Preliminary External Validation Results of the Artificial Intelligence-Based Headache Diagnostic Model: A Multicenter Prospective Observational Study.

The misdiagnosis of headache disorders is a serious issue, and AI-based headache model diagnoses with external validation are scarce. We previously developed an artificial intelligence (AI)-based headache diagnosis model using a database of 4000 patients' questionnaires in a headache-specializing clinic and herein performed external validation prospectively. The validation cohort of 59 headache patients was prospectively collected from August 2023 to February 2024 at our or collaborating multicenter institutions. The ground truth was specialists' diagnoses based on the initial questionnaire and at least a one-month headache diary after the initial consultation. The diagnostic performance of the AI model was evaluated. The mean age was 42.55 ± 12.74 years, and 51/59 (86.67%) of the patients were female. No missing values were reported. Of the 59 patients, 56 (89.83%) had migraines or medication-overuse headaches, and 3 (5.08%) had tension-type headaches. No one had trigeminal autonomic cephalalgias or other headaches. The models' overall accuracy and kappa for the ground truth were 94.92% and 0.65 (95%CI 0.21-1.00), respectively. The sensitivity, specificity, precision, and F values for migraines were 98.21%, 66.67%, 98.21%, and 98.21%, respectively. There was disagreement between the AI diagnosis and the ground truth by headache specialists in two patients. This is the first external validation of the AI headache diagnosis model. Further data collection and external validation are required to strengthen and improve its performance in real-world settings.

Neuralgia in the occipital region associated with ipsilateral trigeminal herpes zoster: Three case reports.

BACKGROUND: Nerve fibers related to pain and temperature sensation in the trigeminal nerve territory converge with the upper cervical spinal nerves from the level of the lower medulla oblongata to the upper cervical cord. This structure is called the trigemino-cervical complex and may cause referred pain in the territory of the trigeminal or upper cervical spinal nerves. CASE SERIES: Here, we report three cases of paroxysmal neuralgia in the occipital region with mild conjunctivitis or a few reddish spots in the ipsilateral trigeminal nerve territory. The patients exhibited gradual progression of these reddish spots evolving into vesicles over the course of several days, despite the absence of a rash in the occipital region. The patients were diagnosed with trigeminal herpes zoster and subsequently received antiherpetic therapy. Remarkably, the neuralgia in the occipital region showed gradual amelioration or complete resolution before the treatment, with no sequelae reported in the occipital region. DISCUSSION: The trigemino-cervical complex has the potential to cause neuralgia in the occipital region, as referred pain, caused by trigeminal herpes zoster. These cases suggest that, even if conjunctivitis or reddish spots appear to be trivial in the trigeminal nerve territory, trigeminal herpes zoster should be considered when neuralgia occurs in the ipsilateral occipital region.

Treatment patterns and characteristics of headache in patients in Japan: A retrospective cross-sectional and longitudinal analysis of health insurance claims data.

BACKGROUND: The present study aimed to investigate prescription patterns for patients aged over 17 years with headaches in the REZULT database. METHODS: We conducted a cross-sectional study (Study 1) of the proportion of over-prescription of acute medications (≥30 tablets/90 days for triptans, combination non-steroidal anti-inflammatory drugs (NSAIDs) and multiple types; ≥45 tablets/90 days for single NSAIDs) among patients with headache diagnosed in 2020. We longitudinally studied (Study 2) patients for >2 years from initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache was diagnosed in 200,055 of 3,638,125 (5.5%) patients: 13,651/200,055 (6.8%) received acute medication. Single NSAIDs were prescribed to 12,297/13,651 (90.1%) patients and triptans to 1710/13,651 (12.5%). Over-prescription was found in 2262/13,651 (16.6%) patients and 1200/13,651 (8.8%) patients received prophylactic medication. In Study 2, 408,183/6,840,618 (6.0%) patients were first diagnosed with headaches, which persisted for ≥2 years. Over time, the proportion of patients over-prescribed acute medications increased. Over 2 years, 37,617/408,183 (9.2%) patients were over-prescribed acute medications and 29,313/408,183 (7.2%) patients were prescribed prophylaxis at least once. CONCLUSIONS: According to real-world data, prophylaxis remains poorly prescribed, and both acute and prophylactic treatment rates for headaches have increased over time.

