Analgesic Efficacy of Multisite rTMS in Fibromyalgia Patients

Official title

Analgesic Efficacy of Multisite rTMS in Depressed and Nondepressed Patients With Fibromyalgia and Prediction of the Response: a Double-Blind Randomized Sham-Controlled Study.

Overview

Repetitive Transcranial Magnetic Stimulation (rTMS) of the motor cortex is a recognized analgesic technique for the treatment of fibromyalgia pain, which represents a largely unmet medical need. However, the effectiveness of motor cortex rTMS is inconsistent, being observed in only about 40% of patients and not always long-lasting. It has been previously shown that predictive factors for a lack of response to motor cortex rTMS include the presence of depressive symptoms, and that prefrontal cortex rTMS is not effective for pain, even though this treatment has proven efficacy in major depressive disorder. The hypothesis is that targeting both the motor and prefrontal cortices with rTMS will yield a particularly beneficial effect in fibromyalgia patients presenting with comorbid depressive symptoms. Given the absence of established biomarkers for predicting rTMS response, an additional aim will be to develop reliable indicators of rTMS efficacy, based on clinical phenotype and measurements of oscillatory patterns assessed by electroencephalogram (EEG) recordings.

Detailed description

This is a monocentric, randomized, double-blind, parallel-group, sham-controlled trial. After providing informed consent, patients will first undergo brain magnetic resonance imaging (MRI) to determine the exact position of the coil for rTMS neuronavigation.

Clinical and psychological outcomes - assessed using validated self-report questionnaires - as well as neurophysiological parameters - including resting-state brain oscillatory activity (EEG) and cortical excitability measures (TMS and electromyography) - will be recorded at three time points: (i) at inclusion, approximately one week before treatment initiation; (ii) after completion of the 5-day intensive stimulation phase; and (iii) at the follow-up visit, two weeks after the end of treatment.

Correlations between the analgesic effects of active or sham rTMS and changes in clinical and electrophysiological parameters will be evaluated.

The treatment consists of 5 daily sessions of high-frequency rTMS of the motor and prefrontal cortex (one 30-minute session per day delivering 3000 pulses). This will be followed by: one session per week for the following 3 weeks; one session every 15 days during the following month.

This results in a total of 10 sessions over approximately 2 months.

Interventions

• Device rTMS
  The active protocol will include 5 daily stimulation sessions during the first week (D1-D5), followed by one session per week for 3 weeks (W2, W3, W4), then 2 sessions spaced 2 weeks apart (W6, W8), for a total of 10 stimulation sessions. Evaluation will continue until 2 weeks after the final stimulation, that is, at week 10 after the start of treatment.
• Device Sham
  The sham protocol will follow an identical session schedule. Participants will be randomized to either the active or sham group in a parallel-group design, meaning each participant will receive only one of the two treatments throughout the entire duration of the study.

Primary outcome measures

• Change in average pain intensity over 10 weeks (Brief Pain Inventory) [Time frame: From enrollment to Week 10.]

Secondary outcome measures (12)

• Weekly pain, fatigue and sleep disturbances [Time frame: At each visit from baseline to Week 10.]
• Immediate effect of rTMS on pain intensity [Time frame: At each visit from baseline to Week 10.]
• Onset of the therapeutic effect [Time frame: At each visit from baseline to Week 10.]
• Brief Pain Inventory (BPI) [Time frame: From enrollment to Week 10.]
• Fibromyalgia Impact Questionnaire (FIQ) [Time frame: At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10.]
• EuroQol 5-Dimension health status questionnaire (EQ-5D-5L) [Time frame: At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10.]
• Hospital Anxiety and Depression Scale (HADS) [Time frame: At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10.]
• Patient Health Questionnaire (PHQ-9) [Time frame: At baseline, after 5 days of treatment, and at Week 10.]
• Pain Catastrophizing Scale (PCS) [Time frame: At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10.]
• Medical Outcome Study Sleep Scale (MOS) [Time frame: At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10.]
• Short-Form McGill Pain Questionnaire (SF-MPQ) [Time frame: At the inclusion visit, baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10.]
• Blinding Assessment Questionnaire [Time frame: At Week 10.]

