This study evaluates the analgesic benefit of two non-invasive brain stimulation techniques: high frequency repetitive transcranial magnetic stimulation (rTMS) and accelerated intermittent theta burst stimulation (aiTBS) - compared to sham stimulation, in patients with chronic neuropathic pain lasting at least 6 months. Transcranial magnetic stimulation, which is delivered by a coil positioned on the scalp over the motor cortex, generates a low-intensity, submotor-threshold electromagnetic field that noninvasively activates targeted brain regions involved in pain perception. The procedure is painless and non-invasive. Sham stimulation uses the inactive face of the same coil and produces an identical sound, ensuring that neither patients nor investigators know which stimulation is being delivered. Conventional rTMS has demonstrated moderate analgesic efficacy in neuropathic pain, but its effect is delayed and requires at least 5 treatment sessions. iTBS delivers the same total stimulation dose in a much shorter time (approximately 8 minutes per session versus 30 minutes for conventional rTMS) and enables accelerated protocols with multiple sessions per day, which have shown promising results in depression. This study compares aiTBS, rTMS and sham by a randomized controlled trial (RCT) with a crossover design: participants are randomized in a 2:1 ratio to receive either active stimulation (both techniques in sequence) or sham stimulation (both techniques in sequence). Each treatment phase consists of either 5 consecutive daily rTMS sessions or 5 aiTBS sessions delivered on a single day (with a 45-min pause between sessions). The cross-over will take place after a 4 to 7-week washout period between the two active or sham treatments. The total study duration per participant is from 10 to 13 weeks, with 11-12 in-person visits. Assessments include self-reported pain diaries numeric pain rating scale (NPRS), validated pain, psychosocial, and quality-of-life questionnaires, resting-state Electroencephalography (EEG) recordings, and transcranial magnetic stimulation (TMS) based measures of intracortical excitability and inhibition. The exploratory aim is to identify neurophysiological and clinical predictors of treatment response, to better personalize the treatment in chronic pain population.
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 13 weeks. It includes the enrollment, the first treatment (about one week after the enrollment), a washout period of approximately 4 to 7 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 7 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
30
The active rTMS treatment consists of 5 sessions (1 per day for 5 consecutive days), each lasting 20 minutes. Each session consists of 15 trains of 10-s pulses at 10 Hz with an inter-train interval of 50 s, delivering 1500 pulses per session for a total of 7500 pulses. The active aiTBS treatment consists of 5 sessions delivered in a single day. Each session lasts 8 minutes, with an inter-session interval of 45 minutes and a 110-minute intervel between the third and fourth sessions. Each burst consists of 3 pulses at 50 Hz; bursts are repeated within a train of 10 bursts at 5 Hz. Each cycle consists of 2 s of train stimulation followed by 8 s of pause. One session is composed of 50 cycles, delivering 1500 pulses per session for a total of 7500 pulses. The sham stimulation will follow the same posology and modality of administration but opposite bobine face
Hopital Ambroise-Paré INSERM U987, 9 Av. Charles de Gaulle
Boulogne-Billancourt, Île-de-France Region, France
RECRUITINGChange in the self-reported average weekly pain intensity (numeric rating pain scale, NPRS, from 0 to 10) over the seven days after the last stimulation
Comparison between the efficacy of active aiTBS, Active rTMS, and sham on weekly average pain intensity measured over one week before the treatment and the average daily pain intensity measured one week after the end of the treatment (from day 2 to day 8 in case of iTBS treatment and from day 6 to day 13 in case of rTMS treatment). Pain intensity is extracted from the pain diary (scored on a 0-10 NPRS, with 0 = no pain and 10 = worst pain imaginable)
Time frame: From one week before the first day of treatment to 7 days after the end of treatment
Comparison of aiTBS, rTMS and sham on average pain intensity and interference with fatigue and sleep in numeric rating scale (NRS) from 0 to 10
Assess the efficacy of aiTBS, rTMS and sham on self-reported average pain intensity and interference with fatigue and sleep on NRS by daily mean scores of pain intensity (from 0 to 10) in pain diary from one week before first day of treatment to 3 weeks after the end of each therapeutic session (weekly average pain intensity reported on pain diary).