Treatment Patterns for and Characteristics of Headache in Children and Adolescents Aged 6-17 Years in Japan: A Retrospective Cross-Sectional and Longitudinal Analysis of Health Insurance Claims Data.

OBJECTIVE: To investigate the prescription patterns for patients aged 6-17 years with headaches in the REZULT database. METHODS: We cross-sectionally investigated (Study 1) the pattern of prescription and the proportion of triptan overprescription (≥30 tablets/90 d of triptans) among patients diagnosed with headaches in 2020. Next, we longitudinally studied patients (Study 2) for more than two years from the initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache diagnoses were assigned to 62,568 of 543,628 (11.51%) patients, and 1524 of 62,568 (2.44%) patients received acute medication. Single nonsteroidal anti-inflammatory drugs and triptans were prescribed to 620/624 (99.36%) and 5/624 (0.80%) of patients aged 6-11 years, respectively, and 827/900 (91.89%) and 91/900 (10.11%) of patients aged 12-17 years, respectively. Triptan overprescription was observed in 11/96 (11.46%) patients, and 5/11 (45.45%) of those patients received prophylactic medication. In Study 2, 80,756/845,470 (9.55%) patients aged 6-17 years were diagnosed with headaches that persisted for at least two years. Over two years, 44/80,756 (0.05%) patients were overprescribed triptans, and 3408/80,756 (4.22%) patients were prescribed prophylaxis on at least one occasion. CONCLUSIONS: Based on real-world data, the appropriate use of prophylactic treatment is still problematic. Overprescription of triptans was observed, although the number of patients was small.

Impact of Migraine on Daily Life: Results of the Observational survey of the Epidemiology, Treatment, and Care of Migraine (OVERCOME [Japan]) Study.

INTRODUCTION: The impacts of migraine on daily life, including daily activities and fundamental health indicators (sleep and mental health), have not been described in detail for people with migraine in Japan. METHODS: The cross-sectional ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) study was conducted between July and September 2020. Impacts of migraine on housework, family/social/leisure activities, driving, and sleep were assessed using questions from the Migraine Disability Assessment (MIDAS), Migraine-Specific Quality-of-Life Questionnaire, and Impact of Migraine on Partners and Adolescent Children scales and questions developed for OVERCOME (Japan). The Migraine Interictal Burden Scale (MIBS-4) evaluated burden on days without headaches. Depression and anxiety were assessed with the Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder (GAD-7) scales, respectively. Impacts on daily life were also described across MIDAS/MIBS-4 categories. RESULTS: Among 17,071 respondents with migraine, 24.8% required assistance with housework at least sometimes. Migraine interfered with relationships, leisure, and social activities at least sometimes for 31.8%, 41.6%, and 18.0% of respondents, respectively. Between headache days, 26.8% of respondents worried about planning social/leisure activities at least sometimes. Among respondents living with family (N = 13,548), migraine also had impacts on participation in and enjoyment of family activities. Among respondents who drove (N = 10,921), 43.9% reported that symptoms interfered with driving at least sometimes. Migraine interfered with sleep and mood at least sometimes for 52.7% and 70.7% of respondents, respectively. PHQ-8 and GAD-7 thresholds for clinical depression and anxiety were met by 28.6% and 22.0% of respondents, respectively. Impact of migraine on daily life increased with increasing severity of MIDAS/MIBS-4 categories. CONCLUSION: The burden of migraine on daily activities, sleep, and mental health is substantial for people with migraine in Japan. In clinical practice, it is important to evaluate the impact of migraine on daily life in addition to migraine symptoms.

Developing an artificial intelligence-based diagnostic model of headaches from a dataset of clinic patients' records.