Eligibility criteria

Inclusion criteria

• Chronic pain lasting at least 6 months, with or without associated depressive symptoms;
• Fibromyalgia (2016 revised ACR criteria and a FIRST questionnaire score of at least 5 out of 6);
• Average pain intensity ≥ 4/10 on a 0-10 numeric rating scale;
• Pain present daily or almost daily (≥ 4 days per week);
• Patients aged over 18 and under 80 years;
• Patients who have provided written informed consent;
• Patients whose analgesic treatment has been stable for at least 1 month prior to inclusion and will not need to be modified during the study;
• Patients who can be followed for the duration of the study (10 weeks);
• Patients covered by a health insurance plan or otherwise eligible.

Exclusion criteria

• Ongoing litigation;
• Contraindication to rTMS:
• Implanted electronic devices and/or conductive objects near the coil: Patients with an active implanted device that is activated or controlled by physiological signals (e.g., pacemakers, implantable cardiac defibrillators \[ICD\], vagus nerve stimulators \[VNS\], wearable cardioverter defibrillators \[WCD\], ocular implants, deep brain stimulation systems, drug infusion pumps or ports, intracardiac leads), even if the device has been removed.
• Non-removable metallic objects near the coil:\*\* Patients with a conductive, ferromagnetic, or magnetically sensitive metal implant in the head or within 30 cm of the coil (e.g., cochlear implants, implanted electrodes/stimulators, aneurysm clips or coils, stents, or bullet fragments);
• Current abuse of drugs or psychoactive substances, including alcohol (according to DSM-5 criteria);
• Pregnancy or breastfeeding;
• Epilepsy or a history of epilepsy;
• Unstable or progressive medical conditions (e.g., cancer);
• Psychosis according to DSM-5 criteria;
• Presence of another pain condition more severe than the one qualifying for inclusion;
• Failure to correctly complete pain self-assessment diaries between inclusion and randomization (fewer than 4 pain scores recorded over 7 days);
• Inability to understand the informed consent form, or subjects under legal guardianship or curatorship;
• Participation in another research protocol within 30 days prior to inclusion.

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

• 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
• Lapa JDDS, da Silva VA, Ciampi de Andrade D. Repetitive transcranial magnetic stimulation for fibromyalgia: are we there yet? Pain Rep. 2025 Jan 13;10(1):e1221. doi: 10.1097/PR9.0000000000001221. eCollection 2025 Feb. PMID 39816903
• Ciampi de Andrade D, Valiengo L. Differential Effects of Repetitive Transcranial Magnetic Stimulation on Mood and Pain Symptoms in People With Chronic Pain and Major Depressive Disorders-A Review. Eur J Pain. 2025 Aug;29(7):e70077. doi: 10.1002/ejp.70077. PMID 40693547
• Silva VA, Baptista AF, Fonseca AS, Carneiro AM, Brunoni AR, Carrilho PEM, Lins CC, Kubota GT, Fernandes AMBL, Lapa JDS, Dos Santos LM, Sasso I, Monte-Silva K, Poindessous-Jazat F, Mori N, Miki K, Baltar A, Tanaka C, Teixeira MJ, Hosomi K, Bouhassira D, Attal N, Ciampi de Andrade D. Motor cortex repetitive transcranial magnetic stimulation in fibromyalgia: a multicentre randomised controlled trial. PMID 40087077
• 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
• Mhalla A, Baudic S, de Andrade DC, Gautron M, Perrot S, Teixeira MJ, Attal N, Bouhassira D. Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia. Pain. 2011 Jul;152(7):1478-1485. doi: 10.1016/j.pain.2011.01.034. Epub 2011 Mar 11. PMID 21397400

Identifiers

NCT: NCT07642882 · 2025-A01369-40

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