Abstract
Non-invasive neuromodulation is emerging as a structured therapeutic option for headache disorders, supported by recent guideline recommendations and expanding clinical evidence. The International Headache Society (IHS) 2025 evidence-based guideline represents a pivotal milestone, synthesizing randomized controlled trials (RCTs) data on FDA-cleared and CE-marked devices (1). It offers conditional recommendations for several non-invasive modalities in acute and preventive migraine treatment (Table 1), while for others, no recommendation was possible due to insufficient evidence, reinforcing the need for more rigorously designed future trials. Importantly, the guideline establishes neuromodulation within the framework of migraine care and emphasizes adherence to a standardized controlled trial design.
Summary of the evidence-based recommendations.
This editorial provides an overview of recent migraine neuromodulation studies and additional research beyond migraine, including applications in cluster headache (CH), cervicogenic headache (CGH), and post-dural puncture headache (PDPH), and discusses trial designs and mechanistic insights.
Remote electrical neuromodulation (REN) in acute migraine: Early use and pediatric emergency care (ED) data
Ailani et al. (2) analyzed real-world data from 55,261 patients and 586,981 treatments. Early REN use within one hour of migraine onset, compared to later use, significantly improved 2-h pain freedom (early: 28.8% vs late: 14.5%) and pain relief (early: 65.1% vs late: 46.6%), with pediatric patients showing greater relative benefit. Orr et al. (3) conducted the first double-dummy RCT in a pediatric emergency setting (n = 22, ages 8–18), comparing REN (45-min session) with intravenous (IV) metoclopramide and ketorolac. At two hours, pain freedom was 11% with REN versus 40% with IV therapy, and pain intensity reduction was 2.4 ± 1.6 (REN) versus 4.0 ± 3.5 (IV therapy); the study was not powered for statistical significance. REN demonstrated fewer adverse events and high acceptability among participants and clinicians (3).
Kinetic oscillation stimulation (KOS) for chronic migraine (CM) prevention
Hoffmann et al. (4) performed a multicenter, sham-controlled RCT in 163 adults with CM. The primary endpoint was the change in monthly moderate/severe headache days (MSD) during weeks 3–6 of treatment. Weekly 10-min intranasal sessions at 85 Hz for six weeks reduced MSD by 3.5 with KOS versus 1.2 with sham (p = 0.013), with sustained benefit four weeks afterwards (KOS −3.2 vs. sham −0.5; p = 0.001). Nearly half (47.1%) achieved ≥30% MSD reduction (4). Likely by engaging trigemino-autonomic pathways, KOS introduces a novel, mechanism-based preventive option with short-term durability.
Targeted cortical modulation: Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS)
Clemente et al. (5) tested accelerated intermittent theta burst stimulation over the dorsolateral prefrontal cortex in CM refractory to CGRP mAbs using a single-arm crossover design (20 sessions over four days; 1620 pulses/session). At two months, among three co-primary outcomes, significant reductions occurred in headache intensity (baseline 8.6 vs. 7.0; p = 0.004) and symptomatic medication use (baseline 19.8 vs. 12.8; p = 0.010), whereas monthly headache days showed no difference. Significant cognitive improvement occurred only in the Symbol Digit Modalities Test and Trail Making Test B (5). Ornello et al.'s (6) TACTIC trial applied bilateral M1 anodal tDCS for five consecutive days (20 min/session) in subjects on stable CGRP mAb, with a 28-day follow-up. The primary outcome, MHD, showed no significant difference (active:10.7 vs. sham: 14.9; p = 0.56), whereas the secondary outcome, monthly migraine days, was significantly reduced (active: 9.2 vs. sham: 16.6; p = 0.008), accompanied by decreased frontal delta power on EEG spectral analysis, suggesting neurophysiological correlates with clinical improvement.