OBJECTIVE: We developed an artificial intelligence (AI)-based headache diagnosis model using a large questionnaire database from a headache-specializing clinic. BACKGROUND: Misdiagnosis of headache disorders is a serious issue and AI-based headache diagnosis models are scarce. METHODS: We developed an AI-based headache diagnosis model and conducted internal validation based on a retrospective investigation of 6058 patients (4240 training dataset for model development and 1818 test dataset for internal validation) diagnosed by a headache specialist. The ground truth was the diagnosis by the headache specialist. The diagnostic performance of the AI model was evaluated. RESULTS: The dataset included 4829/6058 (79.7%) patients with migraine, 834/6058 (13.8%) with tension-type headache, 78/6058 (1.3%) with trigeminal autonomic cephalalgias, 38/6058 (0.6%) with other primary headache disorders, and 279/6058 (4.6%) with other headaches. The mean (standard deviation) age was 34.7 (14.5) years, and 3986/6058 (65.8%) were female. The model's micro-average accuracy, sensitivity (recall), specificity, precision, and F-values for the test dataset were 93.7%, 84.2%, 84.2%, 96.1%, and 84.2%, respectively. The diagnostic performance for migraine was high, with a sensitivity of 88.8% and c-statistics of 0.89 (95% confidence interval 0.87-0.91). CONCLUSIONS: Our AI model demonstrated high diagnostic performance for migraine. If secondary headaches can be ruled out, the model can be a powerful tool for diagnosing migraine; however, further data collection and external validation are required to strengthen the performance, ensure the generalizability in other outpatients, and demonstrate its utility in real-world settings.

Improved quality of life with fremanezumab in Japanese and Korean patients with episodic and chronic migraine: Results of two multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials.

OBJECTIVE: To evaluate quality of life (QoL) endpoints from two 12-week trials investigating fremanezumab efficacy and safety in Japanese/Korean patients with chronic (CM) or episodic (EM) migraine. BACKGROUND: Migraine is a leading cause of disability and affects QoL considerably, interfering with work and daily activities, social and family life, and emotional wellbeing. METHODS: This planned exploratory analysis used data from two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which Migraine-Specific QoL (MSQoL; Role Function-Restrictive [RR], Role Function-Preventive [RP], and Emotional Function [EF] domains) scores and Patient Global Impression of Change (PGIC) scores were pre-specified QoL outcomes in individuals receiving monthly or quarterly fremanezumab or placebo. In both trials, MSQoL was assessed at baseline, and MSQoL and PGIC at Weeks 4, 8, and 12. PGIC responders had a score of ≥5 points, indicating significant improvement. RESULTS: Mean baseline MSQoL scores were similar across groups in both CM (N = 565; RR, 60.3-61.5; RP, 78.5-80.0; EF, 69.0-71.4) and EM (N = 353; RR, 68.6-71.1; RP, 83.1-85.7; EF, 76.7-81.9) trials. In the CM trial, all three MSQoL domains improved in both fremanezumab groups at 12 weeks compared with placebo: least squares mean (LSM) and standard error (SE) change from baseline, p versus placebo (quarterly; monthly; placebo): RR 14.9 (1.3), p = 0.030; 15.1 (1.4), p = 0.020; 11.6 (1.3); RP 8.9 (1.1), p = 0.007; 8.6 (1.1), p = 0.013; 5.4 (1.1); EF 13.3 (1.5), p < 0.001; 12.5 (1.5), p = 0.003; 7.5 (1.5). In the EM trial, RR/EF domains improved in both fremanezumab groups compared with placebo: LSM change from baseline, p versus placebo (quarterly; monthly; placebo): RR 16.3 (1.4), p = 0.003; 16.4 (1.3), p = 0.002; 11.6 (1.4); EF 13.0 (1.3), p < 0.001; 11.5 (1.2), p = 0.004; 7.4 (1.3); RP improved in the quarterly group RP 8.6 (1.1), p = 0.010; 7.6 (1.1), p = 0.066; 5.4 (1.1). The proportion of PGIC responders at Week 12 was greater in the monthly and quarterly fremanezumab groups compared with the placebo group in the CM (96/182 [52.7%] and 98/180 [54.4%] vs. 68/179 [38.0%]; p < 0.05) and EM trial (81/118 [68.6%] and 86/113 [76.1%] vs. 38/111 [34.2%]; p < 0.001). CONCLUSION: Patients with EM/CM receiving monthly or quarterly fremanezumab, for a duration of 12 weeks, showed significant improvements in their QoL.

Outcomes and Factors Associated with Insufficient Effectiveness of Acute Treatments of Migraine in Japan: Results of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) Study.

