Fibromyalgia is characterized by widespread pain, fatigue, non-restorative sleep, and psychocognitive alterations, compromising quality of life and leading to absenteeism and early retirement. Up to 70% of patients discontinue treatment with antidepressants and anticonvulsants due to adverse effects or low efficacy, and more than 30% resort to opioid use. Given the treatment challenges and the scarcity of safe alternatives, there is growing interest in interventions such as transcranial direct current stimulation (tDCS), which has shown efficacy in improving symptoms and functionality, with low cost and few side effects. In this context, we designed a randomized, double-blind, double-dummy clinical trial to compare the non-inferiority of 28 home-based anodal tDCS (2 mA) applied over the primary motor cortex (M1) versus duloxetine 60 mg. Both treatments will be combined with physical exercise and pain education. Outcomes will be assessed through multidimensional measures of pain, functionality, global impression of improvement, and the function of the descending pain inhibitory system. Secondary outcomes include quality of life, depressive symptoms, psychophysical pain measures, and treatment adherence. An additional analysis will compare the results of sham tDCS and duloxetine placebo within the non-inferiority model. Predictors of treatment response will also be explored, including symptom severity and oscillatory patterns of cortical electrical activity, rest-activity rhythm, and autonomic function assessed by R-R interval. Furthermore, serum levels of S100-B protein, brain-derived neurotrophic factor (BDNF), and genetic variants related to neuroplasticity in the BDNF Val66Met, Catechol-O-Methyltransferase (COMT) (rs4680) (G\>A), OPRM1, and PER2 genes will be analyzed. Inflammatory markers (TNF-α, IL-1, IL-2, IL-6, IL-10, C-reactive protein) and serum endorphins will also be assessed. A total of 610 women with fibromyalgia (aged 18 to 75 years) will be randomized into three groups (2:2:1): duloxetine + sham tDCS (n=244); active tDCS + placebo (n=244); and sham tDCS + placebo (n=122). Participants will be assessed during treatment and at 3, 6, and 12 months after completing the intervention protocol. An interim analysis will be conducted when \~50% of participants (n ≈ 305) complete the 3-month follow-up by an independent, blinded Data Monitoring Committee (DMC). (i) The trial may be stopped if the conditional probability of demonstrating non-inferiority is \<10%, based on frequentist or Bayesian methods. (i) The trial will be stopped if serious adverse events (SAEs) in the active tDCS group increase by ≥30% compared to duloxetine (p \< 0.01, adjusted). (ii) Early stopping for efficacy will be considered if active tDCS demonstrates clear non-inferiority or superiority over duloxetine on the primary outcome. Superiority requires: (iii) a clinically relevant difference exceeding the non-inferiority margin (≥10% pain reduction); (ii) statistical significance (p \< 0.005, O'Brien-Fleming adjusted); and (iii) a ≥2-point (20%) improvement on the BPI, confirmed in the ITT analysis. This study aims to generate evidence to support the decision-making process of the National Committee for Health Technology Incorporation (CONITEC) regarding the availability of tDCS in the Brazilian Unified Health System (SUS). In addition, identifying predictors of response to tDCS and duloxetine, through the integration of genetic, neurophysiological, inflammatory, and psychosocial markers using machine learning algorithms, will allow for identifying factors that can personalize fibromyalgia treatment. This approach enhances clinical efficacy, reduces costs associated with ineffective interventions, and supports more accurate therapeutic decisions, expanding access to safe, effective, and sustainable care within the public healthcare system
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
610
Participants will be randomized to receive 28 sessions of active anodal tDCS (2 mA) or sham, with the anode over the left M1 and the cathode over the right supraorbital area, for 20 minutes, combined with pain neuroscience education and physical exercises. Sessions will be self-administered at home, daily for 4 weeks. Electrodes (35 cm²) will be placed using neoprene caps (sizes S to XL), adjusted according to head circumference. Monitoring: the device records session time, duration, and adherence, interrupting the session if impedance exceeds 1 mA (5-second interval) or if current varies \>10%. Developed in partnership with HCPA's Biomedical Engineering, the device is licensed by UFRGS/HCPA and registered with ANVISA (No. 80079190028).
Duloxetine (30 mg and 60 mg) will be purchased from a commercial pharmacy and fractionated by a compounding pharmacy, which will also prepare the placebo. Capsules will be transferred into standardized jars based on dosing schedule: * Jar 01 (white cap): 7 capsules of 30 mg * Jar 02 (green cap): 16 capsules of 60 mg * Jar 03 (green cap): 42 capsules of 60 mg * Jar 04 (white cap): 7 capsules of 30 mg Placebo and duloxetine capsules will be identical in appearance. Kits will be labeled with CAEE number, participant ID (RedCap), pharmacist and PI names, and storage/use instructions. Kits will be stored at the HCPA Pharmacy Service under controlled conditions and dispensed during visits AV1 (Jars 1 and 2), AV2 (Jar 3), and AV3 (Jar 4).
