# Psychosocial and Oxidative Stress Mechanisms of Post-Surgical Chronic Pain

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $472,591

## Abstract

Total knee arthroplasty (TKA) is an increasingly common surgical procedure in older adults. Although
effective for many patients, 15% or more experience unsatisfactory pain outcomes. While limited to post-
surgical chronic pain in some patients, others also develop regional allodynia and hyperalgesia, edema, and
autonomic features indicating Complex Regional Pain Syndrome (CRPS), a particularly difficult to treat chronic
pain condition. The mechanisms of post-TKA chronic pain and CRPS are not well understood. The most
common TKA procedure involves application of a tourniquet to the operated limb for extended periods (up to
≈2 hours). Animal models indicate that extended tourniquet application followed by reperfusion when the
tourniquet is removed leads to ischemic reperfusion injury, which via increased oxidative stress, can result in
prolonged neuropathic pain and clinical features of CRPS. One key objective of this project is to examine for
the first time in humans the impact of baseline and perioperative oxidative stress, as indexed by F2-
isoprostanes, on long-term pain, CRPS, and functional outcomes following TKA. One known predictor of post-
TKA chronic pain is greater preoperative negative affect (specifically, depression and anxiety). Emerging
literature suggests that elevated depression and anxiety may be associated with elevated oxidative stress
levels. The proposed project will test a novel theoretical model that integrates these disparate research areas
by determining whether the influence of depression and anxiety on post-TKA chronic pain outcomes is
conveyed in part through oxidative stress mechanisms. If hypotheses are supported, results will highlight a
novel mechanism of post-surgical chronic pain and CRPS that is potentially amenable to pre-emptive
intervention, and enhance understanding of mechanisms through which psychosocial factors impact on
subsequent postsurgical pain-related and functional outcomes. The project team will be comprised of
investigators with complementary multidisciplinary expertise in chronic pain, CRPS, measurement and health
effects of oxidative stress, TKA procedures, and prospective study designs. The proposed study will enroll 150
unilateral TKA patients all experiencing similar tissue trauma during the course of surgery. Pain, CRPS
symptomatology (using a validated continuous CRPS severity score), depression and anxiety symptoms,
function, and plasma levels of F2-isoprostanes will be systematically assessed at pre-TKA baseline,
intraoperatively, for two days post-surgically, and at 6 week and 6 month follow-up. Analyses will utilize the
prospective nature of the data to examine the impact of baseline and perioperative oxidative stress on
subsequent chronic pain, CRPS, and functional outcomes. Mediation analyses will be used to test whether
depression and anxiety impact on long-term post-TKA pain, CRPS, and function in part via oxidative stress
mechanisms. Results have the potential to enhance understa...

## Key facts

- **NIH application ID:** 9882925
- **Project number:** 5R01AG048915-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Stephen Bruehl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $472,591
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882925

## Citation

> US National Institutes of Health, RePORTER application 9882925, Psychosocial and Oxidative Stress Mechanisms of Post-Surgical Chronic Pain (5R01AG048915-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9882925. Licensed CC0.

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