Time frame: From one week before first day of treatment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS and sham on average pain intensity in Brief Pain Inventory (BPI)
Assess the efficacy of aiTBS versus active rTMS and sham in Brief Pain inventory. It assess the average pain intensity pain, rated from 0 (no pain) to 10 (maximal pain imaginable).
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of aiTBS , rTMS and sham on neuropathic pain symptoms inventory (NPSI)
Assess the efficacy of motor cortex aiTBS versus rTMS and sham in neuropathic symtoms assessed by Neurophatic Pain Symptoms Inventory (NPSI). The NPSI is a patients reported questionnaire that quantifies the mean intensity of 10 neuropathic symptoms and their combination into 5 distinct dimensions during the last 24 hours on 11-point (0-10) numerical scales
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS versus active rTMS and sham on pain interference (BPI)
Comparison of the efficacy of active aiTBS versus active rTMS and sham on pain interference measured by BPI. The Brief Pain Inventory (BPI) has 7 items to investigate pain interference of the BPI rated from 0 (does not interfere), to 10 (complete interference)
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS versus active rTMS and sham on affective and sensory characterististic of pain by the short form McGill Pain Questionnaire (MPQ)
Comparison of active aiTBS, active rTMS and sham on affective and sensory characterististic of pain by the short form MPQ. The sensory and affective score of the short form McGill Pain Questionnaire contains 15 items, of which 11 assess the sensory dimension of pain (rated on 44) and 4 assess the affective dimension of pain (rated on 15)
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS and sham in patient global impression of change (PGIC)
Comparison of active aiTBS, active rTMS and sham in patient global impression of change (PGIC). The PGIC includes 7 items to evaluate the subjective improvement or deterioration (ranging from very much improved to very much deteriorated).
Time frame: 1, 2, 3 weeks after the end of each treatment
Comparison of active aiTBS, active rTMS and sham on clinical global impression of change (CGIC)
Comparison of active aiTBS, active rTMS and sham on clinical global impression of change (CGIC) ranging from very much improved to very much deteriorated
Time frame: 1, 2, 3 weeks after the end of each treatment
Comparison of active aiTBS, active rTMS and sham in pain catastrophizing scale (PCS)
Comparison of active aiTBS, active rTMS and sham in pain catastrophizing scale (PCS). The PCS consists in 13 items describing the thoughts and feelings that individuals may experience during pain. Each item is scored from 0 (not at all) to 4 (all the time), with a total score ranging from 0 to 52, where higher scores indicate greater catastrophizing.
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS and sham on anxiety and depression symptoms assessed by hospital anxiety and depression scale (HADS)
Comparison of active aiTBS, active rTMS and sham on anxiety and depression symptoms assessed by hospital anxiety and depression scale (HADS). The HADS includes 14 items of which 7 assess the anxiety and 7 the depression, the score max for each domaine is 21. Higher scores indicate greater symptom severity
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS and sham on global health status assessed by EuroQol 5 dimensions 3 levels (EQ-5D-3L) questionnaire
Comparison of active aiTBS, active rTMS and sham on health status assessed by EQ-5D-3L. The EQ-5D-3L descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels, representing, in a score from 1 to 3, no problems, moderate problems, and extreme problems.
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS and sham on sleep quality assessed by the Medical Outcome Study Sleep Scale (MOS sleep)
Comparison of active aiTBS, active rTMS and sham on sleep quality assessed by MOS sleep scale. The MOS sleep is a self reported validated questionnaire to assess the main dimensions sleep quality, is composed by 12 items that are rated on a 6-point categorical scale from 1 (all the time) to 6 (never). Scores are converted to a Sleep Problems Index ranging from 0 to 100, where higher scores indicate greater sleep disturbance.
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS and sham in pain relief assessed by the brief pain inventory (BPI)
Comparison of active aiTBS, active rTMS and sham in proportion of pain relief assessed by Brief Pain Inventory (BPI) and ranging from 0 to 100% of relief
Time frame: From enrollment to 3 weeks after the end of treatment
Assess the side effects of rTMS, aiTBS and sham
Assess the safety of aiTBS, rTMS and sham by monitoring the occurrence of adverse effects and their severity using a specific questionnaire during and after treatment.
