3, a reduction of 6.9 MMDs (SD 9.7; p < 0.001) was achieved in the whole group and, specifically, of −4.9 (SD 6.6; p < 0.001) in episodic migraine (EM) and of −8.6 (SD 11.7; p < 0.001) in CM patients. Overall, 60/106 (56.6%) of patients were Responders (60.0% in the EM and 46.4% in the CM group). Non-Responders previously experienced more ineffective treatments than Responders with anti-CGRP mAbs (65.2% vs. 43.3%, respectively, p = 0.031) and with onabotulinumtoxinA (56.5% vs. 28.3%, p = 0.005), and presented more medication overuse at baseline (55.7% vs. 44.3%, p = 0.003). However, no baseline characteristics were significantly associated with the Responder status in the multiple regression analysis. For T0 to T3, MAMs, MIDAS, ASC-12 and mTOQ-6 reduced ( p ≤ 0.001 consistently), and MSQ role-function restriction increased ( p = 0.026), whereas HIT-6 and MIBS-4 did not change. Only seven subjects (7/106, 6.6%) dropped out of atogepant treatment: four for lack of effectiveness and three for adverse events or poor tolerability. Conclusions: The STAR study demonstrates the effectiveness and tolerability of atogepant 60 mg at 12 weeks in a real-world setting. Previous ineffective anti-CGRP mAbs were not a relevant prognostic factor. Trial Registration: The study was preregistered on clinicaltrial.gov, NCT06414044.

Background: The prodrome or premonitory phase is the initial phase of a migraine attack, and it is considered as a symptomatic phase in which prodromal symptoms may occur. There is evidence that attacks start 24–48 hours before the headache phase. Individuals with migraine also report several potential triggers for their attacks, which may be mistaken for premonitory symptoms and hinder migraine research. Methods: This review aims to summarize published studies that describe contributions to understanding the fine difference between prodromal/premonitory symptoms and triggers, give insights for research, and propose a way forward to study these phenomena. We finally aim to formulate a theory to unify migraine triggers and prodromal symptoms. For this purpose, a comprehensive narrative review of the published literature on clinical, neurophysiological and imaging evidence on migraine prodromal symptoms and triggers was conducted using the PubMed database. Results: Brain activity and network connectivity changes occur during the prodromal phase. These changes give rise to prodromal/premonitory symptoms in some individuals, which may be falsely interpreted as triggers at the same time as representing the early manifestation of the beginning of the attack. By contrast, certain migraine triggers, such as stress, hormone changes or sleep deprivation, acting as a catalyst in reducing the migraine threshold, might facilitate these changes and increase the chances of a migraine attack. Migraine triggers and prodromal/premonitory symptoms can be confused and have an intertwined relationship with the hypothalamus as the central hub for integrating external and internal body signals. Conclusions: Differentiating migraine triggers and prodromal symptoms is crucial for shedding light on migraine pathophysiology and improve migraine management.

Pain catastrophizing and cutaneous allodynia are commonly altered in patients with chronic migraine associated with medication overuse headache (CM-MOH) and tend to improve in parallel with clinical improvement. The relation between pain catastrophizing and cutaneous allodynia is poorly understood in patients with CM-MOH receiving OnabotulinumtoxinA therapy. In this single-arm open-label longitudinal observational study, patients with CM-MOH were assigned to structured withdrawal and then administered OnabotulinumtoxinA (5 sessions on a three-month basis, 195 UI per 31 sites). Headache frequency, medication intake, disability, impact, cutaneous allodynia and pain catastrophizing were evaluated with specific questionnaires. In total, 96 patients were enrolled and 79 completed the 12-month follow-up. With the exclusion of cutaneous allodynia and the magnification subscale of the pain catastrophizing questionnaire, all variables showed significant improvement by the sixth month, which was maintained at 12 months. Reduction of pain catastrophizing, and particularly of its helplessness subscale, was a significant predictor of reduction in headache frequency and medication intake. Pain catastrophizing is often implicated in the clinical improvement in patients with CM-MOH receiving behavioral treatments, but, in this study, also showed a role in patients receiving OnabotulinumtoxinA; combining OnabotulinumtoxinA and behavioral treatments specifically addressing pain catastrophizing might further enhance patients’ clinical outcome.

This preliminary analysis of a single-blind phase-III RCT aims to compare the feasibility and short-term efficacy of mindfulness as an add-on to treatment as usual (TaU) in the management of patients with chronic migraine (CM) and medication overuse headache (MOH). Patients were randomized to either TaU (structured withdrawal of overused drugs, patient education and pharmacological prophylaxis) or TaU + MIND, wherein patients additionally received six 90 min weekly group sessions of mindfulness-based therapy. Repeated measures analyses were used to test whether patients in the two arms showed different course with regard to headache frequency and medication intake over a three-month period. Drop-out rates were not different between the two groups: 6/89 (6.7%) and 9/88 (10.2%) among those in TaU and TaU + MIND, respectively. A significant effect of time for all variables was shown, together with a significant effect of time by group, favoring TaU + MIND condition for headache frequency (p = 0.025) and NSAID intake (p = 0.007), controlling for age and CM duration. In total, 45/83 (54.2%) and 69/79 (75.9%) of the patients allocated to TaU and TaU + MIND, respectively, achieved 50% or more headache-day reduction (chi-squared 8.38, p = 0.004). Our preliminary analysis indicates that adding six mindfulness-based sessions to TaU was feasible and showed short-term efficacy in the treatment of patients with CM and MOH.