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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active rTMS of motor and prefrontal cortex | Experimental | Each rTMS session for each cortical target will include 30 trains of pulses delivered at 10 Hz for 10 seconds (100 pulses per train), with a 20-second interval between each train, resulting in a total of 3,000 pulses per session. The total duration will be 15 to 20 minutes per target, and 30 to 40 minutes for both cortical targets combined. The stimulation intensity for the left motor cortex will be set at 80% of the resting motor threshold, defined as the minimal stimulation intensity that induces an electromyographic response of ≥50 µV in the first dorsal interosseous muscle of the hand, contralateral to the stimulated hemisphere, in at least 5 out of 10 trials. For stimulation of the left prefrontal cortex, we will use a stimulation intensity of 120% of the motor threshold, as is customary in psychiatry and as in our previous studies on analgesia (Attal et al., 2021). |
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| Sham rTMS of motor and prefrontal cortex | Sham Comparator | To perform the rTMS, a figure-of-eight Cool-B65 A/P coil (MagVenture) will be used. This coil features a symmetrical design with two indistinguishable faces-one for active stimulation and the other for sham stimulation. The side used for each rTMS session will be determined by a personalized USB key for each patient, which will be connected to the rTMS device. The sound emitted during stimulation will be identical regardless of the side of the coil used. Finally, to further strengthen the treatment blinding for both the patient and the operator, the scalp-tapping sensation induced by active rTMS will be mimicked by low-intensity electrical stimulation applied to the head via surface electrodes. This electrical stimulation will be synchronized with the magnetic pulses during both active and sham stimulation sessions. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rTMS | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in average pain intensity over 10 weeks (Brief Pain Inventory) | The primary outcome measure will be the mean change from baseline over the course of 10 weeks (group x time interaction) in average pain intensity from the Brief Pain Inventory (scored on a 0-10 NRS with 0 = no pain and 10 = maximal pain intensity). Baseline average pain intensity will be assessed at inclusion, and just before the first rTMS session (Day 1) and will correspond to the average of these two values. Pain intensity will be further assessed immediately before each rTMS session at Days 2, 3, 4, 5 then at weeks 2, 3, 4, 6, 8, and finally 2 weeks after the last rTMS session at week 10. | From enrollment to Week 10. |
| Measure | Description | Time Frame |
|---|---|---|
| Weekly pain, fatigue and sleep disturbances | Weekly average of daily patient-reported scores for pain intensity, fatigue, and sleep disturbance, recorded in a self-assessment diary completed throughout the study. Pain intensity and fatigue are each assessed on a numerical rating scale from 0 (no pain/no fatigue) to 10 (worst imaginable pain/worst imaginable fatigue), where higher scores indicate worse outcome. Sleep disturbance is assessed on a numerical rating scale from 0 (no interference) to 10 (completely disrupted sleep), where higher scores indicate worse outcome. |
| Measure | Description | Time Frame |
|---|---|---|
| Predictive value of baseline clinical variables on treatment response to active rTMS and sham | Assess the correlation between baseline clinical variables - including pain characteristics, demographic factors, and psychosocial factors - and treatment response to active rTMS and sham stimulation. | From enrollment to Week 10. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Nadine ATTAL | Contact | +33 1 49 09 59 31 | nadine.attal@aphp.fr | |
| Elisa UMMARINO | Contact | +33 1 49 09 45 56 | elisa.ummarino@inserm.fr |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hopital Ambroise-Paré INSERM U987, 9 Av. Charles de Gaulle | Recruiting | Boulogne-Billancourt | Île-de-France Region | 92100 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34196698 | Background | 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. | |
| 39816903 |
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The plan to share individual participant data has not yet been determined.
