Impact of Susceptibility to Placebo on the Effect of Transcranial Direct Current Stimulation (tDCS) in Fibromyalgia

Study Overview
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Brief Summary
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Fibromyalgia (FM) is a syndrome characterized by generalized musculoskeletal pain, fatigue, non-restorative sleep, cognitive changes, depressive and neurovegetative symptoms. It is known that conventional pharmacological therapies produce responses with little clinical impact in more than 50% of patients. Functional alterations of the motor cortex and its connections with subcortical structures have also been demonstrated in FM. Based on the above, the objective of this research is to identify subgroups of patients with greater potential for responsiveness to treatment with a view to advancing diagnosis and treatment. In this study, the therapeutic target will be transcranial direct current stimulation (tDCS) according to the potential of responsiveness to the placebo effect, with the precise location of the stimulation area by a neuronavigation system, with the objective of counter-regulating the dysfunctional processes responsible for triggering and maintaining FM symptoms. Therefore, this clinical trial aims to compare the efficacy of anodal tDCS applied to the left dorsolateral prefrontal cortex (DLPFC) compared to simulated tDCS in FM, according to susceptibility to placebo effect and serum endorphin levels.

Detailed Description
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This is clinical trial aims to compare the efficacy of anodal tDCS applied to the left dorsolateral prefrontal cortex (DLPFC) compared to simulated tDCS in FM, according to susceptibility to placebo effect and serum endorphin levels, in the following outcomes (1) treatment effectiveness, which includes daily measures recorded in an application by the Brief Pain Inventory (BPI), which allows pain assessment from a multidimensional perspective (pain intensity and interference in general activities, mood, mobility, work, personal relationships, sleep and enjoyment of life, etc.) (primary outcome). Secondary outcomes: the impact of pain on quality of life; levels of depressive symptoms; (2) Outcomes in psychophysical measures: pain threshold to electrical stimulation and heat; temporal summation to electrical stimulus; descending pain modulatory system function; (3) Identify predictors of response to the placebo effect through a hierarchical model with an analytical structure defined a 'priori', considering the hierarchical relationships between potential predictors such as: disability due to pain, catastrophism, depressive symptoms, psychiatric diagnoses, level of central sensitization, endorphin serum levels at baseline, drugs in use, etc. In this randomized, controlled, sham-controlled, parallel, double-blind clinical trial, 84 women with FM will be included, according to the criteria of the American College of Rheumatology (2016), aged between 18 and 70 years. Patients will be submitted to a simulated tDCS face-to-face session, mounted on the left DLPFC, and with a variation presented in the Numerical Verbal Pain Scale (NPS 0-10) equal to or greater than thirty percent of the baseline, the patient will be considered a high responder and below this low responder rate. This will be the criterion used to stratify randomization. They will receive 30 sessions of anodal tDCS lasting 20 min, with a current of 2 mA, applied to the left DLPFC at home. The location of the stimulation area will be done by a neuronavigation system. Patients will receive training in using the tDCS equipment. They will have access to an instructional video on tDCS and a way of communicating with the team through Whatsapp. The follow-up time after the end of stimulation will be 12 weeks as recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). Patients should respond daily to BPI and possible side effects of tDCS. Home tDCS will be carried out with equipment developed by our research group, in partnership with Biomedical Engineering at Hospital de Clínicas de Porto Alegre (HCPA), with patent registration with the National Institute of Industrial Property (INPI) under number BR2020150164500. Our hypothesis is that active tDCS has a greater effect than simulated tDCS and that stimulation on the DLPFC has a greater impact in patients with greater responsiveness to the placebo effect on psychological symptoms, functional capacity for activities of daily living and inhibitory modulatory system function. descendant of pain. It is expected that the level of cortical disinhibition assessed by TMS measurements, as well as serum ß-endorphin levels, can serve as predictors of treatment response.

