Chronic postsurgical pain development is associated with an altered inflammatory response after surgery.

Background: Chronic postsurgical pain (CPSP), a debilitating condition affecting up to 30% of patients, is increasingly linked to maladaptive immune responses. As
neutrophils are among the first responders to surgery-induced tissue damage, differential expression of their markers is thought to reflect the extent of tissue
damage and the subsequent immune response. Dysregulation of the immune response may cause sensory alterations in the early postoperative period that
predisposes patients to postsurgical pain chronification. The aim of the present study is to further explore the relationship between neutrophil activity and the
development of CPSP using point-of-care flow cytometry.
Methods: Patients undergoing elective lower extremity orthopedic surgery at the University Medical Center Utrecht or St. Antonius Hospital Leidsche Rijn, the
Netherlands, were enrolled, and blood samples were collected at baseline, 2–4 weeks and 3 months post-surgery. CPSP was assessed at 3 months using the
Numerical Rating Scale (NRS, 0–10), with CPSP defined as NRS ≥4. Flow cytometry was used to analyze blood samples and neutrophil phenotypical categories were
categorized following de Fraiture et al. (2022) where neutrophil phenotypical categories are defined by visual assessment of two-dimensional CD16/CD62L dot plots.
Results: A total of 56 patients, 45% females, were included, with a mean age of 58 ± 16.79 standard deviation (SD) years and mean BMI of 28.6 ±5.63SD, of whom
10 patients (18%) developed CPSP. Neutrophils of patients not developing CPSP were more frequently classified as category 1 at all timepoints: 20% (CPSP) vs.
35.4% (no CPSP) at baseline, 8.3% vs. 38.6% at 2–4 weeks, and 23.1% vs. 50.0% at 3 months (Figure 1). Both groups showed a strong post-operative inflammatory
response as they were predominantly classified in categories 3 and 4. Multiple linear regression (R² = 0.26, F(5, 42) = 2.99, p = 0.021) indicated that the percentage
of CD16highCD62Llow cells at 2-4 weeks post-op significantly predicted NRS scores at 3 months post-op (β = -0.082, p = 0.020) after adjusting for sex, BMI, surgical
center, and procedure type.
Conclusion: The finding that CD16highCD62Llow neutrophils (category 1) are associated with a lower NRS scores implies that this immune suppressive neutrophil
type is involved in normalizing tissue homeostasis. This suggests that neutrophil phenotyping at 2-4 weeks may help identify patients at risk in developing CPSP.
References
de Fraiture, Emma J., et al. “Visualization of the inflammatory response to injury by Neutrophil Phenotype categories.” European Journal of Trauma and Emergency
Surgery, vol. 49, no. 2, 8 Nov. 2022, pp. 1023–1034, https://doi.org/10.1007/s00068-022-02134-3.
Pillay, Janesh, et al. “A subset of neutrophils in human systemic inflammation inhibits T cell responses through mac-1.” Journal of Clinical Investigation, vol. 122, no.
1, 3 Jan. 2012, pp. 327–336, https://doi.org/10.1172/jci57990.
Figure 1. Percentage neutrophil categorical phenotypes at baseline, post-operation, 2-4 weeks post-operation and 3 months post-operation in patients with (no) CPSP at 3 months. Categorization was performed using methodology described in de Fraiture et al. (2022).