aiTBS and rTMS in Neuropathic Pain and Prediction of Response (TRIPP)

This double-blind, sham-controlled randomized clinical trial investigates the efficacy and safety of two non-invasive brain stimulation techniques, accelerated intermittent theta burst stimulation (aiTBS) and conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), in patients with chronic neuropathic pain.

Chronic neuropathic pain affects 7-10% of the general population and remains difficult to manage because standard pharmacological treatments have limited efficacy and notable side effects. Motor cortex rTMS has shown analgesic effects in several controlled studies, but its effect size is modest, the responder rate is variable, and predicting individual response remains difficult. In the meantime, other stimulation paradigms, such as intermittent theta burst stimulation (iTBS), widely used in psychiatry, have been applied in the pain field to enable shorter treatment durations (minutes rather than 30 minutes per session) and a faster onset of pain relief. This kind of protocol is used in an accelerated way (aiTBS), including several sessions in one day, and has recently proven safe and highly effective in treatment-resistant depression. This study aims to evaluate the transferability of this approach to chronic pain, comparing aiTBS with classic 10 Hz rTMS and sham treatment, and to investigate clinical and neurophysiological predictors of response. Participants will be assessed using neuropsychosocial questionnaires, resting-state EEG recordings, and TMS motor-evoked potentials.

For analgesia, a minimal number of rTMS sessions (usually 4-5) and pulses per session (>500 to 3000) are needed to reach a therapeutic efficacy. To ensure a valid comparison between the two approaches in this trial, the rTMS and aiTBS protocols will deliver the same total number of pulses (5 sessions × 1,500 pulses = 7,500 pulses), administered over 5 consecutive days or on a single day, respectively.

The study will include 30 patients with chronic neuropathic pain in a randomized controlled trial with crossover who will receive either two active interventions (active rTMS and active aiTBS) or two sham conditions (sham rTMS and sham aiTBS). The randomization will occur twice: the first randomization (2:1) will allocate them to either the active or sham arm, and the second randomization (1:1) will decide which treatment to start with.

The total study duration per participant is approximately 10 to 12 weeks. It includes the enrollment, the first treatment (about one week after the enrollment), a washout period of 4 to 6 weeks during which the patient will be assessed, the second treatment (about one week after the re-evaluation) and three weeks of assessment after the end of the treatment. As mentioned, the two treatments will be separated by a wash-out period of 4 to 6 weeks, contingent on pain intensity returning to a baseline ≥ 4/10 on the numeric pain rating scale (NPRS) in the pain diary.

The medical device used for the treatment and the neurophysiological assessment will be a Transcranial Magnetic Stimulation (TMS) system coupled with a robot-assisted neuronavigation system, an EEG device for recording cortical oscillations and an amplification system to assess the motor evoked potentials on the first dorsal interosseus (FDI) hand muscle evoked by TMS. To enable transcranial magnetic stimulation (TMS) neuronavigation, if the patient does not already have a valid scan available, they will undergo a structural brain MRI, which will be performed either on the same day as enrollment or on another day, depending on unit availability.

The primary outcome of the study is the change in weekly average pain intensity (0-10 NPRS) from baseline (one week before treatment) to one week after treatment. Secondary outcomes include questionnaires assessing pain features and psychosocial factors. The exploratory objective is to identify clinical and neurophysiological predictors of treatment response using patient-reported outcome measures (PROMs), resting-state EEG biomarkers, and TMS-derived measures of intracortical excitability and inhibition.

It is hypothesized that the aiTBS treatment will have a similar efficacy to rTMS treatment and a superior efficacy compared with sham treatment on pain intensity and biopsychosocial outcomes. The combination of clinical and neurophysiological measures, as well as the short duration of treatment, is expected to facilitate the identification of predictors of treatments response.