Effect of Low-intensity Transcranial Focused Ultrasound Stimulation on Neuropathic Pain: Protocol for a Randomised, Single-blind, Placebo-controlled, Three-arm, Parallel-group Pilot Trial (TUS-P-02 Study)

IntroductionNeuropathic pain (NP) remains difficult to manage because conventional pharmacological therapies often have limited efficacy and intolerable side effects. Non-invasive neuromodulation techniques have emerged as potential alternatives with fewer adverse effects. Meta-analyses of randomised controlled trials suggest that high-frequency repetitive transcranial magnetic stimulation over the primary motor cortex has analgesic effects; however, its efficacy is modest and restricted by the inability to stimulate deeper brain regions. Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel approach that enables precise targeting of deep brain structures and modulation of neural activity. Although promising in preclinical and preliminary human studies, its long-term therapeutic efficacy for NP remains unknown. This trial aims to evaluate the therapeutic effects and safety of repeated TUS sessions in patients with NP. Methods and analysisThis randomised, participant-blinded, placebo-controlled, three-arm, parallel-group clinical trial will enrol 39 participants with NP (pain duration [≥] 3 months; pain intensity [≥] 4 on the Numerical Rating Scale). Participants will be randomly allocated to one of three groups: (1) TUS targeting the primary motor cortex, (2) TUS targeting the posterior superior insula, or (3) sham stimulation. Each participant will undergo weekly sessions for eight weeks. The primary outcome is change in weekly average pain intensity scores recorded in a pain diary. Secondary outcomes include additional pain scales, quality of life measures, psychological assessments, quantitative sensory testing, motor cortical excitability, and adverse events. Ethics and disseminationThe protocol has been approved by the University of Osaka Clinical Research Review Board. Written informed consent will be obtained from all participants. Findings will be disseminated via scientific presentations and peer-reviewed publications. Trial registration numberjRCTs052240227 STRENGTHS AND LIMITATIONS OF THIS STUDY{Rightarrow} This is the first randomised, participant-blinded, placebo-controlled clinical trial evaluating the long-term effects of transcranial focused ultrasound stimulation (TUS) for neuropathic pain. {Rightarrow}TUS is a novel, non-invasive technique that can precisely target deep brain areas using a navigation system, offering the potential to modulate brain function. {Rightarrow}The single-blind design (participants only) may introduce a risk of performance bias, as operators cannot be blinded owing to technical constraints. {Rightarrow}The small sample size may limit statistical power to detect subtle between-group differences.