Pain. 2015 Feb 5. [Epub ahead of print] Evidence for Sensitized Fatigue Pathways in Patients with Chronic Fatigue Syndrome. Staud R1, Mokthech M, Price DD, Robinson ME. Abstract Patients with Chronic Fatigue Syndrome (CFS) frequently demonstrate intolerance to physical exertion that is often reported as increased and long-lasting fatigue. As no specific metabolic alterations have been identified in CFS patients we hypothesized that sensitized fatigue pathways become activated during exercise corresponding with increased fatigue. After exhausting handgrip-exercise, muscle-metabolites were trapped in the forearm tissues of 39 CFS patients and 29 NC by sudden occlusion for up to 5min. A non-occlusive condition of similar duration was used as control. Repeated fatigue and pain ratings were obtained before and after exercise. Mechanical and heat hyperalgesia were assessed by quantitative sensory testing (QST).All subjects fulfilled the 1994 Fukuda-Criteria for CFS. NC and CFS subjects exercised for 6.6 (2.4) and 7.0 (2.7) min (p>.05). Forearm occlusion lasted for 4.7 (1.3) and 4.9 (1.8) min in NC and CFS subjects, respectively (p>.05). Whereas fatigue ratings of CFS subjects increased from 4.8 (2.0) to 5.6 (2.1) VAS units during forearm occlusion, they decreased from 5.0 (1.8) to 4.8 (2.0) VAS units during the control condition without occlusion (p=.04). A similar time course of fatigue ratings was observed in NC (p>.05) although their ratings were significantly lower than those of CFS subjects (p<.001). QST-testing demonstrated heat and mechanical hyperalgesia in CFS subjects Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise related fatigue in CFS patients consistent with sensitization of fatigue pathways. Future interventions that reduce sensitization of fatigue pathways in CFS patients may be of therapeutic benefit.