Clinically Effective Treatment of Fibromyalgia Pain With High-Definition Transcranial Direct Current Stimulation: Phase II Open-Label Dose Optimization

Abstract

Despite promising preliminary results in treating fibromyalgia (FM) pain, no neuromodulation technique has been adopted in clinical practice because of limited efficacy, low response rate, or poor tolerability. This phase II open-label trial aims to define a methodology for a clinically effective treatment of pain in FM by establishing treatment protocols and screening procedures to maximize efficacy and response rate. High-definition transcranial direct current stimulation (HD-tDCS) provides targeted subthreshold brain stimulation, combining tolerability with specificity. We aimed to establish the number of HD-tDCS sessions required to achieve a 50% FM pain reduction, and to characterize the biometrics of the response, including brain network activation pain scores of contact heat-evoked potentials. We report a clinically significant benefit of a 50% pain reduction in half (n = 7) of the patients (N = 14), with responders and nonresponders alike benefiting from a cumulative effect of treatment, reflected in significant pain reduction (P = .035) as well as improved quality of life (P = .001) over time. We also report an aggregate 6-week response rate of 50% of patients and estimate 15 as the median number of HD-tDCS sessions to reach clinically meaningful outcomes. The methodology for a pivotal FM neuromodulation clinical trial with individualized treatment is thus supported.

Online registration: Registered in Clinicaltrials.gov under registry number NCT01842009.

Perspective: In this article, an optimized protocol for the treatment of fibromyalgia pain with targeted subthreshold brain stimulation using high-definition transcranial direct current stimulation is outlined.

Keywords: Fibromyalgia; high-definition transcranial direct current stimulation; motor cortex; noninvasive brain stimulation; pain.

Figure 1

Study overview illustrating patient visits and response assessment (Assess.) time points. Baseline VAS measures were recorded in a pain diary 1 week before visit 2 (7 days between visits 1 and 2) and HD-tDCS stimulation (Stim) was started on visit 2. Patients reported daily pain scores in pain diaries for every day they remained enrolled in the trial, starting from visit 1. Pain diaries were distributed and discussed on visits 2, 6, 11, 16, 21, 24, and 27 (depending on the patient’s response), as well as on both follow-up visits. Five response assessments were performed on visits 11, 16, 21, 24, and 27 (depending on the patient’s response). During the response assessments, if patients responded (achieved >50% decrease in VAS compared with baseline VAS), HD-tDCS was discontinued and they were scheduled for follow-up visits; if patients were nonresponders (<50% decrease in VAS compared with baseline VAS), they received additional HD-tDCS stimulation sessions (up to a total of 26 sessions). Follow-up visits were performed 2 and 8 weeks after HD-tDCS was discontinued.

Figure 2

(Left) Finite element model of a 4 × 1 HD-tDCS montage over M1 on the scalp. (Middle) Finite element model showing underlying cortical electric field magnitude during HD-tDCS over M1. (Right) Anodal stimulation over left M1 was modeled with a wide radius (~75 mm) 4 × 1 ring. Electric field peaks of .42 V/m were predicted on the motor strip as a result of 2-mA stimulation. Streamline images (gray) demonstrate the direction of current crossing the skull.

Figure 3

(Top) The low temperature (Temp) heat stimuli were applied first, with 2 blocks, each consisting of 20 stimuli. These 2 low-temperature blocks were separated by a 5-minute break, followed by the 2 high-temperature heat stimuli also separated by a 5-minute break. Both the low-temperature and high-temperature blocks were separated by a 15-minute break. HD-tDCS treatment was then administered and the heat stimulation procedure was repeated (post-HD-tDCS). (Bottom) During the heat stimulation blocks, the thermode was placed on the indicated area of the forearm for each stimulus. After the heat stimulus was applied, the thermode was moved slightly in a clockwise manner and the process was repeated for the entirety of the block.

Figure 4

(Top left) RBNM for pain (52°C) showing central theta-delta activation. Red circles represent delta frequency nodes, green circles represent theta frequency nodes, and gray lines represent connectivity between the nodes. Line width and darkness denote connectivity strength. (Top right) Models depicting mapped network propagation over time and area of applied head probe. (Bottom) Time frames of the network showing activity development over time, starting ~330 milliseconds after the heat stimulus.

Figure 5

In the first 4 weeks there were 5 days of treatment, in the last 2 weeks only 3, such that assessment days where on the 11th, 16th, 21st, 24th, and 27th visit. (Top left) Treatment outcome with Monte Carlo simulation performed at all assessment points corresponding to 2, 3, 4, 5, and 6 weeks after treatment commenced or visits 11, 16, 21, 24, and 27, respectively. (Top right) VAS progression over visits for responders and patients in treatment, including follow-up visits, pain diary baseline (green), and visit 1 baseline (magenta). (Bottom left) Patient quality of life, assessed by FIQ, progression over visits, comparing responders and patients in treatment. (Bottom right) PPT measures over visits comparing responders and patients in treatment.

Figure 6

(Top left) Because there were no interactions between time and response, to visualize cumulative effects of treatment between responders and nonresponders, we displayed VAS scores aligned to the last day of treatment. (Top right) Determination of an acute effect between responders and nonresponders by averaging VAS scores before and after HD-tDCS treatment, across all sessions. Here, responders show a significant acute decrease in VAS compared with nonresponders. (Bottom left) ROC analysis examining the acute effect observed on the first treatment day, showing that it is a reasonable predictor of treatment success. (Bottom right) ROC analysis on the BNA scores from the pretreatment session showing that responsiveness can be predicted before the commencement of treatment. All pairwise comparisons between responders and nonresponders used the Wilcoxon rank sum test with N = 14 measures.