aiTBS and rTMS in Neuropathic Pain and Prediction of Response
ConditionChronic Neuropathic Pain
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18-80
SponsorHospital Ambroise Paré Paris
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
Disqualifiers
Ongoing litigation
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)
Trial design
Design model
Parallel
Treatments tested in this trial
Active rTMS, active aiTBS, sham rTMS or sham aiTBS
DeviceThe 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
Treatment groups
30 Participants
are divided into 2 treatment groupsGroup A: Active rTMS of followed by active aiTBS or converselyExperimental treatment 1 intervention
Group B: Sham rTMS followed by sham aiTBS or converselySham comparator 1 intervention
Trial outcomes
Primary outcomes
1
Change 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 treatmentSecondary outcomes
1
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 treatment2
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 treatment3
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 treatment4
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 treatmentOther outcomes
1
Assess the predictive value of baseline clinical variables (pain characteristics, demographic factors and psycho-social factors) on the analgesic response to aiTBS, rTMS and sham
Assess correlation between baseline clinical variables (pain characteristics, demographic factors and psycho-social factors using HADS, NPRS, NPSI, MOS-sleep, EQ5D-5L, CEQ, PCS, DN4 and MPQ) with the analgesic response to aiTBS, rTMS and sham
Time frame
From enrollment to 3 weeks after the end of treatment2
Identify predictors of the clinical response to aiTBS, rTMS and sham, based on baseline intracortical excitability/inhibition parameters using TMS
Identify correlation between motor cortical excitability and inhibition assessed using motor evoked potential (recorded from the hand FDI muscle) elicited by paired pulses-TMS and clinical analgesic response to aiTBS, rTMS and sham
Time frame
From enrollment to 3 weeks after the end of treatment3
Identify predictors of clinical response to aiTBS, rTMS and sham, based on baseline cortical pathological oscillatory EEG biomarkers
Identify correlation between baseline cortical oscillatory patterns extracted by resting state EEG registration and clinical response to motor cortex aiTBS, rTMS and sham. The EEG recording 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 treatmentSponsors and contacts
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Source ClinicalTrials.gov