LDN and tDCS in Fibromyalgia

Study Overview
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Brief Summary
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Fibromyalgia is a complex generalized and diffuse musculoskeletal chronic pain; and pharmacological approaches are widely used to relieve pain and increase life quality. In this context, low-dose naltrexone (LDN) was able to increase nociceptive threshold in patients with fibromyalgia. Moreover, non-pharmacological techniques, like Transcranial Direct Current Stimulation (tDCS), have been shown effective for pain management. This study aims to evaluate the analgesic and neuromodulatory effect of combined LDN followed by tDCS in fibromyalgia patients. This is a randomized, double-blinded, parallel, placebo/sham-controlled trial, in which 92 (10% loss) women with fibromyalgia will be included included and signed the informed consent. Patients will be allocated into 4 groups: tDCS+LDN (n=21), Sham-tDCS+LDN (n=22), tDCS+Placebo (n=22), and Sham-tDCS+Placebo (n=21). LDN or placebo (p.o.) intervention lasts 26 days, in the last five, tDCS will be applied (sham or active, 20min, 2mA). Questionnaires assessed are: Sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Chronic Pain Profile Scale (CPP). Also, pain measures were taken: Pain Pressure Threshold (PPT) and Conditioned Pain Modulation (CPM). Blood samples will be collected to analyze Brain Derived Neurotrophic Factor (BDNF) serum levels.

Official Title
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Association of Low Doses of Naltrexone and Transcranial Direct Current Stimulation in Fibromyalgia: Randomized Clinical Trial, Blind, Controlled With Placebo

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: Low-Dose Naltrexone
* Device: Transcranial Direct Current Stimulation
* Drug: Placebo
* Device: Sham Transcranial Direct Current Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: signed the consent form women from 18 to 65 years confirmed diagnosis of fibromyalgia according 2016 American College of Rheumatology criteria read and write pain higher than 6 in the Visual Analogue Scale (VAS), in the last 3 months chronic stable treatment in the last 3 months. Exclusion Criteria: in use of opioid drugs; pregnancy or not using anticontraceptive history of alcohol or drug abuse in the last 6 months history of neurological pathologies history of arrhythmia history of use of drugs that might change vascular response history of head trauma history of neurosurgery decompensated systemic diseases or chronic inflammatory diseases (lupus, rheumatoid arthritis, Sjogren syndrome, Reiter syndrome) history of non-compensated hypothyroidism personal history of cancer.

Ages Eligible for Study
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Minimum Age: 8 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: A randomized, double-blinded, parallel, controlled with placebo and sham stimulation, clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LDN + tDCS<br>Low Dose Naltrexone and Transcranial Direct Current Stimulation | Drug: Low-Dose Naltrexone<br>* 4.5mg daily dose, orally, during 26 days<br>* Other names: LDN;Device: Transcranial Direct Current Stimulation<br>* An anodal electrode was placed on the scalp above the primary motor cortex (M1), contralateral to the dominant cortex. The cathodal electrode was placed on the supraorbital contralateral area. The current used was 2mA during 20 minutes.<br>* Other names: tDCS;|
| Sham Comparator: LDN + Sham tDCS<br>Low Dose Naltrexone and Sham Transcranial Direct Current Stimulation | Drug: Low-Dose Naltrexone<br>* 4.5mg daily dose, orally, during 26 days<br>* Other names: LDN;Device: Sham Transcranial Direct Current Stimulation<br>* Sham-tDCS stimulation consists of an active current during 30 seconds<br>* Other names: Sham tDCS;|
| Placebo Comparator: Placebo + tDCS<br>Placebo and Transcranial Direct Current Stimulation | Device: Transcranial Direct Current Stimulation<br>* An anodal electrode was placed on the scalp above the primary motor cortex (M1), contralateral to the dominant cortex. The cathodal electrode was placed on the supraorbital contralateral area. The current used was 2mA during 20 minutes.<br>* Other names: tDCS;Drug: Placebo<br>* The capsule presented the same format, size and color as LDN capsules, however the excipient used was starch.<br>|
| Other: Placebo + Sham tDCS<br>Placebo and Sham Transcranial Direct Current Stimulation | Drug: Placebo<br>* The capsule presented the same format, size and color as LDN capsules, however the excipient used was starch.<br>Device: Sham Transcranial Direct Current Stimulation<br>* Sham-tDCS stimulation consists of an active current during 30 seconds<br>* Other names: Sham tDCS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain in VAS | Visual Analogue Scale (VAS) that goes from 0 cm (without pain) to 10cm (worst pain). | Change between baseline and after association (26 days from baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depressive symptoms | Beck Depression Inventory (BDI-II) that goes from 0 (without depressive symptoms) to 63 (worst depressive symptoms) | Change between baseline and after association (26 days from baseline) | 
| Anxiety levels | State-Trait Anxiety Inventory (STAI) divided into state anxiety (from 0 to 52, the higher the worse) and trait anxiety (from 0 to 48, the higher the worse) | Change between baseline and after association (26 days from baseline) | 
| Pain Catastrophizing Thought | Pain Catastrophizing Scale (PCS): divided into rumination (from 0 to 16, the higher the worse), magnification (from 0 to 12, the higher the worse) and hopelessness (from 0 to 24, the higher the worse). Total goes from 0 to 52, the higher the worse | Change between baseline and after association (26 days from baseline) | 
| Profile of Chronic Pain | Profile of Chronic Pain Scale (PCP:S): divided into Frequency and Intensity of Pain (from 0 to 30, the higher the worse), Pain Effect in Activities (from 0 to 36, the higher the worse) and Pain Effect in Emotions (from 0 to 25, the higher the worse) | Change between baseline and after association (26 days from baseline) | 
| Pain Pressure Threshold | Pain Pressure Threshold (PPT) measured using an electronic algometer applied in the right forearm; and patients need to report the first pain sensation (minimum pain) and maximum pain. Threshold goes from 0 to the maximum value the patient can hold, the higher the value, better is the result | Change between baseline and after association (26 days from baseline) | 
| Conditioned Pain Modulation | Conditioned Pain Modulation (CPM) with an algometer (PPT task), the patient informed when felt a pain equal to 6 in the VAS. This pain level was applied in the right forearm for 30 seconds, while the left forearm (non-dominant hand) was submerged in water from 0˚C to 1.5˚C; after 30s, patients reported their pain in each of the arms. CPM = left forearm VAS - 6. (from -4 to 6, the value must be as closest to -4 as possible, meaning the higher the worse) | Change between baseline and after association (26 days from baseline) | 
| Serum BDNF | Blood sample collected and centrifuged, the supernatant aliquoted for BDNF analysis using ELISA technique, according to manufacturer's instructions (values start in 0, patients with fibromyalgia usually have higher levels of serum BDNF, therefore the higher the worse) | Change between baseline and after association (26 days from baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tDCS, LDN, Transcranial Direct Current Stimulation, Low Dose Naltrexone