Headache and Pain Research

Volume 27(3); October 2026

Editorial

Pediatric Migraine in Korea: New Opportunities in the Era of Mechanism-Based Prevention: Sanghyo Ryu; Headache Pain Res. 2026;27(3):171-173. Published online October 7, 2026; DOI: https://doi.org/10.62087/hpr.2026.0026

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Review Articles

Glymphatic System Dysfunction in Migraine: From Cortical Spreading Depression to Migraine Chronification: Jeongwook Park; Headache Pain Res. 2026;27(3):174-185. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0033

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Abstract PDF: Migraine has traditionally been understood as a neurovascular and neuroinflammatory disorder, but the glymphatic system, a brain-wide waste-clearance network mediated by cerebrospinal fluid and interstitial fluid exchange, has been proposed as a contributor to migraine pathophysiology. This review synthesizes current evidence on the role of glymphatic system dysfunction in migraine onset and chronification, integrating findings from preclinical animal models and multimodal clinical neuroimaging studies. Converging data suggest that cortical spreading depression during migraine attacks induces astrocyte swelling and aquaporin-4 (AQP4) depolarization, leading to physical collapse of the perivascular space, disruption of convective bulk flow, and impaired glymphatic clearance. This clearance failure may prolong the accumulation of nociceptive molecules, including calcitonin gene-related peptide, potassium ions, and glutamate, within the brain parenchyma, thereby exacerbating trigeminovascular sensitization and potentially contributing to migraine chronification. Clinically, alterations in neuroimaging markers such as the diffusion tensor imaging analysis along the perivascular space index and enlarged perivascular spaces have been associated with progressive fluid stagnation and an increased brain age gap in patients with chronic migraine. Glymphatic clearance failure may therefore contribute to the cycle of neuroinflammation and pain that sustains migraine. Future therapeutic strategies may benefit from moving beyond single-receptor blockade toward approaches that normalize the brain microenvironment, potentially by supporting glymphatic clearance through targeted pharmacological interventions and AQP4 channel modulation.

Is There a Role for Muscle Relaxants in Migraine Management? A Narrative Review: Heba Banihani, Marta Waliszewska-Prosół, Christopher Robinson, Abdulrazaq S. Albilali, Jeannine Abrons, Kinga Gecse, Merve Kozak, Mario M. F. Peres, Sait Ashina; Headache Pain Res. 2026;27(3):186-192. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0025

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Abstract PDF: Migraine is a debilitating neurological condition that affects approximately 15% of the global population and frequently co-occurs with musculoskeletal conditions that add to its burden. Neck pain affects 73%–90% of patients and often prompts off-label prescribing of muscle relaxants to relieve perceived muscular contributions to headache. This narrative review examines the clinical evidence, pharmacological profiles, and safety considerations for centrally acting antispasmodic and antispasticity agents (tizanidine, baclofen, cyclobenzaprine, and methocarbamol), peripherally acting agents (dantrolene), and other agents (carisoprodol and eperisone). Although limited data from landmark trials in the early 2000s suggest potential preventive benefits of tizanidine and baclofen, high-quality, contemporary evidence supporting the routine use of muscle relaxants for migraine is lacking in the broader literature. Their substantial adverse effects, including sedation, dizziness, and the risk of dependence, may further increase patient disability. This review supports current clinical guidelines that prioritize migraine-specific therapies and suggests reserving muscle relaxants for individual cases with prominent musculoskeletal symptoms. Further studies are needed to assess the efficacy and safety of their short- and long-term use in migraine management.

Original Articles

Feasibility and Safety of Elexir, an External Trigeminal Nerve Electrical Stimulator for the Acute Treatment of Migraine: Soo-Im Jang, Soohyun Cho, Mi Ji Lee; Headache Pain Res. 2026;27(3):193-203. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0041