Participants will be randomized to receive 28 sessions of active anodal tDCS (2 mA) anode over the left M1 and the cathode over the right supraorbital area, for 20 minutes
Duloxetine (30 mg and 60 mg) will be purchased from a commercial pharmacy and fractionated by a compounding pharmacy, which will also prepare the placebo. Capsules will be transferred into standardized jars based on dosing schedule: * Jar 01 (white cap): 7 capsules of 30 mg * Jar 02 (green cap): 16 capsules of 60 mg * Jar 03 (green cap): 42 capsules of 60 mg * Jar 04 (white cap): 7 capsules of 30 mg Placebo and duloxetine capsules will be identical in appearance. Kits will be labeled with CAEE number, participant ID (RedCap), pharmacist and PI names, and storage/use instructions. Kits will be stored at the HCPA Pharmacy Service under controlled conditions and dispensed during visits AV1 (Jars 1 and 2), AV2 (Jar 3), and AV3 (Jar 4).
Hospital de Clínicas de Porto Alegre
Porto Alegre, Rio Grande do Sul, Brazil
RECRUITINGEvaluation of Pain Interference
The Brief Pain Inventory (BPI) assesses pain intensity and interference across seven domains, generating a global interference index using 0-10 scales.
Time frame: Participants will undergo weekly home-based assessments during both the run-in period (Weeks 1 to 3) and the treatment phase (Weeks 4 to 7), as well as at 3, 6, and 12 months after the end of the intervention
Patient Global Impression of Improvement
Patient Global Impression of Improvement (PGI-I): A 7-point scale that assesses the patient's overall perception of change in their condition, ranging from 'very much worse' (1) to 'very much improved' (7). Higher scores indicate greater perceived improvement (e.g., reduced symptoms or better functioning), while lower scores reflect worsening of symptoms or condition.
Time frame: To be assessed at Visit 4, after completing the four-week treatment with either active (a-tDCS), s-tDCS), or duloxetine
Impact of fibromyalgia symptoms on quality of life
Fibromyalgia Impact Questionnaire (FIQ): Brazilian version assessing quality of life across function, overall impact, and symptoms. Scores range from 0 to 100, with higher scores indicating greater impact of fibromyalgia on the individual's daily life and functioning.
Time frame: Participants will be assessed at Visit 1 (prior to the run-in period), at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine), and again at 3, 6, and 12 months following the end of the treatment.
Cognitive symptoms
Barkley Deficits in Executive Functioning Scale (Short Form).Each item is rated on a Likert scale from 1 (never or rarely) to 4 (very often), resulting in a total score range of 20 to 80, with higher scores indicating greater executive functioning impairment
Time frame: Participants will be assessed at Visit 1 (before the run-in period), at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine), and again at 3, 6, and 12 months after the end of the treatment.
Function of the descending pain inhibitory system
Conditioned Pain Modulation (CPM) test: This test assesses descending pain inhibition. This test assesses the efficiency of descending pain inhibitory pathways. Pain intensity is rated using a verbal numerical rating scale (0 = no pain to 10 = worst possible pain) before (T0) and during (T1) cold-water immersion. The CPM effect is calculated as the difference between pain ratings at T0 and T1, with greater reductions indicating more effective pain inhibition.
Time frame: Participants will be assessed at Visit 1 (before the run-in period) and at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine).
Cortical Electrical Activity
Cortical electrical activity will be assessed using resting-state electroencephalography (EEG). Recordings will be performed in a quiet room, with participants seated comfortably and instructed to remain relaxed and still. EEG data will be collected during eyes-closed and eyes-open conditions using a 64-channel EEG system. Signals will be recorded with a band-pass filter of 0.3-200 Hz and a sampling rate of 250 Hz. Spectral power measures will be analyzed to characterize cortical oscillatory activity associated with pain processing and central sensitization in fibromyalgia.
Time frame: Participants will be assessed at Visit 1 (before the run-in period) and at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine).
Depressive Symptoms
Assessed using the Beck Depression Inventory-II (BDI-II), a 21-item self-report questionnaire with total scores ranging from 0 to 63. Higher scores indicate greater severity of depressive symptoms
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.
Subjective Sleep Quality
Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI), a self-questionnaire that evaluates sleep quality over the past month. It generates a global score ranging from 0 to 21, with higher scores indicating poorer sleep quality.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.
