aiTBS and rTMS in Neuropathic Pain and Prediction of Response

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), which is 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 been 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 × 1500 pulses = 7500 pulses), administered over 5 consecutive days or on a single day, respectively.

The study will include participants with chronic neuropathic pain in a randomised controlled trial with crossover. Participants will first be randomised (2:1) to either the active or sham arm. Within each arm, a second randomisation (1:1) will determine the order in which the two interventions are administered: participants in the active arm will receive active rTMS and active aiTBS in randomised order, while participants in the sham arm will receive sham rTMS and sham aiTBS in randomised order. Based on the sample size calculation, 30 participants should complete the protocol. Participants who withdraw from the study before completion will be replaced by additional randomised participants and will be analysed according to the intention-to-treat principle, provided they have completed at least one treatment session.

The treatment allocation of the first randomisation (active/sham) will be concealed on USB drives, each linked to a unique participant number. An independent external operator, following a list created by a computer-based randomisation system, will associate each USB drive with the corresponding participant number to ensure allocation concealment. The TMS, through an automated system, will read the allocation code from the USB drive to determine whether to administer the active treatment or the placebo and give information to flip the coil. In cases where the previous or subsequent use of TMS involves the determination of motor evoked potentials, the flipping of the coil will be managed by another operator. This procedure, combined with the TMS property to mimic a real stimulation, through auditory and sensory cues, preserves full blinding of participants, care providers, and investigators throughout the study.

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 approximately 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 that of rTMS treatment and a superior efficacy compared to 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 treatment response.

Inclusion criteria

• Age over 18 years and less than 80 years
• Average pain intensity ≥ 4/10 on the numerical scale of the Brief Pain Inventory at screening and randomization
• Pain present for at least 4 days per week
• Persistent pain for at least 6 months
• Stable pharmacological treatment for pain for at least 1 month prior to the study.
• Peripheral or central neuropathic pain (postherpetic neuralgia, painful neuropathies, nerve lesions, radiculopathy, trigeminal neuralgia, stabilized multiple sclerosis, spinal cord lesion or stroke) fulfilling criteria for probable or definite neuropathic pain; and scoring ≥ 4 out of 10 on the DN4 questionnaire
• Informed consent
• Patients who can be followed for the whole duration of the study
• Patients affiliated to social security in France

Exclusion criteria

• Ongoing litigation
• Contraindication to rTMS :

• implanted electronic devices and/or conductive objects near the coil: patients with an active implanted device activated or controlled by physiological signals (e.g. pacemakers, implanted cardioverter defibrillators [ICD], vagus nerve stimulators [VNS] and portable cardioverter defibrillators [WCD], ocular implants, deep 16 brain stimulation, drug chambers/pumps, intracardiac leads) even if the device has been removed.
• Non-removable metal objects near the coil: Patients with a conductive implant, ferromagnetic or made of any other metal sensitive to magnetic fields, in the head or at a distance of less than 30 cm from the coil (e.g. cochlear implant, implanted electrodes/pacemakers, aneurysm clips or coils, stents and bullet fragments).
• Current drug or psychoactive substance abuse (DSM V)
• Pregnancy or lactation
• Epilepsia or past epilepsia
• Progressive unsable pathology (eg cancer)
• Current psychosis according to DSM V criteria
• Presence of other pain more severe than that justifying inclusion
• Lack of correct completion of pain self-assessment diaries between inclusion and randomisation (at least 4 weekly pain scores over 7 days),
• Subject unable to understand informed consent, under guardianship or curatorship
• Patients participating in another research protocol within 30 days prior to inclusion.
• Patient who has already received a treatment with rTMS