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Abstract PDF Supplementary Material: Purpose: External trigeminal nerve stimulation (eTNS) is a noninvasive neuromodulation technique used to treat migraine. This study evaluated the feasibility and safety of Elexir®, a newly developed eTNS device, for the acute treatment of migraine at home.
Methods
This prospective, randomized, sham-controlled postmarketing study enrolled participants with migraine who reported 2–8 attacks per month. Participants were assigned 1:1 to verum or sham stimulation and instructed to use Elexir® at home for 60 minutes during an eligible migraine attack. Feasibility of home use was assessed in terms of per-protocol use and treatment completion at both the participant and session levels; session completion was defined by 60 (±5)-minute stimulation recorded in the device log. Assessments also included adverse events (AEs) and exploratory efficacy outcomes: changes in pain intensity, pain freedom and relief, and resolution of associated symptoms.
Results
Of the 100 randomized participants, 79 formed the home-use population. Within this population, 78 (98.7%; 95% confidence interval [CI], 93.2%–99.8%) used Elexir® during an eligible migraine attack, and 75 (94.9%; 95% CI, 87.7%–98.0%) completed at least one session. Of the 139 treatment sessions conducted at home, 103 (74.1%; 95% CI, 66.2%–80.7%) were completed within the protocol-defined duration. Ten participants (10.0%) reported AEs and eight participants (8.0%) reported device-related AEs. No serious device-related AEs were observed. The groups did not differ significantly in exploratory efficacy outcomes.
Conclusion
These findings support the feasibility of using Elexir® for the acute treatment of migraine; no serious device-related AEs were observed. Further studies are required to support efficacy.

Association between Psoriasis and Migraine in a Nationwide Cross-Sectional Study in Korea: Woo-Seok Ha, Soohyun Cho; Headache Pain Res. 2026;27(3):204-210. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0031

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Abstract PDF: Purpose: Psoriasis and migraine are common chronic disorders that may share neuroimmune mechanisms, although the biological basis of their association remains uncertain. This study investigated the association between psoriasis and migraine, focusing on psoriasis severity and migraine subtypes, using a large population-based database.
Methods
This population-based cross-sectional study used data from the Korean National Health Insurance Service database. We identified 329,363 adults who underwent national health screening in 2019, including 8,892 patients with psoriasis and 320,471 individuals without psoriasis. Psoriasis severity was classified according to the use of systemic or biologic agents, and migraine was categorized according to the presence of aura. Multiple logistic regression analyses were performed with adjustment for age, sex, comorbidities, body mass index, smoking status, alcohol consumption, income, and residential area.
Results
In the fully adjusted model, patients with psoriasis had higher odds of prevalent migraine than individuals without psoriasis (odds ratio [OR], 1.172; 95% confidence interval [CI], 1.102–1.246). This association was observed in both mild psoriasis (OR, 1.167) and moderate-to-severe psoriasis (OR, 1.190). Psoriasis was also significantly associated with non-aura-coded migraine (OR, 1.171; 95% CI, 1.100–1.246), whereas migraine with aura was not significantly associated with psoriasis.
Conclusion
Psoriasis was cross-sectionally associated with higher odds of prevalent migraine, including non-aura-coded migraine, after adjustment for measured demographic, clinical, and lifestyle factors. Longitudinal studies are needed to determine temporality and address potential detection bias related to healthcare utilization.

Dynamic Changes in Interictal Burden During 3-Year Follow-Up for Medication Overuse Headache: Yooha Hong, Mi-Kyoung Kang, Soo-Jin Cho; Headache Pain Res. 2026;27(3):211-220. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0039

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Abstract PDF: Purpose: Treatment improves medication overuse headache (MOH), but interictal burden may persist. Limited longitudinal data leave uncertainty about whether residual burden reflects persistent impairment, recovery, or newly emerging burden. We investigated changes in interictal burden during the 3 years after MOH diagnosis.
Methods
This single-center substudy of a nationwide prospective MOH registry enrolled 149 patients at baseline and assessed interictal burden at the 2- and 3-year follow-ups using the 4-item Migraine Interictal Burden Scale (MIBS-4). The Wilcoxon signed-rank test and exact McNemar test were used to analyze paired changes.
Results
At 3 years, clinical follow-up was completed by 89 patients and the MIBS-4 by 61; 57 had paired assessments at 2 and 3 years. At this follow-up, 9 of 89 patients (10.1%) had medication overuse (MO). Among patients with paired MIBS-4 assessments, the median score decreased from 2.0 (0.0–4.0) at 2 years to 1.0 (0.0–3.0) at 3 years (p=0.006), and the proportion with substantial-to-severe interictal burden decreased from 47.4% to 29.8% (p=0.031). Recurrence by 3 years affected 8.3% of patients whose MO had resolved at 2 years. At 3 years, substantial-to-severe interictal burden persisted in 28.6% of patients whose MO had resolved.
Conclusion
Interictal burden improved between 2 and 3 years after MOH diagnosis, yet clinically relevant burden persisted in more than one-quarter of patients whose MO had resolved. These findings suggest that recovery from MO and recovery from interictal burden do not necessarily proceed in parallel, supporting the inclusion of interictal burden in long-term MOH assessment.

