Headache and Pain Research

Review Article

The Hidden Risks of Medication Underuse in Migraine Progression: Heui-Soo Moon, Pil-Wook Chung; Received September 29, 2025 Accepted October 5, 2025 Published online October 23, 2025; DOI: https://doi.org/10.62087/hpr.2025.0019 [Epub ahead of print]

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Abstract PDF: Migraine is a progressive neurological disorder in which inadequate treatment can lead to chronification. For decades, clinical attention has centered on medication overuse headache (MOH) as the primary iatrogenic risk factor for this progression. However, medication underuse (MU) has emerged as a critical yet less established framework for understanding gaps in migraine care. This review reframes MU, which includes ineffective therapies, delayed administration, and non-adherence due to intolerability, as an active contributor to disease progression. Untreated or undertreated migraine attacks promote the development of central sensitization, a state of neuronal hyperexcitability that increases attack frequency, severity, and treatment resistance. This paper posits that MU and MOH are not opposing concepts but interconnected manifestations of suboptimal disease management. Specifically, disease progression driven by MU can directly precipitate the escalating medication use that characterizes MOH, resulting in a more refractory clinical state. Therefore, preventing chronification requires a paradigm shift from merely avoiding overuse to achieving optimal use. This entails adherence to evidence-based guidelines for both acute and preventive therapy—implementing stratified acute care within the neurobiological window to prevent central sensitization and initiating timely preventive treatment in eligible patients to reduce the overall attack burden. The integration of novel targeted therapies provides new opportunities to overcome the limitations of traditional agents. Ultimately, reducing the risks associated with MU through proactive, evidence-based management and strong patient–clinician communication is essential to alter the natural history of migraine and prevent the long-term disability associated with its progression.

Case Report

Isolated Dental and Lower-Facial Pain Mimicking Trigeminal Neuropathy: An Indirect Carotid-Cavernous Fistula: Byoungchul Choi, Chulho Kim, Sung-Hwan Kim, Jong-Hee Sohn; Received September 30, 2025 Accepted October 12, 2025 Published online October 22, 2025; DOI: https://doi.org/10.62087/hpr.2025.0020 [Epub ahead of print]

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Abstract PDF: Carotid-cavernous fistula (CCF) is a pathological arteriovenous communication in which carotid arterial flow is diverted into the cavernous sinus. Clinical manifestations typically include ocular signs, cranial neuropathies, and headache. Neurologic deficits most commonly reflect involvement of cranial nerves III, IV, V1/V2, and VI within or along the cavernous sinus; in contrast, isolated trigeminal presentations are rare, and V3 involvement is particularly uncommon. A 69-year-old woman presented with isolated V2/V3-territory pain, perceived as molar, gingival, and lower facial discomfort. Her symptoms were initially misattributed to trigeminal neuropathy or dental pathology. Subsequently, she developed horizontal diplopia, and bedside testing localized a right abducens palsy. Brain magnetic resonance imaging revealed findings suspicious for a CCF, which was angiographically confirmed as an indirect CCF. Following embolization, the patient’s pain markedly improved, implicating the CCF as the source of the V2/V3 symptoms. This case highlights that an atypical, trigeminal-predominant onset—even with pain limited to the V2/V3 distribution—may indicate an indirect CCF. When atypical trigeminal neuropathy is suspected and dental or other peripheral causes are excluded, clinicians should consider the possibility of a CCF.

Original Article

Trigeminal Autonomic Cephalalgias Following Unilateral Dorsolateral Medullary Infarction: A Case Series and Literature Review: Jae-Myung Kim, Hak-Loh Lee, You-Ri Kang, Joon-Tae Kim, Seung-Han Lee; Received August 10, 2025 Accepted September 17, 2025 Published online October 22, 2025; DOI: https://doi.org/10.62087/hpr.2025.0013 [Epub ahead of print]