BACKGROUND: Knowledge of patient outcomes and treatment effectiveness associated with acute migraine treatments in Japan is lacking. OBJECTIVE: To describe patient-reported outcomes (PROs) and treatment effectiveness in three acute treatment groups from OVERCOME (Japan): over-the-counter (OTC) only, prescription nonsteroidal anti-inflammatory drugs/acetaminophen (Rx-NSAIDs/ACE) only, and triptans. METHODS: OVERCOME (Japan) was an observational, cross-sectional, population-based web survey of people with migraine (July-September 2020). PROs, including the Migraine-Specific Quality of Life Questionnaire (MSQ), Migraine Interictal Burden Scale (MIBS-4), Migraine Disability Assessment (MIDAS), and Work Productivity and Activity Impairment Questionnaire: Migraine (WPAI-M), were compared pairwise between treatment groups. Logistic regression was used to examine treatment effectiveness. RESULTS: The analysis included 9075 survey respondents (OTC only: n = 5791; Rx-NSAIDs/ACE only: n = 751; triptans: n = 2533). Triptan users reported the lowest MSQ scores, most severe disability (MIDAS: 20.7% versus 6.3% and 11.6%) and severe interictal burden (MIBS-4: 50.1% versus 21.2% and 19.8%), and greatest work impairment (WPAI-M: 50.4% versus 32.2% and 30.8%) compared with the OTC and Rx-NSAIDs/ACE groups, respectively. Treatment effectiveness was very poor-to-poor for 60.9%, 43.1%, and 47.6% of the triptan, OTC, and Rx-NSAIDs/ACE groups, respectively. Severe interictal burden was significantly associated with insufficient treatment effectiveness (odds ratios, severe versus no burden: 0.47 [95% confidence interval: 0.40-0.54], 0.56 [0.35-0.89], and 0.41 [0.32-0.52], for the OTC, Rx-NSAIDs/ACE, and triptan groups, respectively). CONCLUSION: People with high migraine burden used triptans for acute treatment, but many reported poor treatment effectiveness. Education may be required to promote better treatments, including earlier introduction of migraine-specific acute and preventive medications.

School-based online survey on chronic headache, migraine, and medication-overuse headache prevalence among children and adolescents in Japanese one city - Itoigawa Benizuwaigani study.

BACKGROUND: We investigated the prevalence of headache, migraine, and medication-overuse headache (MOH) among children and adolescents through a school-based online questionnaire. We also investigated the triggers for migraine among them and the effect of the COVID-19 pandemic on headache frequency. METHODS: Children and adolescents aged 6-17 y.o. completed an online questionnaire. Migraine, MOH was defined as The International Classification of Headache Disorders Third edition. Factor and clustering analyses were performed for migraine triggers. The effect of the coronavirus disease 2019 (COVID-19) pandemic on headache frequency was also asked. RESULTS: Of the 2489 respondents, the prevalence of headache, migraine, and MOH were 36.44%, 9.48%, and 0.44%, respectively. Up to 70% of the respondents with headaches complained of the disturbance to daily life, but about 30% consulted doctors. The migraine triggers were grouped into 5 factors by factor analysis. The sensitivities of the migraineurs against the factors were divided into 3 clusters. Cluster 1 had stronger sensitivity for several triggers. Cluster 2 was sensitive to weather, smartphones, and video games. Cluster 3 had less sensitivity for triggers. Cluster 2 less consulted doctors even though the burden of migraine was enormous. During the COVID-19 pandemic, 10.25% of respondents increased headache attacks, while 3.97% decreased. CONCLUSIONS: This is the first detailed study on headache prevalence in Japanese students from elementary school to high school in one region. The burden of headaches is large among children and adolescents, and the unmet needs of its clinical practice should be corrected.

Efficacy of Kampo medicine Kakkonto as acute medication to treat tension-type headache among musculoskeletal pain patients using regular analgesics.

