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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
36
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.
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.
Hopital Ambroise-Paré INSERM U987, 9 Av. Charles de Gaulle
Boulogne-Billancourt, Île-de-France Region, France
RECRUITINGChange 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.
Time frame: From enrollment to Week 10.
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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
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)
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: At each visit from baseline to Week 10.
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