Time frame: From first day of treatment to week 3 after treatment
Comparison between aiTMS, rTMS and sham in numbers needed to treat for pain relief
The Numbers Needed to Treat for 30% and 50% pain relief based on weekly average pain intensity o numeric pain rating scale (NPRS) reportend in pain diary and on the 5th item of the brief pain inventory (BPI) assessing pain relief
Time frame: From enrollment to 3 weeks after the end of treatment
Assess the blinding using a blinding questionnaire at the end of the study
The blinding using a short blinding questionnaire to ask the patients what treatment they think they have received and the reasons
Time frame: Immediately after treatment and at 3 weeks after the end of the treatment
Comparison of active aiTBS, active rTMS and sham in hours of spontaneus pain during the last 24 hours assessed by the neuropathic pain symptoms inventory (NPSI)
Comparison of active aiTBS, active rTMS and sham in hours of spontaneus pain during the last 24 hours by the neuropathic pain symptoms inventory (NPSI) scale ranging from "less than 1h/day" to "between 8 and 12 h/day"
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS and sham in number of painfull crisis during the last 24 hours assessed by the Neuropathic Pain Symptoms Inventory (NPSI)
Comparison of active aiTBS, active rTMS and sham in number of painfull crisis during the last 24 hours by neuropathic pain symptoms inventory (NPSI) ranging from "no pain crisis" to "more than 20 pain crisis"
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison between aiTBS, rTMS and sham in present pain intensity by short form McGill pain questionnaire (MPQ)
Comparison between aiTBS, rTMS and sham in present pain intensity ranging from 0 (no pain) to 5 (excruciating) by short form McGill pain questionnaire
Time frame: From enrollment to 3 weeks after the end of treatment
Assess the potential effect of aiTBS, rTMS and sham on cortical pathological oscillatory patterns using electroencephalography (EEG)
Assess the potential effect of aiTBS, rTMS and sham on cortical pathological oscillatory patterns using resting state EEG. It will be performed by a 5 minute eyes open and 5 minutes with eyes close registration using a 32 channel cap. The EEG features taken into account will be the power in alpha, beta, delta, theta and gamma bands, the peak alpha frequency, the global mean field potential, the local mean field potential, the aperiodic activity 1/f, the alpha asimmetry and the connectivity (by the debiased weight phase lag index and the amplitude envelope correlation)
Time frame: From the first day of treatment (before treatment) to 3 weeks after the end of treatment
Assess the potential effect of aiTBS, rTMS and sham in intracortical excitability/inhibition parameters extracted from motor evoked potentials (MEP) by transcranial magnetic stimulation (TMS)
Assess the potential effect of aiTBS, rTMS and sham in intracortical excitability/inhibition assessed by MEP, recorded from the first dorsal interosseus (FDI) muscle, elicited by paired pulses TMS
Time frame: From enrollment to 3 weeks after the end of treatment
Compare the aiTBS, rTMS and sham group on credibility and expectancy questionnaire (CEQ)
Compare the aiTBS, rTMS and sham group before treatment on credibility and expectancy relative to the treatment using the first 4 items of the credibility and expectancy questionnaire (CEQ). The first four items are rated on a scale from 1 to 9, where higher scores indicate greater treatment credibility and expectancy.
Time frame: From enrollment to the first day of each treatment (before treatment)
Comparation between the aiTBS, rTMS and sham on number of responders based on 30% and 50% of pain relief
The percentage of pain relief is based on weekly average pain intensity assessed by numeric pain rating scale (NPRS) ranging from 0 to 10 with higher scores indicating greater pain intensity and on the item 5 of Brief Pain Inventory (BPI) ranging from 0% to 100% of pain relief
Time frame: From enrollment to 3 weeks after the end of treatment
Comparison of active aiTBS, active rTMS, and sham on the patient's self-rated health status assessed by the 0-100 visual analog scale from the EuroQol questionnaire (EQ VAS)
Comparison of active aiTBS, active rTMS, and sham on the patient's self-rated health status, assessed using a 0-100 visual analog scale, where 0 represents the worst health imaginable, and 100 represents the best health imaginable.
Time frame: From enrollment to 3 weeks after the end of the treatment
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