OBJECTIVES: Tension-type headache (TTH) is the most prevalent type of primary headache disorder. Its acute pharmacotherapy is acetaminophen or non-steroidal anti-inflammatory drugs based on the Japanese Clinical Practice Guideline for Headache Disorders 2021. With Japan's aging population, however, the number of TTH patients with comorbidities that have been treated by analgesics is increasing. Under this context, it is sometimes difficult to select an acute pharmacotherapy for TTH. Kakkonto, Japanese traditional herbal kampo medicine, is empirically used for TTH. We hypothesized that kakkonto has efficacy for TTH with painful comorbidities. MATERIALS AND METHODS: We prospectively collected 10 consecutive TTH patients who had already taken analgesics for comorbidities. We prescribed 2.5 g of kakkonto (TJ-1), and patients took it. A numerical rating scale for pain before and 2 hours after kakkonto intake was evaluated. RESULTS: Eight women and 2 men were included. The mean age was 71.0 ± 13.4 years old. Four patients had lower back pain, 2 had lumbar spinal stenosis, 2 had knee pain, 1 had neck pain, and 1 had shoulder myofasciitis. Celecoxib was used for 4 patients, acetaminophen for 3, loxoprofen for 2, and a combination of tramadol and acetaminophen for 1, as routinely used analgesics. The median numerical rating scale statistically improved from the median of 4 to that of 0. There were no side effects of kakkonto. CONCLUSION: Kakkonto showed efficacy as an acute medication for TTH with comorbidities that have been treated by analgesic.

Headache education by leaflet distribution during COVID-19 vaccination and school-based on-demand e-learning: Itoigawa Geopark Headache Awareness Campaign.

OBJECTIVE: We prospectively performed the Itoigawa Headache Awareness Campaign from August 2021 to June 2022, with two main interventions, and evaluated its effectiveness. BACKGROUND: Headache is a common public health problem, but its burden could be reduced by raising awareness about headache and the appropriate use of acute and prophylactic medication. However, few studies on raising headache awareness in the general public have been reported. METHODS: The target group was the general public aged 15-64. We performed two main interventions synergistically supported by other small interventions. Intervention 1 included leaflet distribution and a paper-based questionnaire about headache during COVID-19 vaccination, and intervention 2 included on-demand e-learning and online survey through schools. In these interventions, we emphasize the six important topics for the general public that were described in the Clinical Practice Guideline for Headache Disorders 2021. Each response among the two interventions' cohorts was collected on pre and post occasions. The awareness of the six topics before and after the campaign was evaluated. RESULTS: We obtained 4016 valid responses from 6382 individuals who underwent vaccination in intervention 1 and 2577 from 594 students and 1983 parents in intervention 2; thus, 6593 of 20,458 (32.2%) of the overall working-age population in Itoigawa city experienced these interventions. The percentage of individuals' aware of the six topics significantly increased after the two main interventions ranging from 6.6% (39/594)-40.0% (1606/4016) to 64.1% (381/594)-92.6% (1836/1983) (p < 0.001, all). CONCLUSIONS: We conducted this campaign through two main interventions with an improved percentage of individuals who know about headache. The two methods of community-based interventions could raise headache awareness effectively. Furthermore, we can achieve outstanding results by doing something to raise disease awareness during mass vaccination, when almost all residents gather in a certain place, and school-based e-learning without face-to-face instruction due to the COVID-19 pandemic.

Safety profile of lasmiditan in patients with migraine in an Asian population.

BACKGROUND: MONONOFU, a multicenter, randomized, double-blind, placebo-controlled phase 2 study of Japanese patients with migraine, was pivotal for lasmiditan approval in Japan. However, treatment-emergent adverse events (TEAEs) were more common than in global studies. A detailed safety profile would assist patient management. RESEARCH DESIGN AND METHODS: Safety assessments in MONONOFU included specific terms reported, frequency, severity, time to onset, duration, TEAE management, common TEAE risk factors, and TEAE-efficacy associations. RESULTS: Of 846 participants, 691 were assessed for safety. The proportion of participants reporting ≥1 TEAE was 23.4% with placebo and 70.9% with lasmiditan; 87.3% of TEAEs with lasmiditan were mild. The most frequent TEAEs with lasmiditan, dizziness (39.4%) and somnolence (19.3%), started ≤1 hour postdose (median durations: 2.5 and 3.3 hours, respectively). Higher lasmiditan dose, but not patient factors including body size, was identified as a clinically meaningful predictor of dizziness and somnolence. There were no adverse consequences of neurological TEAEs, which did not appear to adversely affect lasmiditan efficacy. CONCLUSIONS: In the MONONOFU study, TEAEs appeared typically mild, transient, and self-limiting. Lasmiditan may represent a useful and well-tolerated acute treatment option for smaller (body mass index <30 kg/m2) patients and Asian patients with migraine.

Potential Unmet Needs in Acute Treatment of Migraine in Japan: Results of the OVERCOME (Japan) Study.

