A Series of N-of-1 Trials Characterizing Individual Responses to Theta-Burst Stimulation in Post-traumatic Trigeminal Neuropathic Pain

Post-traumatic trigeminal neuropathic pain (PTNP) is challenging to treat, as conventional therapies have limited efficacy and side-effects, requiring individualized management. N-of-1 trials focus on individualized/personalized medicine. Theta burst stimulation (TBS), a modified form of high-frequency repetitive transcranial magnetic stimulation (rTMS), has shown promising effects on chronic pain. This study explored the potential of N-of-1 trials to characterize individual responses across active (continuous TBS) and sham rTMS sessions in patients with PTNP. Eight patients (48±16 years) with PTNP received active or sham rTMS sessions for four weeks targeting primary somatosensory cortex (face area) in a single-blinded, randomized cross-over N-of-1 design (active-sham-active-sham or sham-active-sham-active). Pain intensity (primary outcome) and secondary outcomes including perceptual distortion (PD), somatic symptoms, anxiety, jaw function, quality of life, sleep, and catastrophizing were assessed at baseline, end of treatment (EOT), and 1- and 3-month follow-up. Individual pain and PD trajectories were analyzed using segmented regression models including all repeated measurements and accounting for serial correlation. Pain intensity decreased in five patients at the EOT and 1-month follow-up and in four patients at 3 months, although changes varied across participants and sessions. PD magnitude decreased in three patients at the EOT and 1 month, while increasing in one. Psychosocial and clinical outcomes also showed heterogeneous individual changes. Improvements were observed after both active and sham sessions, without a consistent treatment-specific pattern. Thus, N-of-1 trials allow identification of individual treatment responses to rTMS in PTNP, while highlighting marked interindividual variability that should be considered when planning future randomized clinical trials. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT06577649) PERSPECTIVE: This study explored the potential of N-of-1 trials to evaluate neuromodulation outcomes in post-traumatic trigeminal neuropathic pain (PTNP). N-of-1 trials enable identification of patient-specific treatment responses to theta-burst stimulation in PTNP, supporting personalized treatment strategies, improving clinical decision-making and informing the design of future randomized clinical trials.