Preliminary Quantitative Electroencephalographic Evidence of Depression-Aligned Neurophysiological Patterns in Interictal Migraine: A Multi-Dataset Study: Dokyung Lee; Headache Pain Res. 2026;27(3):221-230. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0022

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Abstract PDF: Purpose: This study aimed to examine whether interictal migraine shows neurophysiological patterns aligned with an external major depressive disorder (MDD) reference dataset, using quantitative electroencephalography (qEEG) indices less sensitive to absolute amplifier gain.
Methods
Three datasets were analyzed: ds005385 (normative reference, n=608; age-matched subset, 45–70 years, n=309), TDBRAIN (MDD, n=120; insomnia, n=30; healthy controls, n=47), and 25 patients with interictal migraine (chronic migraine, n=7; episodic migraine, n=18; mean age, 60.0 years; female, n=17). Eight candidate qEEG indices were ranked by effect size in TDBRAIN; the aperiodic exponent and frontal-parietal low-beta asymmetry (FP_asym_LowBeta) showed the largest effects and were selected for analysis. Four arousal-state windows were evaluated: eyes-closed resting, hyperventilation, post-hyperventilation 120 seconds, and post-hyperventilation 300 seconds.
Results
In TDBRAIN, patients with MDD showed a reduced aperiodic exponent (Cohen’s d=–0.63, p=0.001) and elevated FP_ asym_LowBeta (Cohen’s d=+0.83, p<0.001) versus healthy controls. In migraine, FP_asym_LowBeta was significantly elevated versus the age-matched normative reference after false discovery rate (FDR) correction during hyperventilation (p=0.015), post-hyperventilation 120 seconds (p=0.004), and post-hyperventilation 300 seconds (p=0.003); the eyes-closed resting window showed a nonsignificant trend (p=0.058). Compared with episodic migraine, chronic migraine showed a consistent but exploratory trend toward a lower aperiodic exponent across windows (Cohen’s d=-0.95 to -1.12, using sample-size-weighted pooled standard deviations), though no comparison survived FDR correction. A linear mixed-effects model showed no significant main effect of migraine subtype (p=0.084).
Conclusion
Interictal migraine showed preliminary qEEG patterns aligned with those observed in an external MDD reference dataset, particularly in frontal-parietal low-beta asymmetry during hyperventilation and recovery. However, these exploratory findings require validation in larger, age-matched cohorts with appropriate control for medication use and mood-related confounders.

Early Development of Spinal Cord Herniation in Spontaneous Intracranial Hypotension: Seung Ae Kim, Soyoun Choi, Kyunghoon Yang, Hye Jin Yoo, Ja-Young Choi, Mi Ji Lee; Headache Pain Res. 2026;27(3):231-240. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0043

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Abstract PDF: Purpose: Spinal cord herniation has been recognized as a very rare, late complication of spontaneous intracranial hypotension (SIH). This study examined the incidence and timing of early spinal cord herniation in SIH and the factors associated with its development.
Methods
Data from a prospective cohort of patients with SIH at Seoul National University Hospital (2022–2024) were analyzed retrospectively. Eligible patients presented within 1 year of symptom onset, had a spinal longitudinal epidural collection, and had no spinal cord herniation at baseline. Kaplan–Meier analysis was used to estimate the cumulative incidence of spinal cord herniation, and Cox regression was used to evaluate risk factors.
Results
The study included 92 patients with SIH who presented within 1 year of onset (mean age, 40.6 years; 39.1% male). Spinal cord herniation was first detected in eight patients, a mean of 174.1±180.5 days after symptom onset. Its cumulative incidence reached 10.3% by 1 year and 14.2% by 2 years.
Conclusion
In patients presenting within 1 year of symptom onset with a type 1 leak, spinal cord herniation may develop earlier than previously recognized, even without neurological symptoms. Careful follow-up is essential to ensure timely, appropriate management. Caution is warranted, however, when generalizing these incidence estimates to the overall SIH population.

