Association between Multisite and Site-specific Chronic Pain, Analgesic Use, Metabolic–Proteomic Profile, and Incident Chronic Kidney Disease in Diabetes

BACKGROUND: Although chronic pain is highly prevalent among individuals with diabetes, its relationship with the risk of developing chronic kidney disease (CKD) in this population remains poorly understood. The authors aimed to explore the associations between multisite chronic pain and analgesic use with CKD risk in people with diabetes, and to further characterize the underlying metabolic and proteomic signatures. METHODS: The authors analyzed data from 20,208 UK Biobank participants with diabetes and complete chronic pain site information (headache, facial, neck/shoulder, back, stomach/abdominal, hip, knee). Using multivariable Cox regression models, they evaluated the prospective associations between chronic pain (both site specific and multisite), analgesic use (ibuprofen, paracetamol, opioid), and incident CKD risk. Multiomics data (248 metabolites, 2,911 proteins) were integrated to explore biological pathways. RESULTS: During a median follow-up of 13.2 yr, 2,589 incident CKD cases were documented. Chronic pain was associated with an 18% higher CKD risk (adjusted hazard ratio [HR], 1.18; 95% CI, 1.08 to 1.28). Site-specific analysis identified significant associations between CKD risk and pain in neck/shoulder, back, hip, knee, and stomach/abdominal regions, while headache and facial pain showed no significant associations. Multisite pain exhibited a dose-dependent relationship with CKD risk (per additional site: adjusted HR, 1.08; 95% CI, 1.05 to 1.12). Among participants with chronic pain, opioid use showed significant positive associations with CKD risk (adjusted HR, 1.22; 95% CI, 1.06 to 1.40), whereas ibuprofen and paracetamol demonstrated no significant associations. Multiomics secondary analysis identified three consistently dysregulated biomarkers across all five significant pain sites: elevated chromogranin-A, increased glycoprotein acetyls, and reduced omega-3 to total fatty acids ratio. Protein network analysis revealed tumor necrosis factor (TNF) and epidermal growth factor receptor (EGFR) as central nodes in the observed chronic pain-CKD risk associations. CONCLUSIONS: Multisite chronic pain and opioid use are associated with elevated CKD risk in diabetes, supported by metabolomic/proteomic signatures. These findings highlight the need for renal-conscious pain management in diabetes care.