Beyond migraine: PDPH, CGH, and CH
Gjikolaj et al. (7) conducted two sham-controlled RCTs applying anodal tDCS (dominant M1; three sessions over three days) for PDPH: one as treatment after PDPH onset and one as prophylaxis immediately after lumbar puncture (LP). The therapeutic trial showed a significant between-group difference in pain intensity (VAS) two days after PDPH (active: 39.8 vs sham: 72.3, p = 0.029). The preventive trial showed a lower incidence of PDPH than sham two days after LP (active: 20% vs. sham: 40%; p = 0.046) (7). Jobin et al. (8) randomized 32 patients with CGH to tDCS (ipsilateral M1; 18 sessions over six weeks) versus sham, combined with home-based exercise therapy. At six weeks, reductions in average pain (β = −1.37) and headache frequency (β = −0.15) were observed with active tDCS compared to sham, with sustained effects at 12 weeks for pain (β = −1.84) and headache frequency (β = −0.19) (8).
Fernandes et al. (9) reported the findings of an 11-year real-world study evaluating non-invasive vagus nerve stimulation (nVNS) in the acute or preventive treatment of trigeminal autonomic cephalalgias, mostly CH. Among 108 patients, 65% found nVNS useful, predominantly for prevention (84%), with 70% achieving >50% attack reduction. Median effective use was 47 months; adverse events were mild (22%) and non-serious. Withdrawal was frequent (55%), mostly due to perceived inefficacy. In an open-label trial of 36 refractory chronic CH patients, Fogh-Andersen et al. (10) applied occipital TENS twice daily for ≥30 min over 8–12 weeks, reducing the weekly attack frequency by ≥30% in 36% of patients and improving attack duration and abortive medication use.
Lessons from 2025
Early application of neuromodulation devices at attack onset may improve clinical outcomes and facilitate practical use. Although causality remains unproven, early application seems reasonable and aligns with principles established in acute migraine treatment. Mechanistic targeting, from trigemino-autonomic pathways to cortico-limbic networks, offers opportunities to refine both patient selection and endpoints. Methodological limitations, such as small sample sizes, short follow-up periods, incomplete blinding, and challenges in sham validation, complicate the efficacy interpretation. Dose-response relationships and adherence metrics are inconsistently reported. Long-term observational data suggest safety and possible sustained benefit but are biased toward adherent responders. Real-world studies and RCTs serve complementary roles: real-world studies provide insights into effectiveness and implementation in naturalistic settings, whereas RCTs remain essential for establishing causality and optimizing dosing and trial standards. Coverage decisions depend on factors beyond RCT, including cost-effectiveness, patient preferences, and health system priorities. Future priorities include rigorously designed studies to strengthen evidence and advance neuromodulation science, while expanding coverage to ensure equitable access.
The 2025 literature signals a pragmatic shift. With evidence-based guidelines, earlier deployment, mechanistically informed protocols, and expansion into PDPH, CGH, and CH, noninvasive neuromodulation is evolving into a versatile alternative or adjunct across the headache spectrum. The next step should focus on large, methodologically rigorous RCTs aligned with IHS standards, complemented by real-world studies that capture adherence, cost-effectiveness, and implementation outcomes. Together, these approaches will advance neuromodulation to precision and integration into routine clinical care.
Footnotes
Acknowledgment
During the preparation of this manuscript, the authors utilized Grammarly (Grammarly, Inc., San Francisco, CA) and Microsoft 365 Copilot (Microsoft Corporation, Redmond, WA), accessed via Thomas Jefferson University's enterprise license. All content generated or refined using these tools was subsequently reviewed and edited by the authors, who take full responsibility for the final version of the publication.
Author contributions
HY: Conceptualization; Methodology; Writing – Original Draft; Writing – Review & Editing; Supervision; Project Administration; Final Approval of Manuscript.
CCN: Conceptualization; Methodology; Writing – Original Draft; Writing – Review & Editing.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Within the past 24 months, CCN has received advisor and speaker fees from AbbVie and speaker fees from Lundbeck. Within the past 24 months, HY has received funding from AHS Early-Stage Investigator Research Award, Pfizer-Jefferson Collaborative Research; institutional support for serving as an investigator from Teva, AbbVie, Ipsen, Rehaler, Pfizer, Shiratronics, Lundbeck, Johnson & Johnson; consultant/advisory fees from Salvia, AbbVie, Pfizer, Cerenovus; and royalties from Cambridge University Press and MedLink Neurology.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