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| ID | Term |
|---|---|
| D005356 | Fibromyalgia |
| D059350 | Chronic Pain |
| D003863 | Depression |
| ID | Term |
|---|---|
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D009468 | Neuromuscular Diseases |
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| Sham | Device | 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. |
|
| At each visit from baseline to Week 10. |
| Immediate effect of rTMS on pain intensity | Pain intensity at the present moment assessed immediately after each rTMS session using a Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst imaginable pain). | At each visit from baseline to Week 10. |
| Onset of the therapeutic effect | The time to onset of the therapeutic effect from the first stimulation, assessed by measuring 24-hour pain scores recorded in the patient's self-assessment diary. | At each visit from baseline to Week 10. |
| Brief Pain Inventory (BPI) | The validated French version of the BPI (Cleeland and Ryan, 1994) will be used to assess maximum and minimum pain over the past 24 hours and at the present moment, as well as the impact of pain (general activity, mood, ability to walk, usual work, relationships with others, sleep, quality of life), on numerical scales from 0 to 10. | From enrollment to Week 10. |
| Fibromyalgia Impact Questionnaire (FIQ) | A validated self-report questionnaire specifically designed to assess the impact of fibromyalgia on quality of life. Scores range from 0 to 100, where higher scores indicate greater impact of fibromyalgia on functioning and worse outcome. | At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10. |
| EuroQol 5-Dimension health status questionnaire (EQ-5D-5L) | A self-report questionnaire assessing health-related quality of life across 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on a 5-level scale from 1 (no problems) to 5 (extreme problems), where higher scores indicate worse outcome. A Visual Analogue Scale (EQ-VAS) ranging from 0 (worst imaginable health) to 100 (best imaginable health) is also included, where higher scores indicate better outcome. | At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10. |
| Hospital Anxiety and Depression Scale (HADS) | A self-report questionnaire assessing the severity of anxiety and depressive symptoms over the past week. It consists of two 7-item subscales - one for anxiety (HADS-A) and one for depression (HADS-D) - each scored from 0 to 21, where higher scores indicate greater symptom severity. | At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10. |
| Patient Health Questionnaire (PHQ-9) | A validated 9-item self-report questionnaire assessing the presence and severity of depressive symptoms over the past two weeks. Total scores range from 0 to 27, where higher scores indicate greater severity of depressive symptoms. | At baseline, after 5 days of treatment, and at Week 10. |
| Pain Catastrophizing Scale (PCS) | A 13-item self-report questionnaire assessing the tendency to magnify, ruminate, and feel helpless in response to 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. | At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10. |
| Medical Outcome Study Sleep Scale (MOS) | A 12-item self-report questionnaire assessing the main dimensions of sleep quality, commonly used in chronic pain syndromes. Each item is 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. | At baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10. |
| Short-Form McGill Pain Questionnaire (SF-MPQ) | A 15-item self-report questionnaire assessing the sensory and affective dimensions of pain. Eleven items evaluate the sensory dimension and 4 items evaluate the affective dimension, each rated on a scale from 0 (none) to 3 (severe). Total scores range from 0 to 45, where higher scores indicate greater pain intensity. | At the inclusion visit, baseline, after 5 days of treatment, at weeks 4, 6, 8 and 10. |
| Blinding Assessment Questionnaire | A validated questionnaire administered at the end of the study to assess the integrity of blinding. Participants are asked which treatment they believe they received (active, sham, or unsure) and the reasons for their belief (side effects, symptom relief, or other). | At Week 10. |
| Patient and examiner's global clinical impression (PGIC, CGIC) | Single-item scales assessing the patient's and clinician's overall impression of change since the beginning of treatment, respectively. Both are rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), where higher scores indicate worse outcome. | From Week 2 to Week 10. |
| Credibility/expectancy questionnaire (CEQ) | A validated self-report questionnaire administered prior to treatment initiation to assess patients' beliefs about the credibility of the assigned treatment and their expectations regarding its therapeutic outcome. The first four items (Set 1), evaluating the cognitive dimensions of credibility and expectancy, will be used. Items are rated on a scale from 1 to 9, where higher scores indicate greater treatment credibility and expectancy. | At baseline and after the first week of treatment. |
| Treatment responders | The percentage of treatment responders (patients whose pain is reduced by at least 30% and 50%) at the end of treatment. | At Week 10. |
| Incidence of Treatment-Emergent Adverse Events | The safety and tolerability of the treatment, assessed by asking patients about any side effects experienced during the rTMS sessions. | At each visit from baseline to Week 10. |
| Predictive value of baseline intracortical excitability and inhibition parameters assessed with TMS on treatment response to active rTMS and sham |
Identify the correlation between motor cortical excitability and inhibition - assessed via motor evoked potentials (recorded from the first dorsal interosseous muscle of the hand) elicited by paired-pulse TMS - and treatment response to active rTMS and sham stimulation. |
| From enrollment to Week 10. |
| Predictive value of baseline cortical oscillatory EEG biomarkers on treatment response to active rTMS and sham | Identify the correlation between baseline cortical oscillatory patterns extracted from resting-state EEG recordings and treatment response to active rTMS and sham stimulation. EEG recordings will consist of a 5-minute eyes-open and a 5-minute eyes-closed session using a 32-channel cap. | From enrollment to Week 10. |
| 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. |
| 40693547 | Background | 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. |
| 40087077 | Background | 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. Br J Anaesth. 2025 Jun;134(6):1756-1764. doi: 10.1016/j.bja.2024.12.045. Epub 2025 Mar 13. |
| 17872930 | Background | 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. |
| 21397400 | Background | 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. |
| D009422 |
| Nervous System Diseases |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |