The Relationship Between Chronic Postoperative Pain and Circulating Inflammatory Biomarkers (CC-Chemokine Ligand 5, Adiponectin, and Resistin) After Fracture-Related Surgery in Pain Chronification.

Abstract

Background: After fracture-related surgery, chronic posttraumatic and/or postsurgical pain (CPSP) has a high incidence rate of up to 43% a year after surgery. Yet the underlying mechanisms are poorly understood. Murine and clinical evidence suggest immunological modulation of postsurgical pain. However, the specific cytokine profiles of patients who develop CPSP after fracture-related surgery remain to be determined. Therefore, we analyzed in an exploratory manner cytokines, chemokines and adipocytokines in patients with and without CPSP up to 1 year after fracture-related surgery.

Methods: A prospective longitudinal serum profiling of 30 patients with traumatic fractures that required osteosynthesis was conducted on the first day (D1), at 6 weeks (W6) and 1 year after surgery (Y1). Patients with CPSP at Y1 were compared to those who did not develop CPSP. A total of 22 pro- and anti-inflammatory serum cytokines, including adipocytokines, were quantified using Luminex technology. Statistical analyses included χ² test, t test, and Mann-Whitney U test, Spearman's rank correlations, and repeated-measures mixed models with Bonferroni correction for cytokine differences between patients with and without CPSP. Receiver-operating characteristic (ROC) curves evaluated the discriminatory ability of specific cytokines regarding the development of CPSP.

Results: Patients with CPSP 1 year after surgery (n = 12/30, 40%) exhibited elevated resistin levels at Y1 (CPSP: 1.04 ± 1.04 vs no-CPSP: 0.41 ± 0.31 pg/mL; P < .001) as well as higher adiponectin levels at Y1 (CPSP: 9.37 ± 8.23 vs no-CPSP: 5.57 ± 2.75 μg/mL; P = .008). Patients with CPSP had higher Rantes/CCL5 (CC-chemokine ligand 5) levels immediately after surgery on D1 than patients without CPSP (mean difference [MD] = 5.5, confidence interval [CI], 1.7-9.3 ng/mL; P = .014). At W6 and Y1, adiponectin and CCL5 levels correlated with pain intensity in patients with CPSP (adiponectin: r = 0.50, P = .03; CCL5: r = -0.50, P = .03). Across the entire patient population, resistin levels were correlated with pain intensity (r = 0.34, P < .001; D1-Y1).

Conclusions: Our explorative cytokine analysis uncovered an imbalance in serum cytokines and chemokines during the chronification process in patients who developed CPSP 1 year after surgically treated fractures. In particular, adiponectin and resistin were noted to be novel biomarkers for CPSP development. These data provide preliminary insight into a potential unexplored crosstalk between chronic postoperative pain and adipocytokines in the chronification of CPSP, which remains to be further analyzed.