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Abstract PDF: Purpose: Secondary trigeminal autonomic cephalalgias (TACs) are typically associated with posterior fossa abnormalities, such as tumors and vascular malformations. However, TACs following brainstem infarctions are rarely reported. This study aimed to characterize the clinical and anatomical features of TACs after unilateral dorsolateral medullary infarction.
Methods
We analyzed four patients with dorsolateral medullary infarction who developed secondary TACs, diagnosed using the International Classification of Headache Disorders, third edition criteria. All patients underwent detailed neurological examinations and neuroimaging, including diffusion-weighted magnetic resonance imaging and magnetic resonance angiography. Additionally, five published cases were identified through a literature review and analyzed in conjunction with our cohort.
Results
All patients exhibited stabbing or electric shock-like pain in the ipsilateral periorbital, hemifacial, and temporal regions. Headaches developed weeks to months post-stroke with brief attacks (1–2 minutes) occurring 1–5 times daily. Lacrimation and conjunctival injection were common. Three patients were diagnosed with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), while a fourth had short-lasting unilateral neuralgiform with cranial autonomic symptoms (SUNA). Each patient, as well as four of the five from the literature, exhibited ipsilateral facial sensory loss, suggesting involvement of the trigeminal spinal tract and nucleus. Delayed headache onset was more frequent in persistent cases.
Conclusion
Headache characteristics were more consistent with SUNCT/SUNA than with typical cluster headaches. Careful neurological examination is essential to detect focal signs and guide neuroimaging for identifying secondary causes. Clinicians should consider secondary TACs in patients with new-onset SUNCT/SUNA and focal brainstem signs.

Review Articles

Interictal Burden of Migraine: A Narrative Review: Soo-Kyoung Kim, Todd J. Schwedt; Received September 14, 2025 Accepted October 5, 2025 Published online October 21, 2025; DOI: https://doi.org/10.62087/hpr.2025.0018 [Epub ahead of print]

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Abstract PDF: Migraine is a chronic neurological disorder associated with substantial disability and societal costs. Traditionally, research and clinical care have focused on the ictal phase, characterized by headache and accompanying symptoms. However, growing evidence suggests that a considerable portion of migraine-related disability occurs between attacks, known as the interictal burden (IIB). IIB encompasses a wide spectrum of cognitive, emotional, sensory, and functional impairments that persist during headache-free periods, including fatigue, allodynia, photophobia, cognitive dysfunction, anticipatory anxiety, and social withdrawal. These symptoms can markedly reduce quality of life, work productivity, and family functioning, even in individuals with infrequent attacks. In a descriptive survey of 506 migraine respondents, 67% experienced severe IIB. The effects of IIB extend beyond patients themselves, contributing to presenteeism in the workplace and imposing emotional and logistical strain within families. Several instruments, including the Migraine Interictal Burden Scale (MIBS-4), Migraine-Specific Quality of Life Questionnaire (MSQ v2.1), Headache Impact Test (HIT-6), and Migraine Disability Assessment (MIDAS), have been employed to assess different dimensions of IIB. Nonetheless, no single comprehensive and standardized tool fully captures the multidimensional nature of IIB. Recognizing and addressing IIB is essential for delivering holistic, patient-centered migraine care. Future research should focus on developing validated assessment instruments and incorporating IIB measures into clinical trials and routine practice to better understand and alleviate the hidden burden of migraine.

Gepants for Migraine: An Update on Long-Term Outcomes and Safety Profiles: Soohyun Cho, Kimoon Chang; Received August 5, 2025 Accepted September 4, 2025 Published online October 21, 2025; DOI: https://doi.org/10.62087/hpr.2025.0012 [Epub ahead of print]

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Abstract PDF: Calcitonin gene-related peptide receptor antagonists, also referred to as gepants, represent a transformative advancement in migraine pharmacotherapy, providing both acute and preventive treatment options without the vasoconstrictive limitations of triptans. Since their initial approval in 2019, gepants have gained widespread clinical adoption, necessitating comprehensive evaluation of their long-term safety and efficacy. This review synthesizes current evidence on four calcitonin gene-related peptide receptor antagonists (rimegepant, atogepant, ubrogepant, and zavegepant) derived from pivotal trials, open-label extension studies, and real-world observational data. Rimegepant demonstrates sustained efficacy and minimal adverse events over 52 weeks, with no evidence of medication-overuse headaches or hepatotoxicity. Atogepant maintains progressive clinical benefits and favorable tolerability for up to 1 year, exhibiting low rates of treatment-emergent adverse events and discontinuation. Ubrogepant remains effective and well-tolerated during long-term intermittent use, with no clinically significant safety signals over extended exposure. Zavegepant, the first intranasal gepant, shows promising long-term tolerability, with the most frequently reported localized adverse event being transient dysgeusia. No consistent hepatic, cardiovascular, or serious systemic toxicity has emerged for any of the agents, and discontinuation rates due to adverse events remain consistently low. Current evidence supports gepants as safe and effective therapies for long-term migraine management, although ongoing surveillance and extended-duration studies remain essential to fully characterize their safety profile, particularly in high-risk populations and combination therapy scenarios. In conclusion, gepants offer a well-tolerated, non-vasoconstrictive alternative for migraine patients who require sustained treatment, representing a significant therapeutic advancement in migraine.

