A Pivotal Phase III Multi-Site Clinical Trial of High-Frequency Repetitive Transcranial Magnetic Stimulation at Primary Motor Cortex for Trigeminal Neuropathic Pain - PROJECT SUMMARY / ABSTRACT Trigeminal neuropathic pain (TNP), caused by a lesion or disease affecting the trigeminal nerve or its central pathways, is among the most disabling and treatment-resistant chronic pain conditions. Emerging evidence indicates that TNP reflects not only peripheral nerve injury but also maladaptive reorganization of central pain processing circuits, indicating that chronic TNP is, at least in part, a brain disorder. Repetitive transcranial magnetic stimulation (rTMS)—which is capable of precisely stimulating the cerebral cortex via a coil applied to the scalp—offers a non-invasive approach to directly modulate these central brain circuits. Although rigorous clinical trials of rTMS for pain are limited, high-frequency rTMS (HF-rTMS) targeting the primary motor cortex (M1) opposite pain has established pain-relieving efficacy for neuropathic pain and is approved for this indication in Europe. Patients with TNP appear particularly responsive to M1 rTMS yet have been underrepresented in prior neuropathic pain cohorts. Critically, the capacity of rTMS to produce durable, clinically meaningful benefit lasting several months has not been proven. Achieving this key durability milestone will be required for regulatory approval in the US. To definitively evaluate the safety, efficacy, and durability of HF-rTMS at M1, our group developed and validated a 10-Hz HF-rTMS protocol optimized for TNP, with pilot data demonstrating feasibility, safety, and robust short- term efficacy. Building on these results, we refined stimulation parameters, assessment methods, and statistical procedures; assembled a consortium of experienced trial sites; and obtained preliminary positive feedback from the FDA supporting a pivotal study design. The finalized protocol is an FDA-aligned, double-blind, randomized, controlled, multi-site RCT integrating best practices from the rTMS literature with empirically derived refinements from the pilot trial. In the UG3 phase of this award, we will complete all preparatory activities for multi-site implementation, including protocol harmonization, operator and assessor training, centralized data and quality system setup, and an independent blinding integrity study, as recommended by the FDA. In the UH3 phase, we will conduct the pivotal multi-site RCT to evaluate the efficacy, durability, and safety of M1 HF-rTMS for refractory TNP, while collecting standardized clinical, imaging, and neurophysiological data to identify mechanistic predictors of treatment response and refine diagnostic criteria for facial pain disorders. By integrating rigorous clinical evaluation with mechanistic and physiological measures, this project will provide the most definitive assessment to date of M1 rTMS for facial pain. Successful completion will establish a safe, effective, and scalable noninvasive therapy for facial pain and provide critical additional information to guide its practical use and widespread adoption for TNP.
