Background: Muscle soreness occurs after exercise and also under morbid conditions, such as fibromyalgia (FM). However, how the morbid soreness manifests in FM and how it affects the disease remain unknown. Also, whether the non-exertional soreness in FM differs from exercise-induced soreness phenotypically is unclear.Methods: Fifty-one newly diagnosed FM patients from 166 consecutive cases of chronic musculoskeletal pain and 41 healthy controls were prospectively recruited. Musculoskeletal

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... toms and metabolomics data were analyzed before the initiation of pharmacotherapy. Clinical manifestations and therapeutic responses were recorded with a follow-up of 4 weeks. Results: Soreness complaints were common in FM (92.2%). Soreness had clinical impacts different from pain, and affected stiffness and restless conditions. In terms of manifestations and metabolomic features, phenotypes diverged between cases with prominent soreness (FM-PS) and those without symptoms (FM-P). Conventional treatment did not ameliorate soreness severity despite its efficacy on pain. Moreover, despite the salient therapeutic efficacy on pain relief, current treatment did not improve the general disease severity in FM-PS versus FM-P. Metabolomics analyses suggested oxidative metabolism dysregulation in FM. Also, high malondialdehyde level indicated excessive oxidative stress in FM individuals (p=0.008). Contrary to exercise-induced soreness, lactate levels were significantly lower in FM individuals than controls, especially in FM-PS. Moreover, FM-PS cases exclusively featured increased malondialdehyde level (p=0.008) and its correlation with soreness intensity (r=0.337, p=0.086). Conclusion: Morbid soreness symptoms were prevalent in FM, with presentation distinct from exercise-induced soreness. Assessments of non-exertional soreness in FM may provide valid approaches for phenotype classification and therapeutic prediction.