Headache as a Somatic Symptom in Pediatrics: Diagnosis and Integrated Management: Hye Eun Kwon; Received September 9, 2025 Accepted October 2, 2025 Published online October 20, 2025; DOI: https://doi.org/10.62087/hpr.2025.0016 [Epub ahead of print]

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Abstract PDF: Somatization—the expression of psychological distress through physical symptoms—presents a frequent and complex challenge in pediatric practice. Headache and dizziness are among its most common manifestations. This review addresses the diagnostic challenge of determining whether these symptoms indicate a primary headache disorder or reflect somatic symptom presentations. The difficulty becomes particularly evident when conditions manifest in severe or persistent forms, such as chronic primary headache (CPH) and somatic symptom and related disorders (SSRD), where clinical overlap is considerable and coexistence may occur. We first explore the shared pathophysiological mechanisms, emphasizing central sensitization as a unifying process. We then propose a clinical framework for differential diagnosis that includes careful evaluation of predisposing risk factors and contrasts the defined diagnostic criteria of CPH with the maladaptive psychological responses frequently observed in SSRD. Management strategies diverge pharmacologically but converge on key non-pharmacological approaches. For primary headaches, pharmacotherapy is primarily used for prophylaxis, although its efficacy remains limited in pediatric trials. In contrast, for somatic presentations, medication typically serves as an adjunctive treatment targeting comorbidities, while psychotherapy (particularly cognitive behavioral therapy [CBT]) functions as the cornerstone of care. Non-pharmacological interventions such as CBT and biofeedback are essential for improving functioning across both conditions. Therefore, effective management relies on a framework of comprehensive psychoeducation, holistic assessment, and integrated interdisciplinary care.

Editorial

Toward Precision Migraine Care: Genetics, Symptoms, and Big-Data-Driven Approaches: Soo-Jin Cho; Received September 13, 2025 Accepted October 2, 2025 Published online October 17, 2025; DOI: https://doi.org/10.62087/hpr.2025.0017 [Epub ahead of print]

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Review Article

A Practical Approach to Headache in Moyamoya Disease: Mi-Yeon  Eun, Jin-Man Jung, Jay Chol Choi; Received July 17, 2025 Accepted September 17, 2025 Published online October 17, 2025; DOI: https://doi.org/10.62087/hpr.2025.0011 [Epub ahead of print]

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Abstract PDF: Moyamoya disease (MMD) is a progressive steno-occlusive cerebrovascular disorder of the intracranial internal carotid arteries characterized by fragile collateral vessel formation. Although ischemic and hemorrhagic strokes are the most widely recognized manifestations of MMD, headaches are common, often disabling, and remain underacknowledged. Epidemiological studies report headache in 17%–85% of MMD patients, with particularly high rates among pediatric patients. Clinically, headache phenotypes are diverse and include migraine-like headaches with or without aura, tension-type, cluster, and hemiplegic variants. These presentations often overlap with primary headache disorders, complicating the diagnosis and sometimes delaying the recognition of underlying MMD. The pathophysiology of MMD-related headaches is multifactorial, involving vascular stenosis, abnormal collateral circulation, altered hemodynamics, and neurogenic inflammation. Chronic hypoperfusion may lower the threshold for cortical spreading depression, contributing to migraine-like or aura-associated symptoms. Surgical revascularization has been reported to alleviate headaches in both pediatric and adult patients, but persistent or new headaches may occur postoperatively, and long-term outcomes remain inconsistent. Management often involves general analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs, but vasoconstrictive agents (e.g., triptans and ergotamines) should be avoided. Lasmiditan, a non-vasoconstrictive 5-HT1F agonist, may represent a safer option for acute treatment, while the efficacy of other pharmacological agents remains unclear due to limited evidence. In conclusion, headaches in MMD are not only a frequent source of disability but also a potential clinical marker of disease activity. Wider recognition of their epidemiology, phenotypes, and mechanisms may improve the diagnosis, guide individualized treatment, and ultimately enhance quality of life for patients.

