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
Woman aged between 18 and 75 years
Right-handed
Literate in reading and writing
Clinical diagnosis of fibromyalgia based on the American College of Rheumatology (ACR) 2010-2016 criteria
Living more than 250 km from Porto Alegre
Pregnancy
Decompensated systemic diseases
Chronic inflammatory rheumatologic diseases
Factorial
Transcranial direct current stimulation (tDCS) plus placebo.
DeviceParticipants 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 (60 mg) once daily
DrugDuloxetine (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).
Home-based transcranial direct current stimulation
DeviceParticipants 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 60 mg
DrugDuloxetine (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).
Evaluation 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.
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.
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.
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
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
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.
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.
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.
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