Circadian Profile (Chronotype)
Chronotype will be measured using the Munich ChronoType Questionnaire (MCTQ) which evaluates individual sleep-wake patterns and chronotype based on the timing of sleep on workdays and free days. The key metric is the mid-sleep point on free days (MSF), which is based on sleep onset and wake-up times. The corrected version (MSFsc) accounts for workweek sleep debt and better reflects chronotype: lower values indicate morning types; higher values, evening types.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.
Objective Sleep and Activity (Actigraphy)
Actigraphy (accelerometer) assesses sleep quality and physical mobility. Mean values are calculated across days for parameters such as total sleep time, sleep efficiency, and activity levels. Higher sleep efficiency and activity indicate better sleep quality and physical functioning; lower values suggest disturbances or impairment.
Time frame: Actigraph use during the run-in period (Weeks 1 to 3) and throughout the treatment phase (weeks 4 to 7)
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Analgesic Use
The use of analgesics will be assessed by recording the number of tablets of each analgesic taken per week during the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7)
Time frame: Analgesic use during the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7).
Functional Capacity
Functional interference of pain is assessed using the Brazilian Profile of Chronic Pain: Screen (B-PCP: S), which captures pain intensity, interference in daily life, and emotional impact. Scores range from 0 to 100, with higher scores indicating greater pain-related interference and effects.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.
Heat Pain Threshold
Heat pain threshold will be assessed via quantitative sensory testing (QST) on the left forearm using a thermode that increases temperature from 30°C to 52°C at a rate of 1°C per second. The pain threshold is calculated as the average temperature at which pain is first reported across three trials. Higher values indicate greater pain threshold.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Pressure Pain Threshold
Pressure pain threshold will be measured using a pressure algometer applied to the left forearm. The threshold is defined as the point at which pressure sensation becomes painful, averaged across three trials. Higher values indicate lower pain sensitivity.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Cold Pressor Test Pain Intensity
Cold Pressor Test: Non-dominant hand immersed in ice water (\~1°C) for up to 2 minutes with continuous movement. Pain intensity is continuously rated via electronic visual analog scale (0-100%), enabling calculation of peak pain, mean pain, and area under the curve (AUC).allowing calculation of peak pain, mean pain, and area under the curve (AUC). Higher scores reflect greater pain intensity.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Patient-Defined Goals
Patients will select three priority areas-physical, psychological, functional, or social-and define personalized, measurable goals at Visit 1 (V1) and evaluate them at the end of the treatment period (Visit 4).
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Treatment Adherence
tDCS adherence: Assessed by the number and duration of valid sessions recorded by the device software, based on impedance and resistance parameters. Pharmacological treatment adherence: Assessed by pill count at Visit 3 and Visit 4, based on the number of capsules consumed
Time frame: Assessment timepoints: Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Side Effects
The adverse effects of duloxetine will be assessed weekly throughout the run-in period (Weeks 1 to 3) and during the treatment phase (Weeks 4 to 7) using structured questionnaires that include common side effects such as nausea, dry mouth, dizziness, and somnolence, which will be recorded as 'yes' or 'no'. Adverse effects related to tDCS-such as tingling, itching, burning, or headache-will be assessed weekly during the treatment phase (Weeks 4 to 7), also using 'yes' or 'no' responses.
Time frame: Assessment timepoints: During the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7).
Satisfaction with Treatment
Assessed using the Numeric Satisfaction with Treatment Scale (NSTS), ranging from 0 (not at all satisfied) to 10 (extremely satisfied).
Time frame: Assessment timepoints: Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Global Cognitive Function (MoCA)
Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA), a screening tool for global cognition. Scores range from 0 to 30, with higher scores indicating better cognitive performance. A score below 26 is suggestive of cognitive impairment
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Attention and Working Memory (Digit Span - WAIS-III)
Attention and working memory will be assessed using the Digit Span subtest of the WAIS-III. The total score is based on correct forward and backward digit recall, with higher scores indicating better performance.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Processing Speed (Symbol Search - WAIS-III)
Processing speed will be assessed using the Symbol Search subtest of the WAIS-III. The outcome is a scaled score ranging from 1 to 19, with higher scores indicating faster processing.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Inhibitory Control (Stop Signal Task)
Inhibitory control will be assessed using the Stop Signal Task. The primary outcome is Stop Signal Reaction Time (SSRT), measured in milliseconds. Lower reaction times indicate better inhibitory control.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)
Cognitive Flexibility (Trail Making Test A and B)
Executive function and cognitive flexibility will be assessed using the Trail Making Test Parts A and B. The outcome is total time to completion in seconds. Longer completion times indicate worse performance.
Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)