Correction

Erratum to “Premonitory Symptoms in Migraine: Implications for Disease Burden and Cognitive Impairment, with Some Promising Answers”: Utku Topbaş, Bahar Taşdelen, Nevra Öksüz Gürlen, Aynur Özge; Published online August 20, 2025; DOI: https://doi.org/10.62087/hpr.2024.0031.e1 [Epub ahead of print]; Corrects: Headache Pain Res 2025;26(2):130

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Original Articles

Clinical Characteristics of Migraine and Serum Beta-Endorphin Levels in Undergraduate Students in Osun State, Nigeria: Adebimpe Ogunmodede, Ahmed Idowu, Ahmad Sanusi, Uchenna Eke, Akintunde Adebowale, Michael Fawale, Morenikeji Komolafe; Headache Pain Res. 2025;26(2):162-170. Published online June 30, 2025; DOI: https://doi.org/10.62087/hpr.2025.0006

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Abstract PDF: Purpose: Migraine is a common neurological disorder diagnosed using the International Classification of Headache Disorders (ICHD). Beta-endorphin has pain-reducing properties and may serve as a future prognostic marker for migraine. This study aimed to assess the clinical characteristics of migraine and compare serum beta-endorphin levels in migraine patients and healthy controls among young undergraduate students.
Methods
This comparative cross-sectional study was conducted among undergraduate students at Obafemi Awolowo University, Nigeria. Fifty participants with migraine headaches were recruited using purposive sampling according to the ICHD-3 criteria. Healthy controls were recruited using convenience sampling and matched for age and sex. A study questionnaire was administered to all participants. Serum beta-endorphin concentrations in both migraineurs and healthy controls were measured using enzyme-linked immunosorbent assays. The beta-endorphin levels between migraine patients and healthy controls were compared using the Mann-Whitney U-test. The data were analyzed using SPSS version 26.0. A p-value of <0.05 was considered statistically significant.
Results
A total of 12 males and 38 females were recruited in both groups.The most commonly used medication for acute migraine treatment was paracetamol, while amitriptyline was the most frequently used prophylactic. Median serum beta-endorphin levels were significantly lower in the migraine group, at 385.4 pg/mL (328.5–423.4 pg/mL), compared to the control group, at 442.9 pg/mL (357.5–477.6 pg/mL) (p=0.01).
Conclusion
Serum beta-endorphin levels were significantly lower in young adults with migraine, suggesting a potential role for reduced endogenous analgesia in migraine pathophysiology. This supports the potential utility of beta-endorphin as a prognostic biomarker for migraine.

Validity of Migraine Diagnoses in Korean National Health Insurance Claims Data: Yoonkyung Chang, Soyoun Choi, Byung-Su Kim, Tae-Jin Song; Headache Pain Res. 2025;26(2):154-161. Published online June 19, 2025; DOI: https://doi.org/10.62087/hpr.2025.0004

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Abstract PDF Supplementary Material: Purpose: Accurate case identification using administrative datasets relies on diagnostic coding, yet these codes’ accuracy for migraine remains uncertain. This study aimed to validate the diagnostic accuracy of International Statistical Classification of Diseases and Related Health Problems 10th Revision (International Classification of Diseases, ICD-10) codes for migraine, migraine without aura (MOA), and migraine with aura (MA) in the Korean National Health Insurance Service database.
Methods
We retrospectively reviewed the electronic medical records of 500 patients (migraine [G43.X], 200; MOA [G43.0], 200; MA [G43.1], 100) from secondary and tertiary hospitals between January 2019 and December 2024. Diagnoses confirmed by headache specialists using the International Classification of Headache Disorders, third edition served as the gold standard. Validation metrics included the positive predictive value (PPV), negative predictive value, sensitivity, specificity, and the kappa statistic. Diagnostic accuracy was assessed based on ICD-10 claim frequency and improved by combining diagnostic codes with prescriptions for migraine medications.
Results
A single ICD-10 claim had a PPV of 74.00%. Accuracy improved significantly with increased claim frequency (≥3 claims: PPV, 81.14%; sensitivity, 98.61%; specificity, 28.26%), particularly when combined with medication prescriptions (≥3 claims with medication: PPV, 94.96%; sensitivity, 91.87%; specificity, 85.37%). MOA (≥3 claims with medication: PPV, 95.20%) and MA (≥3 claims with medication: PPV, 93.65%) showed similar trends. Excellent inter-rater reliability was observed (kappa, 0.806–0.951), with no significant accuracy differences between hospitals.
Conclusion
Employing multiple claims and prescriptions improved the accuracy of migraine diagnoses using ICD-10 codes, supporting the use of this method in epidemiological studies and health policy decisions.

