Early identification of postsurgical pain chronification

Pain is a nearly universal consequence of surgery, typically short-term and resolving with tissue healing. However, in some patients, it persists beyond the recovery period and develops into chronic postsurgical pain (CPSP). CPSP significantly impairs recovery and quality of life, and its inadequate management has contributed to opioid overuse. As life expectancy rises, increasing surgical demand will place more patients at risk of CPSP.

This thesis aimed to advance the understanding of postsurgical pain chronification by evaluating strategies for early identification and examining the underlying sensory and immunological mechanisms.

Two prediction models were developed to identify vulnerability to CPSP. Patients at risk for CPSP could best be identified two weeks after surgery by a high pain intensity, painful cold sensations, use of opioids before surgery, and surgery involving bones. The link between painful cold sensations and CPSP suggests changes in nervous system pain processing, potentially driven by the immune response to surgery-induced tissue injury.

Therefore, emphasis was placed on assessing changes in pain transmission and immune responses as potential mechanisms underlying the chronification of postsurgical pain. Quantitative Sensory Testing (QST) enables researchers to quantify sensory changes and altered pain processing. This thesis provided a review of its feasibility, applications, and limitations in assessing sensory processing, along with a practical guide to the German Research Network on Neuropathic Pain (DFNS) protocol. This formed the basis for presenting the Sensory Changes and Immunological Parameters in Postsurgical Pain (SCIP-Pain) study.

The SCIP-Pain study is a prospective cohort study designed to identify sensory and immunological changes associated with the development of CPSP with neuropathic features in a high-risk population. Patients undergoing elective lower extremity orthopaedic surgery complete self-report questionnaires, undergo QST, and provide blood samples preoperatively, and at two weeks and three months postoperatively. Although the study is ongoing, this thesis presented its preliminary findings.

Preliminary QST results addressed two major concerns regarding the DFNS protocol: its capacity to reflect patients’ self-reported sensory symptoms and its resource-intensive nature. The relationship between experimentally evoked and self-reported pain was examined by comparing thermal QST results with patients’ reports of painful cold sensations on the Douleur Neuropathique en 4 (DN4) questionnaire. To reduce the protocol’s resource demands, three optimisation strategies were evaluated: (1) using normative reference data instead of contralateral comparisons, (2) excluding redundant QST parameters, and (3) reducing repeated measurements while maintaining classification accuracy.
An exploratory study into perioperative immune changes focused on the association between neutrophil markers Fc-γ receptor III (CD16) and L-selectin (CD62L) and CPSP development using point-of-care flow cytometry.

Evidence in this thesis points to a critical time window of two to four weeks following surgical trauma during which CPSP becomes established. The SCIP-Pain study is expected to advance understanding of postsurgical pain chronification by characterising the temporal evolution of sensory and immunological changes and their modulation by pre-, intra-, and postoperative factors. These insights are essential for optimising the timing of prediction, prevention, and treatment strategies to halt the onset or progression of CPSP.