209: Pre?operative clinical phenotype and biological pathways in knee and thoracic cohorts of the A2CPS

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Chronic postsurgical pain, Omics (Proteomics/Metabolomics/Transcriptomics/Genomics), Assessment and Measurement of Pain/Nociception

Background and Aims: Chronic postsurgical pain (CPSP) results in impaired postoperative long-term outcomes and reduced quality of life. CPSP impacts nearly 20% of patients undergoing knee arthroplasty and 30% of those undergoing thoracotomy. While numerous biopsychosocial factors contribute to the transition to chronic pain, there is limited understanding of biological factors that may contribute to pre-operative disease severity, which may increase risks for adverse health outcomes. This study aimed to characterize pre‑operative clinical phenotypes using biopsychosocial measures and to determine the metabolomic and proteomic pathways associated with clinical severity. This is a secondary analysis from the A2CPS baseline data (v2.1.0).

Methods: Individuals scheduled for knee replacement or thoracotomy completed baseline measures of pain severity, pain interference, psychosocial factors, and quantitative sensory testing. Plasma was isolated from whole blood; metabolites were analyzed via GC/MS while proteins were analyzed via targeted LC-MS/MS. Cluster analysis identified clinical measure-based subgroups in the knee and thoracic cohorts. Peptide-level concentrations were used as readouts of protein abundance and compared between clusters using Wilcoxon rank-sum and t-tests. Log-transformed normalized metabolite abundances were compared between groups using linear models adjusting for cofounders . Pathway analysis was used to explore biological pathways associated with differentially expressed metabolites and proteins.

Results: Baseline measures were completed in 1,042 knee-cohort individuals and 357 thoracic. Three knee-cluster groups differed in pain severity, interference, psychological distress, and pain sensitivity(p<.05), while two thoracic-cluster groups differed in pain sensitivity(p<.05). Twenty‑one metabolites and eight proteins were differentially regulated in the knee cohort clusters(p<.05), 24 metabolites and four proteins in the thoracic cohort clusters(p<.05). Pathway analyses revealed alterations in the knee (neurotransmitter and neuroimmune signaling, inflammatory and acute-phase response pathways, carbohydrate and energy metabolism) and thoracic (amino acid metabolism and neurotransmitter biosynthesis, carbohydrate metabolism and energy pathways, oxidative stress and mitochondrial redox regulation) cohorts.

Conclusions: Distinct pre‑operative clinical phenotypes were associated with biologically meaningful alterations in metabolomic and proteomic pathways across knee and thoracic cohorts. These differentially regulated pathways highlight mechanistic differences underlying disease severity and offer potential targets for early risk stratification and intervention to mitigate chronic postsurgical pain. Multi‑omics analyses combining metabolomics, proteomics, lipidomics, and genomic profiling may elucidate a more complete mechanistic landscape of pre‑operative disease severity and susceptibility to CPSP.

References: 1. https://a2cps.org/

2. Berardi G, Frey-Law L, Sluka KA, Bayman EO, Coffey CS, Ecklund D, Vance CGT, Dailey DL, Burns J, Buvanendran A, McCarthy RJ, Jacobs J, Zhou XJ, Wixson R, Balach T, Brummett CM, Clauw D, Colquhoun D, Harte SE, Harris RE, Williams DA, Chang AC, Waljee J, Fisch KM, Jepsen K, Laurent LC, Olivier M, Langefeld CD, Howard TD, Fiehn O, Jacobs JM, Dakup P, Qian WJ, Swensen AC, Lokshin A, Lindquist M, Caffo BS, Crainiceanu C, Zeger S, Kahn A, Wager T, Taub M, Ford J, Sutherland SP, Wandner LD. Multi-Site Observational Study to Assess Biomarkers for Susceptibility or Resilience to Chronic Pain: The Acute to Chronic Pain Signatures (A2CPS) Study Protocol. Front Med (Lausanne). 2022 Apr 25;9:849214. doi: 10.3389/fmed.2022.849214. PMID: 35547202; PMCID: PMC9082267.

3. Sluka KA, Wager TD, Sutherland SP, Labosky PA, Balach T, Bayman EO, Berardi G, Brummett CM, Burns J, Buvanendran A, Caffo B, Calhoun VD, Clauw D, Chang A, Coffey CS, Dailey DL, Ecklund D, Fiehn O, Fisch KM, Frey Law LA, Harris RE, Harte SE, Howard TD, Jacobs J, Jacobs JM, Jepsen K, Johnston N, Langefeld CD, Laurent LC, Lenzi R, Lindquist MA, Lokshin A, Kahn A, McCarthy RJ, Olivier M, Porter L, Qian WJ, Sankar CA, Satterlee J, Swensen AC, Vance CGT, Waljee J, Wandner LD, Williams DA, Wixson RL, Zhou XJ; A2CPS Consortium. Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures. Pain. 2023 Sep 1;164(9):1912-1926. doi: 10.1097/j.pain.0000000000002938. Epub 2023 Jun 15. PMID: 37326643; PMCID: PMC10436361.

Presenting Author: Giovanni Berardi
Submitting Author: Giovanni Berardi

Senior Author: Kathleen A Sluka

IASP 2026 Global Year theme of Neuropathic Pain: No

• Margaret A. Taub - Johns Hopkins
• Panshak P Dakup - Pacific Northwest National Laboratory
• Jon M Jacobs - Pacific Northwest National Laboratory
• Michael Olivier - Wake Forest
• Benlian Wang - Wake Forest
• Oliver Fiehn - University of California San Diego
• A2CPS Consortium - Acute to Chronic Pain Signatures Consortium