INTRODUCTION: Using data from the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE study in Japan (OVERCOME [Japan]), we describe the current status of the acute treatment of migraine in Japan. METHODS: OVERCOME (Japan) was a cross-sectional, observational, population-based web survey of people with migraine in Japan (met modified International Classification of Headache Disorders criteria or had a physician diagnosis of migraine) conducted between July and September 2020. Respondents reported current acute medication use and effectiveness (assessed using the Migraine Treatment Optimization Questionnaire [mTOQ-4]). Cardiovascular history and risk factors of the respondents were also recorded. Potential unmet acute treatment needs were defined as insufficient effect of current acute treatments (mTOQ-4 score ≤ 5), a history of oral triptan use (and not currently taking any triptan), potential contraindications to triptans due to cardiovascular comorbidities, and/or cardiovascular risk factors. RESULTS: In total, 17,071 people with migraine in Japan completed the survey; 14,869 (87.1%) of these were currently using acute treatments. Poor effectiveness of current acute treatment was reported by 7170 respondents (42.0%), 900 respondents (5.3%) were former triptan users, 1759 (10.3%) had contraindications to triptans, and 9026 (52.9%) reported at least one cardiovascular risk factor. Overall, 12,649 (74.1%) of OVERCOME (Japan) respondents were categorized into one or more of these groups and were considered to have potential unmet acute treatment needs. CONCLUSION: Almost three-quarters of people with migraine in Japan may have potential unmet needs for acute treatment of migraine. There are substantial opportunities for improving care for people with migraine in Japan, including prescription of novel acute medications.

Rapid Onset and Sustained Efficacy of Lasmiditan Among Japanese Patients with Migraine: Prespecified Analyses of a Randomized Controlled Trial.

INTRODUCTION: Rapid onset and sustained efficacy are important for acute migraine treatment. Global phase 3 trials have demonstrated the early onset and sustained efficacy of the 5-HT1F receptor agonist lasmiditan. In this prespecified analysis of the MONONOFU study, we assessed the onset and sustained efficacy of lasmiditan in Japanese patients with migraine. METHODS: MONONOFU was a multicenter, randomized, placebo-controlled, phase 2 study conducted in Japan (May 2019-June 2020). Eligible adults with migraine (N = 846; modified intent-to-treat population, N = 682) were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg, taken orally within 4 h of moderate-to-severe migraine onset. Patients recorded headache severity and symptoms predose and 0.5-48 h postdose. Sustained and modified sustained pain freedom were defined as patients who were headache pain-free 2 h postdose and had no pain (sustained pain freedom) or had mild or no pain (modified sustained pain freedom) at 24 or 48 h without rescue/recurrence medications. Efficacy outcomes were analyzed by logistic regression. Patients also recorded the actual time of pain-free and of meaningful pain relief (Kaplan-Meier analysis). RESULTS: Compared with placebo, significantly more lasmiditan-treated (100 or 200 mg) patients were headache pain-free, had pain relief, were free of their most bothersome symptom, or had total migraine freedom (no headache or migraine-associated symptoms) within 30-60 min. Median time to pain-free was 9.26, 6.88, 2.75, and 2.30 h in placebo, 50-mg, 100-mg, and 200-mg lasmiditan groups, respectively. Significantly greater proportions of patients treated with 100 (19.7-29.5%) or 200 mg (21.1-35.7%) lasmiditan had sustained or modified sustained pain freedom at 24 or 48 h compared with placebo (10.4-15.8%). CONCLUSION: This prespecified analysis of data from MONONOFU has confirmed that the efficacy of lasmiditan is rapid in onset and sustained in patients with moderate-to-severe migraine in Japan. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03962738).

Questionnaire-Based Survey during COVID-19 Vaccination on the Prevalence of Elderly's Migraine, Chronic Daily Headache, and Medication-Overuse Headache in One Japanese City-Itoigawa Hisui Study.

