A randomised, double-blind, sham-controlled, 2×2 factorial trial of aerobic vs. non-aerobic exercise and motor cortex transcranial direct current stimulation in fibromyalgia: effects on clinical outcomes and descending pain modulation.

Background: Exercise is first-line therapy for fibromyalgia, but the superiority of aerobic vs. non-aerobic modalities is uncertain. Motor-cortex transcranial direct current stimulation (tDCS) may enhance descending pain inhibition. We tested the effects of exercise modality and tDCS on conditioned pain modulation (CPM) and clinical outcomes. Methods: Double-blind, randomised 2 × 2 factorial trial in Boston, USA (2019-2024; allocation 1:1:1:1). Adults with fibromyalgia were assigned to aerobic + active tDCS, aerobic + sham, non-aerobic + active, or non-aerobic + sham. Participants completed 16 in-person sessions over 4 weeks, combining concurrent tDCS and exercise. The non-aerobic condition involved light treadmill walking matched for duration but below aerobic threshold (<40% HRmax). Primary outcomes were changes in CPM and temporal summation of pain (TSP) at week 6; secondary outcomes were pain, fatigue, sleep, quality of life, and depressive symptoms. Findings: Of 116 participants (mean age 47.1 ± 11.9 years), 88.8% were female. Active tDCS improved CPM vs. sham (Cohen's d = 0.66; p = 0.015), independent of exercise modality, and showed a small, nonsignificant improvement in TSP (mean change -0.19 [95% CI -0.90, 0.51]). All groups showed moderate-to-large improvements in pain, fatigue, and quality of life (Cohen's d 0.60-0.92), with no added benefit from tDCS. Non-aerobic and aerobic exercise produced comparable symptom improvements. Greater age and lower body mass index (BMI) were associated with enhanced response. Changes in pain modulation were not mediated by short-term clinical changes. Interpretation: Supervised aerobic and non-aerobic exercise produced meaningful short-term clinical improvements. Motor-cortex tDCS enhanced descending pain inhibition but did not add clinical benefit beyond exercise over 6 weeks. Funding: National Institutes of health (R01 1R01AT009491-01A1).