Case Report

Spontaneous Intracranial Hypotension Masquerading as Headache from an Unruptured Middle Cerebral Artery Aneurysm: Myoung-Jin Cha, Jiyoung Kim; Headache Pain Res. 2026;27(3):241-245. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0040

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Abstract PDF: Spontaneous intracranial hypotension (SIH) is characterized by neurological symptoms resulting from cerebrospinal fluid leakage or volume depletion. Although orthostatic headache is the hallmark symptom, SIH can also present with nausea, vomiting, dizziness, tinnitus, and other neurological symptoms. In this case, a cerebral aneurysm identified during evaluation of the headache was initially considered a potential cause, prompting a decision to treat it. However, an orthostatic headache severe enough to interfere with standing or physical activity had been overlooked. After a pre-existing subdural effusion was identified, the evolving orthostatic features of the headache and the imaging findings raised suspicion of SIH. The headache resolved after a lumbar epidural blood patch. Although a cerebral aneurysm is a potential cause of headache, SIH may be difficult to recognize early. Careful history taking, particularly about the characteristics and postural nature of the headache, is therefore essential to appropriately evaluate patients with headache.

Review Article

Pediatric Headache: Children and Adolescents

Gepants for the Treatment of Migraine in Children and Adolescents: Acute and Preventive Roles, Current Evidence, and Ongoing Trials: Ji-Hoon Na; Headache Pain Res. 2026;27(3):246-257. Published online October 19, 2026; DOI: https://doi.org/10.62087/hpr.2026.0034

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Abstract PDF: Migraine affects approximately 10% of children and adolescents and is often disabling, but evidence-based options for acute treatment and prevention remain limited. A high placebo response has also complicated pivotal pediatric trials. Therapies targeting the calcitonin gene-related peptide (CGRP) pathway have reshaped adult migraine care, and the approval of one CGRP monoclonal antibody for pediatric prevention has validated this target in pediatric patients. Gepants, small-molecule oral or intranasal CGRP receptor antagonists, are of particular interest because, unlike injectable antibodies, they offer acute or preventive treatment without vasoconstrictive activity. This review summarizes the pharmacology and adult evidence for the four approved gepants, their emerging pediatric use, and ongoing clinical trials. Depending on the agent, gepants have established efficacy for acute treatment or prevention in adults, with favorable long-term safety and no new hepatic or cardiovascular safety signals. Pediatric evidence is limited to small retrospective studies of off-label use in patients whose migraine is refractory to standard therapy. These reports suggest acceptable tolerability and possible benefit in some patients, but controlled trials are needed to determine efficacy. Phase 3 randomized trials are evaluating ubrogepant for acute treatment and atogepant and rimegepant for the prevention of episodic and chronic migraine in pediatric patients aged 6–17 years for acute treatment and episodic migraine prevention, and 12–17 years for chronic migraine prevention, with estimated completion expected between 2027 and 2032. Until controlled data become available, gepant use should be individualized and restricted to patients who have not responded to standard therapies. Pediatric dosing, long-term safety, and the lower age limit of benefit remain key questions.

Case Report

Pediatric Headache: Children and Adolescents

Early Infantile Onset of Presumed Recurrent Painful Ophthalmoplegic Neuropathy: Kristen M. Yang, Robert H. Fryer; Headache Pain Res. 2026;27(3):258-262. Published online October 19, 2026; DOI: https://doi.org/10.62087/hpr.2026.0032

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Abstract PDF: Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare recurrent cranial neuropathy that usually presents in childhood, most often before 10 years of age. Although RPON primarily affects pediatric patients, onset before 1 year of age is exceedingly rare. We report the case of a 10-month-old boy who presented with recurrent episodes of disconjugate gaze and left-sided ptosis, leading to a presumptive diagnosis of RPON. Magnetic resonance imaging (MRI) showed enhancement of the left oculomotor nerve, a characteristic finding of RPON. To our knowledge, this is one of the youngest reported cases of presumed RPON with oculomotor nerve enhancement on MRI. This case highlights the importance of including RPON in the differential diagnosis of acute ophthalmoplegia in infants, outlines key diagnostic considerations, and compares the patient’s clinical and radiographic findings with those reported in previously published pediatric cases.

Letters to the Editor