Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM are not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype and FM symptoms in relevant clinical populations. LPS-evoked and spontaneous secretion of IL-5 and other select cytokines from circulating monocytes was higher in women with FM compared to women without pain. Additionally, greater secretion of IL-5 was significantly associated with pain and other clinically relevant psychological and somatic symptoms of FM. Further, higher levels of pain and pain-related symptoms were associated with a lower percentage of intermediate monocytes (CD14/CD16) and a greater percentage of non-classical monocytes (CD14/CD16) in women with FM. Based on findings from individuals with FM, we examined the role of IL-5, an atypical cytokine secreted from monocytes, in an animal model of widespread muscle pain. Results from the animal model show that IL-5 produces analgesia and polarizes monocytes toward an anti-inflammatory phenotype (CD206). Taken together, our data suggest that monocyte phenotype and their cytokine profiles are associated with pain-related symptoms in individuals with FM. Furthermore, our data show that IL-5 has a potential role in analgesia in an animal model of FM. Thus, targeting anti-inflammatory cytokines such as IL-5 in secreted by circulating leukocytes could serve as a promising intervention to control pain and other somatic symptoms associated with FM.

Exercise training is an effective therapy for many pain-related conditions, and trained athletes have lower pain perception compared to unconditioned people. Some painful conditions, including strenuous exercise, are associated with elevated levels of protons, metabolites and inflammatory factors, which may activate receptors and/or ion channels, including acid-sensing ion channels (ASICs), on nociceptive sensory neurons. We hypothesized that ASICs are required for immediate exercise-induced muscle pain (IEIP), and that exercise training diminishes IEIP by modulating ASICs within muscle afferents. We found high-intensity interval training (HIIT) reduced IEIP in C57BL/6 mice, diminished ASICs mRNA levels in lumber dorsal root ganglia (DRG), and this downregulation of ASICs correlated with improved exercise capacity. Additionally, we found that ASIC3 -/- mice did not develop IEIP, however the exercise capacity of ASIC3 -/- was similar to wild-type mice. These results suggest that ASICs are required for IEIP, and that diminishment of IEIP after exercise training correlates with downregulation of ASICs in sensory neurons.

Wrist-worn accelerometers are increasingly used to assess free-living physical activity (PA), but the implications of different processing methods are not well characterized. To advance research in this area it is important to better understand how choice of processing method influences estimates of free-living PA behavior. This study compared PA profiles resulting from processing wrist-worn data collected under free-living conditions using four different methods in a clinical sample of 160 women with chronic pain, a condition for which PA serves as a treatment. Participants wore monitors on their non-dominant wrist for 7 days and completed a self-report PA measure. Processing methods were Hildebrand linear, a modified nonlinear Hildebrand, Staudenmayer linear, and Staudenmayer random forest. Using each method, minutes per day in sedentary, light, and moderate-to-vigorous PA (MVPA) were estimated and individuals were classified as meeting PA guidelines based on their accumulated MVPA. Comparisons of outcomes among processing methods and with self-reported PA were made using repeated measures ANOVA, correlations, and kappa statistics. With few exceptions, estimated time at each intensity differed significantly across processing methods and with self-report ( p < .001). Correlations between methods ranged widely (ρ range = 0.09 to 1.00) and showed inconsistent agreement for classifying individuals as meeting PA guidelines (κ range : −0.02 to 0.90). Thus, choice of processing method significantly influenced conclusions regarding free-living PA. Researchers and clinicians should exercise caution when interpreting accelerometer activity data and comparing across existing studies using different processing methods when examining how PA influences clinical conditions.

Objective: Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. We evaluated if using TENS during activity would improve movement-evoked pain and other patient-reported outcomes in women with FM. Methods: Participants were randomly assigned to receive active-TENS (n=103), placebo-TENS (n=99) or no-TENS (n=99) and instructed to use it at home 2h/day during activity for 4- weeks. TENS was applied to the lumbar and cervicothoracic regions using a modulated frequency (2-125Hz) at the highest tolerable intensity. Participants rated movement-evoked pain (primary outcome) and fatigue on an 11-point scale before and during application of TENS. Primary and secondary patient-reported outcomes were assessed at randomization and 4weeks. Results: After 4-weeks, the active-TENS group reported a greater reduction in movement-evoked pain and fatigue than placebo-TENS (Pain, Group mean difference(95% CI): -1.0(-1.8, -0.2), p=0.008; Fatigue: -1.4(-2.4, -0.4), p=0.001) and no-TENS groups (Pain: -1.8(-2.6. -1.0), p<0.0001; Fatigue: -1.9(-2.9, -0.9), p=<0.0001). A greater percentage of the active-TENS group reported improvement on the global impression of change when compared to placebo-TENS (70% vs. 31%, p<0.0001) and no-TENS (9%, p<0.0001). There were no TENS-related serious adverse events and less than 5% of participants experienced minor adverse events from TENS. Conclusion: Among women with FM and stable medication, 4-weeks of active-TENS use compared with placebo-TENS or no-TENS resulted in a significant improvement in movement-evoked pain and other clinical outcomes. Further research is needed to examine effectiveness in a real world, pragmatic setting to establish clinical importance of these findings.

Currently, there are no established biomarkers for the diagnosis or symptoms of pain and fatigue in individuals with fibromyalgia (FM). The objective of this study was to identify potential biomarkers in individuals with FM, and to correlate these putative biomarkers with FM-symptoms using a targeted metabolomics approach. The current study was a secondary analysis from baseline data taken in the Fibromyalgia Activity Study with TENS (FAST). We analyzed plasma samples and baseline patient-reported outcomes for resting pain and fatigue from 59 women with FM (mean±SD; age=49.69±11.54, BMI=35.23±10.91) matched with 38 healthy controls (HC) (age=51.0±11.46, BMI=32.33±8.66). Serum/plasma metabolomic extracts were derivatized and analyzed by gas chromatography mass spectrometry for 63 key metabolites representing the tricarboxylic acid cycle, glycolysis, pentose phosphate pathway, amino acid metabolism, neurotransmission, reactive oxygen species defense, and energetics. Differences between FM and HC were assessed for each metabolite using unpaired t-tests (corrected p<0.008) and Pearson's correlation coefficients were assessed between significant metabolites and baseline pain and fatigue. Ten of the 63 metabolites showed significant between-group differences (P<0.0001). 2-hydroxybutyrate, asparagine, cysteine, fumarate, histidine and tryptophan were negatively correlated with pain and fatigue (P=0.002 to 0.0001, r=-0.315 to -0.894) while 6-phosphogluconate, hypoxanthine, and sphingosine were positively correlated (P=0.004 to 0.0001, r=0.291 to 0.366). The results of this study demonstrate individuals with FM have different resting levels of a variety of metabolites compared to HC, which correlate with their symptoms. These metabolites are generally involved in reduction-oxidation pathways and energy metabolism. Future work will confirm these findings in a new cohort and examine if interventions can alter these metabolites and symptomology. Funded by NIH grant AR06338 and AR06338S1.