Given recent increasing opioid-related deaths and evidence showing against the use of opioids for non-malignant chronic pain, there is growing need for non-narcotic pain management. Fibromyalgia is a difficult to treat chronic pain condition that is often treated with opioids despite existing evidence. The prevalence of fibromyalgia is increased among Veterans returning from the gulf war and is already a significant burden in senior Veterans who may have suffered with chronic pain for decades already. Many treatment options for fibromyalgia carry intolerable side effects. CES (Cranial Electrical Stimulation) is a FDA-approved, non-pharmacologic therapy that is currently utilized within the military and VA system, but sufficient evidence regarding its outcomes and neural mechanisms have not been adequately investigated. An understanding of its neural underpinnings and analgesic effects could lead to 1) improvements in pain management and quality of life, 2) cost-savings and 3) development of new techniques to address pain.
RESEARCH PLAN: In the setting of the opioid epidemic, it is crucial to develop non-pharmacologic treatments for pain and biomarkers to accurately assess pain treatment outcomes. In the present investigation, the investigators assess a novel non-pharmacologic approach to chronic pain treatment in patients suffering from fibromyalgia (a notoriously difficult to treat pain syndrome), utilizing neuroimaging as a biomarker. Resting state functional connectivity MRI (rs-fcMRI), a specific neuroimaging technique, has emerged as a reliable research tool to objectively assess, understand, and predict clinical pain in syndromes such as fibromyalgia. Preliminary results reveal a trend towards improved pain and function with a FDA-approved, non-pharmacologic therapy - auricular Cranial Electrical Stimulation (CES) - over standard therapy control, correlating to altered network connectivity on rs-fcMRI. CES-related improvements continued through 12 weeks following the completion of treatment and correlated to changes in cross-network connectivity, which differed between groups. OBJECTIVE: The proposed CDA-2, a randomized, sham-controlled trial of auricular CES, evaluates 1) the clinical utility of CES for fibromyalgia as compared to sham placebo control, 2) short- and long-term CES-related neural changes visualized on rs-fcMRI and 3) the ability of rs-fcMRI to predict CES treatment response. HYPOTHESIS: True CES results in non-placebo-related short- and long-term pain and functional improvements that can be correlated with altered connectivity and predicted by baseline rs-fcMRI. METHODS: Fifty total subjects (male and female Veterans, age 20-60 years old) will be randomized to either sham (n=25) or true (n=25) auricular CES. Neuroimaging data, self-reported pain, and function will be assessed at baseline and at 1 and 12 weeks post-treatment to evaluate neural correlates of CES-related treatment. Subjects who meet study criteria will receive baseline assessments including rs-fcMRI, Defense and Veterans Pain Rating Scale (DVPRS) measures, PROMIS measures, arm curl, 30-s chair stand, handgrip strength tests, and baseline analgesic consumption. Subjects will be block-randomized, stratified based on gender, to either true or sham CES (series of 4, weekly) treatments and assessed for rs-fcMRI and functional changes at 1 and 12 weeks post-treatment. This study addresses the critical need to identify and understand neural correlates of pain and non-opioid pain management.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
50
The device for both groups is the Alpha-stim, a FDA-approved device similar to the Military Field Stimulator (MFS/Neuro-Stim System), a cranial electrical stimulation (CES) device.
Atlanta VA Medical and Rehab Center, Decatur, GA
Decatur, Georgia, United States
Clinical Pain Change
For subjects with fibromyalgia, clinical pain was assessed in both groups using the Defense Veterans Pain Rating Scale (DVPRS), a validated measurement tool for pain, as well as analgesic consumption. Clinical pain was measured at baseline, 6 weeks following treatment, and 12 weeks following treatment completion in both groups. Mean differences were measured between the baseline score and the 12-week score. The DVPRS is a combination of several different pain scales including the VAS, verbal rating scale, FACES scale, and numerical rating scale. Measurements will be graded on a scale of 0-10 with 0 being "no pain" and 10 being "severe" or "worst pain."
Time frame: baseline, 6 weeks into treatment, and 12 weeks post treatment
Change in Rs-fcMRI Connectivity Effect Size
The region of interest (ROI) was the right Cerebellar 7b seed, and a 2x2 mixed ANOVA interaction was conducted with Family -Wise Error (FWE) constraints to control for multiple comparisons. Voxel threshold was set to p\<0.005 uncorrected, cluster threshold of p\<0.05 FWE corrected. A Fisher-transform z-score represents the mean connectivity values for each covariate in the model (i.e. groups) for each significant cluster. A z-score value of 0 indicates no difference in functional connectivity. Positive z-scores denote stronger, and negative z-scores weaker, connectivity with the ROI; further research is needed to determine their clinical implications and whether these changes denote a positive or negative outcome.
Time frame: baseline, 6 weeks into treatment, and 12 weeks post treatment (change from baseline to 12 weeks post reported)
Sit-to-stand
Tests of function (sit-to-stand, bicep curl, handgrip strength) was performed in both groups at baseline, 6 weeks, and 12 weeks following treatment. Mean difference was measured between baseline and 12 weeks. The sit-to-stand test tests how many full sit-to-stands a subject can perform within a 30 second interval.
Time frame: baseline, 6 weeks into treatment, and 12 weeks post treatment
Bicep-curl
Tests of function (sit-to-stand, bicep curl, handgrip strength) was performed in both groups at baseline, 6 weeks, and 12 weeks following treatment. Mean difference was measured between baseline and 12 weeks. The bicep curl tests how many full bicep curls with gender specific weights (8 pounds for male, 5 pounds for female) a subject can perform within a 30 second interval. Both arms were tested.
Time frame: baseline, 6 weeks into treatment, and 12 weeks post treatment
Handgrip Strength
Tests of function (sit-to-stand, bicep curl, handgrip strength) was performed in both groups at baseline, 6 weeks, and 12 weeks following treatment. Mean difference was measured between baseline and 12 weeks. The handgrip strength test uses a dynamometer to gauge the pressure that a subject can apply with their handgrip. Both hands were tested.
Time frame: baseline, 6 weeks into treatment, and 12 weeks post treatment
PROMIS Change
NIH Patient-Reported Outcomes Measurement Information System (PROMIS) measures were assessed using a validated survey created from independently validated NIH survey questions in both groups. Mean differences in T-scores were measured between the baseline visit and the 12-week visit. PROMIS measures included: PROMIS Item Bank v1.0 - Fatigue - Short Form 6a, PROMIS Item Bank v1.0 - Emotional Distress-Depression - Short Form 4a, PROMIS Item Bank v.1.0 - Emotional Distress - Anxiety- Short Form 7a. For each measure, a lower T-score represents a better clinical outcome. All of the PROMIS measures reported (Fatigue, Depression, and Anxiety) have been standardized to have a mean of 50 and an SD of 10. This standardization means that a score of 50 is the average level in the population, and any 10-point change in either direction (greater or lesser) represents one SD difference.
Time frame: baseline visit and 12 weeks post treatment
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