aiTBS and rTMS in Neuropathic Pain and Prediction of Response

Official title

A Double-blind, Randomized, Sham-controlled Crossover Trial Comparing the Analgesic Effects of Accelerated Intermittent Theta Burst Stimulation (aiTBS) and Classical High-frequency rTMS Targeting the Motor Cortex in Chronic Neuropathic Pain, and Prediction of Response.

Overview

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 6-week washout period between the two active or sham treatments. The total study duration per participant is from 10 to 12 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.

Detailed description

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.

Interventions

• Device Active rTMS, active aiTBS, sham rTMS or sham aiTBS
  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 c

Primary outcome measures

• 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 [Time frame: From one week before the first day of treatment to 7 days after the end of treatment]

Secondary outcome measures (12)

• 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 [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) [Time frame: From enrollment to 3 weeks after the end of treatment]
• Comparison of aiTBS , rTMS and sham on neuropathic pain symptoms inventory (NPSI) [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) [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) [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) [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) [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) [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) [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 [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) [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) [Time frame: From enrollment to 3 weeks after the end of treatment]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 1 center

• Hopital Ambroise-Paré INSERM U987, 9 Av. Charles de Gaulle — Boulogne-Billancourt

Publications

• Soliman N, Moisset X, Ferraro MC, de Andrade DC, Baron R, Belton J, Bennett DLH, Calvo M, Dougherty P, Gilron I, Hietaharju AJ, Hosomi K, Kamerman PR, Kemp H, Enax-Krumova EK, McNicol E, Price TJ, Raja SN, Rice ASC, Smith BH, Talkington F, Truini A, Vollert J, Attal N, Finnerup NB, Haroutounian S; NeuPSIG Review Update Study Group. Pharmacotherapy and non-invasive neuromodulation for neuropathic p PMID 40252663
• Passard A, Attal N, Benadhira R, Brasseur L, Saba G, Sichere P, Perrot S, Januel D, Bouhassira D. Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain. 2007 Oct;130(Pt 10):2661-70. doi: 10.1093/brain/awm189. Epub 2007 Sep 14. PMID 17872930
• Moisset X, Bouhassira D, Avez Couturier J, Alchaar H, Conradi S, Delmotte MH, Lanteri-Minet M, Lefaucheur JP, Mick G, Piano V, Pickering G, Piquet E, Regis C, Salvat E, Attal N. Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev Neurol (Paris). 2020 May;176(5):325-352. doi: 10.1016/j.neurol.2020.01.361. Epub 2020 Apr 7. PMID 32276788
• Kim JK, You J, Son S, Suh I, Lim JY. Comparison of intermittent theta burst stimulation and high-frequency repetitive transcranial magnetic stimulation on spinal cord injury-related neuropathic pain: A sham-controlled study. J Spinal Cord Med. 2025 Mar;48(2):241-247. doi: 10.1080/10790268.2023.2277964. Epub 2023 Nov 20. PMID 37982995
• Hodkinson DJ, Drabek MM, Horvath S, Pszczolkowski S, Tench C, Tanasescu R, Lankappa ST, Walsh DA, Morriss R, Auer DP. Accelerated intermittent theta burst transcranial magnetic stimulation of the dorsolateral prefrontal cortex for chronic knee osteoarthritis pain. Clin Neurophysiol. 2025 Aug;176:2010680. doi: 10.1016/j.clinph.2025.02.267. Epub 2025 Mar 10. PMID 40118759
• Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. PMID 34711062
• Cole E, O'Sullivan SJ, Tik M, Williams NR. Accelerated Theta Burst Stimulation: Safety, Efficacy, and Future Advancements. Biol Psychiatry. 2024 Mar 15;95(6):523-535. doi: 10.1016/j.biopsych.2023.12.004. PMID 38383091
• Bouhassira D, Jazat-Poindessous F, Farnes N, Franchisseur C, Stubhaug A, Bismuth J, Lefaucheur JP, Hansson P, Attal N. Comparison of the analgesic effects of "superficial" and "deep" repetitive transcranial magnetic stimulation in patients with central neuropathic pain: a randomized sham-controlled multicenter international crossover study. Pain. 2024 Apr 1;165(4):884-892. doi: 10.1097/j.pain.0000 PMID 37851075

Identifiers

NCT: NCT07650526 · 2025-A01824-45

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