BACKGROUND: The prevalence of headache disorders, migraine, chronic daily headache (CDH), and medication-overuse headache (MOH) among the elderly in Japan has not been sufficiently investigated. We performed a questionnaire-based survey and revealed 3-month headache prevalence and headaches' characteristics. METHODS: The population aged over 64 was investigated in Itoigawa during their third coronavirus disease 2019 vaccination. Migraine, MOH was defined as The International Classification of Headache Disorders Third edition. CDH was defined as a headache occurring at least 15 days per month. K-means++ were used to perform clustering. RESULTS: Among 2858 valid responses, headache disorders, migraine, CDH, and MOH prevalence was 11.97%, 0.91%, 1.57%, and 0.70%, respectively. Combined-analgesic and non-opioid analgesic were widely used. Only one migraineur used prophylactic medication. We performed k-means++ to group the 332 MOH patients into four clusters. Cluster 1 seemed to have tension-type headache-like headache characteristics, cluster 2 seemed to have MOH-like headache characteristics, cluster 3 seemed to have severe headaches with comorbidities such as dyslipidemia, stroke, and depression, and cluster 4 seemed to have migraine-like headache characteristics with photophobia and phonophobia. CONCLUSIONS: This is the largest prevalence survey in the Japanese elderly. Headache disorders are still the elderly's burden. Clustering suggested that severe headaches associated with some comorbidities may be unique to the elderly.

Early onset of efficacy with erenumab for migraine prevention in Japanese patients: Analysis of two randomized, double-blind, placebo-controlled studies.

PURPOSE: In two 24-week migraine prevention studies in Japan, erenumab was associated with significantly greater reductions in migraine frequency versus placebo over Weeks 13-24 (primary endpoint). This post hoc analysis evaluated the onset of efficacy within the first 4 weeks after the initiation of erenumab from the 24-week double-blind periods of these studies. METHODS: Placebo-adjusted differences in least squares mean (LSM) change from baseline in weekly migraine days (WMD) were assessed weekly in each study and by migraine type (episodic (EM]/chronic [CM]) (Study 20170609). RESULTS: A total of 407 patients from Study 20120309 (70 mg: N = 135; 140 mg: N = 136; placebo: N = 136) and 261 patients from Study 20170609 ([EM] 70 mg: N = 78; placebo: N = 81; [CM] 70 mg: N = 52; placebo: N = 50) were included. For Study 20120309, onset of efficacy was observed as early as Week 1 in favor of erenumab versus placebo. Placebo-adjusted differences in LSM (95% confidence interval [CI]) change from baseline in WMD at Week 1 were -0.38 (-0.71 to -0.05; p = .022) and -0.49 (-0.82 to -0.16; p = .004) in favor of erenumab 70 and 140 mg, respectively. For Study 20170609, significant placebo-adjusted differences were observed with erenumab 70 mg at Week 1 in patients with EM (LSM [95% CI]: -0.55 [-0.97 to -0.12; p = .012]), and at Week 2 in patients with CM (LSM [95% CI]: -0.81 [-1.53 to -0.09; p = .028]) and for the overall population (LSM [95% CI]: -0.71 [-1.09 to -0.33; p < .001]). CONCLUSIONS: Erenumab treatment significantly reduced WMD compared with placebo. Onset of erenumab efficacy occurred as early as Week 1 in patients with migraine.

Questionnaire-based survey on the prevalence of medication-overuse headache in Japanese one city-Itoigawa study.

OBJECTIVE: The medication-overuse headache (MOH) prevalence has not been investigated in a general Japanese population. We performed questionnaire-based survey and revealed MOH prevalence and its characteristics. We also performed clustering to obtain insight for MOH subgrouping. METHODS: In this cross-sectional study, the 15-64-year-old population was investigated in Itoigawa during their COVID-19 vaccination under the national policy. MOH was defined as ≥ 15 days/month plus self-report of use of pain medications ≥ 10 or 15 days/month in the last 3 months. Ward method and k-means + + were used to perform clustering MOH patients. RESULTS: Among 5865 valid responses, MOH prevalence was 2.32%. MOH was common among females and the middle-aged. Combination-analgesic is the most overused as 50%. MOH had aggravation by routine physical activity, moderate or severe pain, and migraine-like, compared to non-MOH. The 136 MOH patients could be grouped into 3 clusters. Age and frequency of acute medication use were essential factors for clustering. CONCLUSIONS: This is the first study of MOH prevalence in Japan. Most MOH characteristics were similar to previous reports worldwide. Public awareness of proper headache treatment knowledge is still needed. Clustering results may be important for subtype grouping from a social perspective apart from existing clinical subtypes.

Burden of Migraine in Japan: Results of the ObserVational Survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) Study.

