aiTBS and rTMS in Neuropathic Pain and Prediction of Response

NCT07650526 | Recruiting

• 1 other identifier: 2025-A01824-45
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Chronic Neuropathic Pain

Outcome Measures

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)

  From one week before the first day of treatment to 7 days after the end of treatment

Secondary Outcomes (23)

• 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

  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)

  From enrollment to 3 weeks after the end of treatment

• Comparison of aiTBS , rTMS and sham on neuropathic pain symptoms inventory (NPSI)

  From enrollment to 3 weeks after the end of treatment

• Comparison of active aiTBS versus active rTMS and sham on pain interference (BPI)

  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)

  From enrollment to 3 weeks after the end of treatment

Other Outcomes (3)

• 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

  From enrollment to 3 weeks after the end of treatment

• Identify predictors of the clinical response to aiTBS, rTMS and sham, based on baseline intracortical excitability/inhibition parameters using TMS

  From enrollment to 3 weeks after the end of treatment

• Identify predictors of clinical response to aiTBS, rTMS and sham, based on baseline cortical pathological oscillatory EEG biomarkers

  From the first day of treatment (before treatment) to 3 weeks after the end of treatment

Study Arms (2)

Active rTMS of followed by active aiTBS or conversely

EXPERIMENTAL

Both the interventions target the motor cortex representing the first dorsal interosseus muscle (FDI) and the stimulation is delivered at 80% of resting motor threshold (RMT). Active rTMS consists of 5 stimulation sessions distributed over 5 consecutive days. Each session (25 to 30 minutes) consists of 15 series of 10-s pulses with a frequency of 10 Hz and an inter-train interval of 50s, for a total of 1500 pulses per session. Active aiTBS consists of 5 stimulation sessions given in a single day with an intersession interval of 45 minutes and a 110-minute break between the third and the fourth session. One session is composed of 50 cycles. Each cycle consists of 2 s of train stimulation and 8 s of pause. Each train consists of 10 bursts at 5 Hz, and each burst consists of 3 pulses at 50 Hz. In both interventions a total of 7500 pulses are delivered. The order of the two interventions will be decided by randomization and there will be a wash-out period of 4 to 6 weeks in between

Device: Active rTMS, active aiTBS, sham rTMS or sham aiTBS

Sham rTMS followed by sham aiTBS or conversely

SHAM COMPARATOR

Sham rTMS followed by sham aiTBS, or conversely, as decided by randomization. The sham stimulation will be delivered using the reverse face of the same coil, identical in size, colour, and shape to the active one, and producing an identical sound. In addition, in both conditions, active and sham, a low-intensity transcutaneous electrical stimulation will be applied to the ipsilateral frontal muscle to mask the active stimulation. Coil orientation will be determined by a pendrive linked to the concealed randomization allocation. To ensure double-blinding, the coil will be flipped, depending on the instructions provided when inserting a USB drive. In cases where the previous or subsequent use of TMS involves the determination of motor evoked potentials, the flipping of the coil will be handled by another operator.

Device: Active rTMS, active aiTBS, sham rTMS or sham aiTBS

Interventions

Active rTMS, active aiTBS, sham rTMS or sham aiTBS DEVICE

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

Active rTMS of followed by active aiTBS or conversely; Sham rTMS followed by sham aiTBS or conversely

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Subject unable to understand informed consent, under guardianship or curatorship
• Patient who has already received a treatment with rTMS

Sponsors & Collaborators

• Hospital Ambroise Paré Paris: lead

Study Sites (1)

Hopital Ambroise-Paré INSERM U987, 9 Av. Charles de Gaulle

Boulogne-Billancourt, Île-de-France Region, 92100, France

RECRUITING

Related Publications (10)

• 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 pain: a systematic review and meta-analysis. Lancet Neurol. 2025 May;24(5):413-428. doi: 10.1016/S1474-4422(25)00068-7.

  PMID: 40252663 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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. Am J Psychiatry. 2022 Feb;179(2):132-141. doi: 10.1176/appi.ajp.2021.20101429. Epub 2021 Oct 29.

  PMID: 34711062 RESULT

• 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 RESULT

• 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.0000000000003082. Epub 2023 Oct 18.

  PMID: 37851075 RESULT

• Attal N, Poindessous-Jazat F, De Chauvigny E, Quesada C, Mhalla A, Ayache SS, Fermanian C, Nizard J, Peyron R, Lefaucheur JP, Bouhassira D. Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial. Brain. 2021 Dec 16;144(11):3328-3339. doi: 10.1093/brain/awab208.

  PMID: 34196698 RESULT

• Attal N, Branders S, Pereira A, Bouhassira D. Prediction of the response to repetitive transcranial magnetic stimulation of the motor cortex in peripheral neuropathic pain and validation of a new algorithm. Pain. 2025 Jan 1;166(1):34-41. doi: 10.1097/j.pain.0000000000003297. Epub 2024 Jun 14.

  PMID: 38875120 RESULT

Central Study Contacts

Nadine ATTAL

CONTACT

0033149095931; nadine.attal@aphp.fr

Lorenzo Sargolini, PhD Fellow

CONTACT

+330743665255; lorenzo.sargolini@inserm.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Coordinator

Study Record Dates

• First Submitted: June 1, 2026
• First Posted: June 16, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: July 7, 2026

Record last verified: 2026-06

Locations

FR (1)