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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Osteoarthritis, Knee, Total Knee Arthroplasty, Chronic Postsurgical Pain

Intervention / Treatment
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* Drug: GlyNAC (combination of glycine and n-acetylcysteine)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, controlled, mixed between/within-subject longitudinal trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GlyNAC (combination of glycine and n-acetylcysteine)<br>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. | Drug: GlyNAC (combination of glycine and n-acetylcysteine)<br>* 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.<br>* Other names: GlyNAC;|
| Placebo Comparator: Placebo (alanine)<br>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. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours | Mean within participant changes in NRS intensity ratings of worst pain in past 24 hours of measurement at 6 months post TKA. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = no pain and 100 = worst possible pain). | Baseline to 6 months post TKA (approximately 7 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours | Mean within participant changes in NRS intensity ratings of worst pain in past 24 hours of measurement. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = no pain and 100 = worst possible pain) | Baseline to 6 weeks and 12 months post TKA (13 months) | 
| Numeric Rating Scale of Average Pain in the past 24 hours | Mean within participant changes in NRS intensity ratings of average pain in past 24 hours of measurement. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = no pain and 100 = worst possible pain). | Baseline to 6 weeks, 6 months and 12 months post TKA (13 months) | 
| Numeric Rating Scale of Least Pain in the past 24 hours | Mean within participant changes in NRS intensity ratings of least pain in past 24 hours of measurement. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = no pain and 100 = worst possible pain). | Baseline to 6 weeks, 6 months and 12 months post TKA (13 months) | 
| Mean change in McGill Pain Questionnaire-2 (MPQ-2) ratings of knee pain for average pain over past week of measurement. | Mean within participant changes in McGill Pain Questionnaire-2 (MPQ-2) ratings of knee pain for average pain over past week of measurement. The MPQ-2 score ranges from 0-10 where 0 represents no pain and 10 represents the most intense pain. | Baseline to 6 weeks, 6 months and 12 months post TKA (13 months) | 
| Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) | Mean within participant changes in KOOS-JR ratings to assess movement evoked pain and functional limitations. Scores range from 0 to 100 with a score of 0 indicating total knee disability and 100 indicating perfect knee health. | Baseline to 6 weeks, 6 months and 12 months post TKA (13 months) | 
| PROMIS Short Form V1.0 - Pain Interference 8a scale | Mean within participant changes in PROMIS Short Form V1.0 - Pain Interference 8a scale to assess pain-related life interference over the week preceding assessments. This is an 8 item questionnaire with scores ranging from 0-40. 0 indicates no pain interference and 40 indicates the highest level of pain interference. | Baseline to 6 weeks, 6 months and 12 months post TKA (13 months) | 
| Postsurgical Opioid Use (pill count) | Number of prescribed opioid pills used since hospital discharge following TKA. This is based on a combination of prescribed postsurgical opioid amounts and number of refills recorded in the electronic health record combined with pill counts conducted at each in-person post-TKA follow-up assessment. | Post-TKA discharge to 6 weeks, 6 months and 12 months post-TKA (12 months)] | 
| Postsurgical Opioid Use (days of opioid use in the past week) | Number of days opioids were used in the past week at each in-person post-TKA follow-up assessment. | 6 weeks, 6 months and 12 months post-TKA (12 months) | 
| F2-Isoprostane/Isofuran (IsoP/IsoF) levels | Changes in mean IsoP/IsoF levels from initial pre-intervention baseline. This is a measure of oxidative stress and is a mechanistic marker of the effects of the study antioxidant intervention (GlyNAC). | Baseline to 4 week pre-TKA assessment, and 6 weeks, 6 months and 12 months post TKA (13 months) | 
| Glutathione levels | Changes in mean glutathione levels from initial pre-intervention baseline. This is a measure of antioxidant capacity and is a mechanistic marker of the effects of the study antioxidant intervention (GlyNAC). | Baseline to 4 week pre-TKA assessment, and 6 weeks, 6 months and 12 months post TKA (13 months) |