Official Title
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Impact of Susceptibility to Placebo on the Effect of Transcranial Direct Current Stimulation (tDCS) in Fibromyalgia: a Randomized Clinical Trial With Extended Home Stimulation

Conditions
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Fibromyalgia

Intervention / Treatment
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* Device: s-tDCS
* Device: a- tDCS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18 to 65 years; who can read and write, with a confirmed diagnosis of FM according to the American College of Rheumatology criteria (2010-2016). Pain score equal to or greater than six on the Numerical Pain Scale (NPS 0-10) on most days of the last 3 months. Exclusion Criteria: Residing outside the greater Porto Alegre area and pregnancy. Contraindications to TMS and tDCS: metallic implant in the brain; medical devices implanted in the brain, cardiac pacemakers; cochlear implant; history of alcohol or drug abuse in the last 6 months; neurological pathologies; hx of head trauma or neurosurgery; decompensated systemic diseases and chronic inflammatory diseases (lupus, rheumatoid arthritis, Reiter's syndrome); uncompensated hypothyroidism; personal history of cancer, past or undergoing treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-Blind, Randomized, Parallel Group, Sham-Controlled Clinical Trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Respondres placebo effect<br>Intervention: 'Transcranial Direct Current Stimulation - tDCS The patients will receive tDCS stimulation treatment prefrontal cortex dorso lateral According to 10-20 EEG system, anode will be placed at left F3 and cathode at contralateral F4. Placebo stimulation uses a 2 milliamperes current during in the first minutes, in the 10 min and in 19 minutes. | Device: s-tDCS<br>* - Intervention: tDCS is a therapeutic method that modulates the membrane potential, where anodic stimuli induce cortical excitability and cathodic stimuli reduce it<br>Device: a- tDCS<br>* - Intervention: tDCS is a therapeutic method that modulates the membrane potential, where anodic stimuli induce cortical excitability and cathodic stimuli reduce it<br>|
| Active Comparator: No respondres placebo effect<br>Intervention: 'Transcranial Direct Current Stimulation - tDCS The patients will receive tDCS stimulation treatment prefrontal cortex dorso lateral According to 10-20 EEG system, anode will be placed at left F3 and cathode at contralateral F4. Active stimulation uses a 2 milliamperes current during 20 minutes. | Device: s-tDCS<br>* - Intervention: tDCS is a therapeutic method that modulates the membrane potential, where anodic stimuli induce cortical excitability and cathodic stimuli reduce it<br>Device: a- tDCS<br>* - Intervention: tDCS is a therapeutic method that modulates the membrane potential, where anodic stimuli induce cortical excitability and cathodic stimuli reduce it<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1.Change in pain level - first phase | Change from before and after the First phase of treatment on Pain scores assessed by a Numerical Pain Scale (NPS 0 to 10) (0 means no pain - 10 means the worst pain imaginable) | Time Frame: 1 month | 
| Change in functional capacity - first phase | The Brief Pain Inventory (BPI) rapidly assesses the severity of pain and its impact on functioning | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain level - second phase | Change from before and after the Second phase of treatment on Pain scores assessed by a visual analogue scale (VAS 0 to 100mm) (0 means no pain - 100 means the worst pain imaginable) | 3 months | 
| Change in functional capacity - second phase | Change from before and after the First phase of treatment on Total score on the Brazilian Profile of Chronic Pain: Screen (BPCP:S) (range from 0 to 93; high numbers means more pain severity, interference in daily activities and emotional burden) | 3 months | 
| Change in Function of modulatory descending system | Change from before and after the First phase of treatment on the score in a numerical pain scale (NPS 0-10) for a moderate heat pain stimulus to the right arm (ventral region) during a conditioned pain modulation task (CPM-task), where participant keeps the counter-lateral hand in an iced cold water (0 to 1º Celsius) | 1 month | 
| Change in Function of corticospinal pathway | Change from before and after the First phase of treatment on measures of motor threshold (MT), motor evoked potential (MEP), intracortical facilitation (ICF), short intracortical inhibition (SICI), and cortical silent period (CSP) assessed with transcranial magnetic stimulation (TMS). | Time Frame: 1 month | 
| 7. Change in levels of Brain derived neurotrophic factor - BDNF | Blood samples will be collected at baseline and after the First phase of intervention in order to determine BDNF serum levels using a standardized kit | Time Frame: 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibromyalgia; tDCS; ß-endorphin; placebo effect; pain