Reducing Perioperative Oxidative Stress to Prevent Postoperative Chronic Pain Following Total Knee Arthroplasty

NCT ID: NCT06083480

Last Updated: 2025-12-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 148 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-12-06
• Study Completion Date: 2029-03-31

Brief Summary

This is a prospective randomized controlled trial that will assess preoperative, perioperative, and long-term oxidative stress (OS); pain; and functional outcomes over a 12 month period and test the hypothesis that a potent antioxidant intervention (glycine + N-acetyl-cysteine(GlyNAC)) reduces oxidative stress and chronic post surgical pain (CPSP) in patients undergoing total knee arthroplasty (TKA).

Detailed Description

One of the most common surgical procedures performed in older adults is total knee arthroplasty (TKA), with an estimated 1 million TKAs performed annually in the United States. TKA directly addresses the pathology underlying knee joint pain and mobility limitations resulting from osteoarthritis. For most patients, TKA is effective for pain reduction and increasing function. However, a subgroup of 15-20% of TKA patients report unsatisfactory long-term pain outcomes well after postsurgical healing has occurred despite technical success of the procedure. Chronic postsurgical pain (CPSP) following TKA has been reported to be worse than the preoperative pain in 7% of TKA patients at up to 4-years. A potential biological mechanism is perioperative oxidative stress (OS),

The proposed project seeks to confirm the mechanistic role of OS in post-TKA CPSP and test the hypothesis that a perioperative intervention to reduce OS may reduce risk for CPSP post-TKA. This is a prospective randomized controlled trial that will assess preoperative, perioperative, and long-term oxidative stress (OS); pain; and functional outcomes over a 12 month period and test the hypothesis that a potent antioxidant intervention (GlyNAC) reduces OS and CPSP in patients undergoing total knee arthroplasty (TKA).

Conditions

Osteoarthritis, Knee; Total Knee Arthroplasty; Chronic Postsurgical Pain

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

GlyNAC (combination of glycine and n-acetylcysteine)

GlyNAC 200 mg/kg/day (100mg glycine and 100mg N-acetyl-cysteine) will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively. The preparation will be a commercially available product of 1:1 ratio of glycine and N-acetyl-cysteine.

Group Type: EXPERIMENTAL

GlyNAC (combination of glycine and n-acetylcysteine)

Intervention Type: DRUG

GlyNAC 200 mg/kg/day (100mg glycine and 100mg N-acetyl-cysteine) will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively. The preparation will be a commercially available product of 1:1 ratio of glycine and N-acetyl-cysteine.

Placebo (alanine)

Placebo (alanine) 200 mg/kg/day will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo (alanine) 200 mg/kg/day will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively.

Interventions

GlyNAC (combination of glycine and n-acetylcysteine)

GlyNAC 200 mg/kg/day (100mg glycine and 100mg N-acetyl-cysteine) will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively. The preparation will be a commercially available product of 1:1 ratio of glycine and N-acetyl-cysteine.

Intervention Type: DRUG

Placebo

Placebo (alanine) 200 mg/kg/day will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively.

Intervention Type: DRUG

Other Intervention Names

GlyNAC

Eligibility Criteria

Inclusion Criteria

• Age 50 or older
• Intact cognitive status and ability to provide informed consent (based on cognitive screening with the Mini Mental State Examination)
• Ability to read and write in English sufficiently to understand and complete study questionnaires
• Undergoing unilateral primary TKA
• Medical diagnosis of osteoarthritis
• Past 24 hour worst numeric rating scale (NRS) pain of at least 4/10.

Exclusion Criteria

• Diagnosis of pre-existing neuropathy
• Untreated hypo/hyperthyroidism
• Untreated heart disease
• Alanine transaminase/aspartate transaminase >2x upper-limit of normal range
• serum creatinine >1.5 mg/dl
• Pregnancy
• Complex Regional Pain Syndrome (CRPS) diagnosis prior to undergoing TKA
• Presence of lower extremity vascular disease, inflammatory or autoimmune disorders, or malignancy
• Presence of current clinically significant chronic pain conditions outside of the lower extremity ( daily pain for >3 months and greater ≥3/10 in intensity or the focus of medical care)
• Presence of other medical conditions that in the opinion of the orthopedic surgeon co-investigators would make a patient's study participation unsafe

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Stephen Bruehl, PhD

Professor of Anethesiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Stephen Bruehl, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Frederic T Billings, IV, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Stephen Bruehl, Ph.D.

Role: CONTACT

stephen.bruehl@vumc.org

(615) 936-1821

Gail Mayo, RN

Role: CONTACT

gail.mayo@vumc.org

615-936-1705

Facility Contacts

Stephen Bruehl, PhD

Role: primary

Other Identifiers

1R01AG085287-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

231668

Identifier Type: -

Identifier Source: org_study_id