Availability, Accessibility, and Utilization of Diagnostics and Therapeutics for Spontaneous Intracranial Hypotension in Asia: Soyoun Choi, Woo-Seok Ha, Soo-Jin Cho, Aynur Özge, Betül Baykan, Esme Ekizoglu, Kiratikorn Vongvaivanich, Koichi Hirata, Linh Tuyen Nguyen, Mamoru Shibata, Min Kyung Chu, Otgonbayar Luvsannorov, Ryotaro Ishii, Shengyuan Yu, Shih-Pin Chen, Shuu-Jiun Wang, Takao Takeshima, Tsubasa Takizawa, Vinh Khang Nguyen, Wei-Ta Chen, Yen-Feng Wang, Soo-Kyoung Kim, Mi Ji Lee; Headache Pain Res. 2025;26(2):142-153. Published online June 16, 2025; DOI: https://doi.org/10.62087/hpr.2025.0005

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Abstract PDF Supplementary Material: Purpose: Recent advances in imaging techniques have significantly enhanced the diagnosis of spontaneous intracranial hypotension (SIH). However, these developments have been reported mostly in Europe and the United States. This study aimed to evaluate the availability and utilization of diagnostic and treatment modalities for SIH in Asia, through a survey of regional headache specialists.
Methods
A literature search was conducted using PubMed, and members of the Asian Regional Consortium for Headache were contacted. Participants completed a two-step survey evaluating the availability, accessibility, and frequency of SIH diagnostic and treatment methods in their countries and institutions. Descriptive statistics were used to analyze the data.
Results
Twenty physicians from eight countries completed both rounds of the survey. Lumbar puncture, brain magnetic resonance imaging (MRI), and spinal MRI are widely available across Asia, but real-time imaging techniques—such as dynamic computed tomography myelography and digital subtraction myelography—that precisely localize cerebrospinal fluid leaks are less accessible. Blind or semi-targeted epidural blood patches (EBPs) are available at most centers, but are easily accessible in only about half of cases. Surgical interventions are rarely available.
Conclusion
Most diagnostic methods for SIH are available in Asia, despite some regional disparities. The utilization of EBP and surgical interventions remains somewhat limited. This highlights the need for greater awareness and standardization of diagnostic methods in Asia.

Review Article

Vestibular Migraine: Challenges in Diagnosis and Management: Byung-Kun Kim; Headache Pain Res. 2025;26(2):106-115. Published online June 11, 2025; DOI: https://doi.org/10.62087/hpr.2025.0001

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Abstract PDF: Vestibular migraine (VM) remains a clinical challenge due to its heterogeneous presentation and the frequent absence of typical migraine features during vestibular episodes. Although many studies have adopted the diagnostic criteria defined by the International Classification of Headache Disorders (ICHD), interpretation of findings is often complicated by variability in how these criteria are applied across studies. VM is frequently underdiagnosed or misdiagnosed, owing to its clinical overlap with other vestibular disorders. This review provides a comprehensive overview of the epidemiology, diagnostic criteria, differential diagnosis, and treatment strategies for VM. Particular emphasis is placed on distinguishing VM from other causes of vertigo to support accurate diagnosis and tailored management. By synthesizing current evidence, this review aims to improve clinical recognition, diagnostic precision, and therapeutic outcomes for patients with this under-recognized and often debilitating condition.

Editorial

Tension-Type Headache and Primary Stabbing Headache: Primary Headaches Beyond Migraine: Mi-Kyoung Kang; Headache Pain Res. 2025;26(2):89-90. Published online June 5, 2025; DOI: https://doi.org/10.62087/hpr.2025.0007

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Review Article

Genetic Architecture of Migraine: From Broad Insights to East Asian Perspectives: Joonho Kim, Min Kyung Chu; Headache Pain Res. 2025;26(2):116-129. Published online May 27, 2025; DOI: https://doi.org/10.62087/hpr.2025.0003

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Abstract PDF: Migraine is a complex neurological disorder with a strong genetic component, ranging from rare monogenic forms, such as familial hemiplegic migraine (FHM), to common polygenic migraine. FHM is primarily caused by mutations in CACNA1A, ATP1A2, and SCN1A, which affect ion channel function and cortical excitability. Additional genes, including PRRT2, have also been implicated, broadening the genetic landscape of monogenic migraine. Genome-wide association studies (GWAS) have identified multiple susceptibility loci for common migraine, highlighting key pathways related to neuronal excitability and vascular function. These findings have reinforced the neurovascular hypothesis of migraine pathogenesis. GWAS on other headache disorders, such as broadly defined headache or cluster headache, have also revealed both overlapping and distinct genetic risk factors. Genetic studies in East Asians have identified both ancestry-specific risk variants and overlapping loci with European populations, suggesting similarities in biological pathways while also highlighting population-specific differences in migraine susceptibility. Expanding research on the genetics of migraine in East Asian populations is essential for uncovering novel risk factors and improving the generalizability of genetic findings.

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