INTRODUCTION: The ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE study in Japan (OVERCOME [Japan]) assessed the impact and burden of migraine in Japan. METHODS: OVERCOME (Japan) was a cross-sectional, observational, population-based web survey of Japanese people with migraine conducted between July and September 2020. The burden and impact of migraine were assessed using the Migraine Disability Assessment (MIDAS), Migraine-Specific Quality-of-Life Questionnaire (MSQ), Migraine Interictal Burden Scale (MIBS-4), and Work Productivity and Activity Impairment-Migraine scale. Results were stratified by average number of monthly headache days (0-3, 4-7, 8-14, ≥ 15). RESULTS: In total, 17,071 Japanese people with migraine completed the survey. Of these, 14,033 (82.2%) met International Classification of Headache Disorders, 3rd edition criteria for migraine and 9667 (56.6%) reported a physician diagnosis of migraine. Overall, 20.7% of respondents experienced moderate-to-severe disability (MIDAS). Moderate-to-severe interictal burden (MIBS-4) was experienced by 41.5% of respondents. MSQ scores in all domains were lowest in respondents with the most frequent headaches (≥ 15 monthly headache days) and highest in those with the lowest frequency headaches (≤ 3 monthly headache days), indicating poorer quality of life in those with more frequent headaches. Work time missed due to migraine (absenteeism) increased with increasing headache frequency, from 3.8 to 6.2%; presenteeism affected 29.8-49.9% of work time. Although migraine burden was greatest in people with the most frequent headaches, those with the lowest headache frequency still experienced substantial disability, interictal burden, and impacts on productivity and quality of life. There was also substantial unmet need for migraine care: 36.5% of respondents had ever hesitated to seek medical care for their headaches, and 89.8% had never used preventive medication. CONCLUSION: In Japan, the burden of migraine and barriers to migraine care are substantial. Improving patient awareness and healthcare provider vigilance may help improve patient outcomes.

Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial.

BACKGROUND: These subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) ("failed-yes" and "failed-no" subgroups) and with/without concomitant preventive treatment ("concomitant preventive-yes" and "concomitant preventive-no" subgroups). METHODS: Overall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4-6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated. RESULTS: Of the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4-6 (treatment difference versus placebo [95% CI], failed-yes: - 1.9 [- 3.3, - 0.4]; failed-no: - 1.4 [- 2.6, - 0.3]; concomitant preventive-yes: - 1.7 [- 3.3, 0.0]; concomitant preventive-no: - 1.6 [- 2.6, - 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup. CONCLUSION: Erenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment. TRIAL REGISTRATION: Clinicaltrials.gov . NCT03812224. Registered January 23, 2019.

Comprehensive population-based survey of migraine in Japan: results of the ObserVational Survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) study.

OBJECTIVE: The ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE study in Japan (OVERCOME [Japan]) aimed to provide an up-to-date assessment of migraine epidemiology in Japan. METHODS: OVERCOME (Japan) was a cross-sectional, population-based web survey of Japanese adults recruited from consumer panels. People with active migraine (met modified International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria or had a self-reported physician diagnosis of migraine) answered questions about headache features, physician consultation patterns, and migraine medication use. The burden and impact of migraine were assessed using Migraine Disability Assessment (MIDAS) and Work Productivity and Activity Impairment scales. RESULTS: In total, 231,747 respondents accessed the screener, provided consent, and were eligible for the survey. The migraine group included 17,071 respondents (mean ± SD age 40.7 ± 13.0 years; 66.5% female). ICHD-3 migraine criteria were met by 14,033 (82.2%) respondents; 9667 (56.6%) self-reported a physician diagnosis of migraine. The mean number of monthly headache days was 4.5 ± 5.7 and pain severity (0-10 scale) was 5.1 ± 2.2. In the migraine group, 20.7% experienced moderate to severe migraine-related disability (MIDAS score ≥ 11). Work productivity loss was 36.2% of work time missed, including 34.3% presenteeism. Only 57.4% of respondents had ever sought medical care for migraine/severe headache. Most respondents (75.2%) were currently using over-the-counter medications for migraine; 36.7% were using prescription nonsteroidal anti-inflammatory drugs, and only 14.8% were using triptans. Very few (9.2%) used preventive medications. CONCLUSIONS: Unmet needs for migraine health care among people with migraine in Japan include low rates of seeking care and suboptimal treatment.