GlyNAC for Postoperative Pain After Knee Replacement

Overseen By Gail Mayo, RN

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Vanderbilt University Medical Center

Disqualifiers: Neuropathy, Heart disease, Pregnancy, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is GlyNAC safe for humans?

N-Acetylcysteine (NAC), a component of GlyNAC, is generally considered safe for humans and is used to protect cells from damage and treat acetaminophen overdose. It has been studied for various conditions, including pain management and knee osteoarthritis, without significant safety concerns. ^{1 2 3 4 5}

How does the drug GlyNAC differ from other treatments for postoperative pain after knee replacement?

GlyNAC is unique because it combines glycine and N-acetylcysteine, which are thought to work together to reduce oxidative stress and inflammation, potentially offering a novel approach to managing postoperative pain compared to traditional pain relief methods like opioids or nerve blocks. ^{6 7 8 9 10}

Research Team

Stephen Bruehl, Ph.D.

Principal Investigator

Vanderbilt University Medical Center

Frederic T Billings, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for individuals over 50 with osteoarthritis who are experiencing significant pain and are scheduled for total knee replacement surgery. They must be able to understand and consent to the study, as well as complete questionnaires in English. People with pregnancy, vascular diseases, autoimmune disorders, cancer, neuropathy, untreated thyroid or heart conditions, certain liver or kidney issues, or other significant chronic pains are not eligible.

Inclusion Criteria

I am 50 years old or older.

I am mentally capable of understanding and agreeing to the trial.

My worst pain in the last 24 hours was at least a 4 out of 10.

Exclusion Criteria

I have chronic pain not in my legs that's moderate or has been treated for over 3 months.

I have been diagnosed with neuropathy before.

I have untreated thyroid issues.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preoperative Treatment

Participants receive GlyNAC or placebo for four weeks prior to TKA

4 weeks

Regular monitoring visits

Perioperative Treatment

Participants continue GlyNAC or placebo for six weeks postoperatively

6 weeks

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

In-person visits at 6 weeks, 6 months, and 12 months post-TKA

Treatment Details

Interventions

• GlyNAC (Antioxidant)
• Placebo (Other)

Trial Overview The trial is testing whether a combination of antioxidants called GlyNAC (glycine and n-acetylcysteine) can reduce oxidative stress and prevent long-term chronic pain after knee replacement surgery. Participants will receive either GlyNAC or a placebo before and after their surgery in this randomized controlled study.

Participant Groups

Group I: GlyNAC (combination of glycine and n-acetylcysteine) Experimental Treatment 1 Intervention

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 II: Placebo (alanine) Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

In a study of 64 patients treated with intravenous acetylcysteine for acetaminophen toxicity, the treatment was found to be safe and effective, with only 6% of patients experiencing death and 3% requiring liver transplants.

Patients who received intravenous acetylcysteine within 8 hours of acetaminophen ingestion had significantly better outcomes, with no deaths or liver failure, and a shorter hospital stay compared to those treated later.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of acetadote for acetaminophen toxicity. Whyte, AJ., Kehrl, T., Brooks, DE., et al.[2013]

N-Acetylcysteine (NAC) effectively prevents sensory neuronal loss after peripheral nerve transection in a dose-dependent manner, with significant protection observed at doses of 10 mg/kg/day and above.

The study, using a rat model, indicates that higher doses (150 and 300 mg/kg/day) completely prevent neuronal loss, suggesting NAC has a wide therapeutic range and potential for clinical use in nerve injury recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the dose-response of N-acetylcysteine in the prevention of sensory neuronal loss after peripheral nerve injury. West, CA., Hart, AM., Terenghi, G., et al.[2019]

N-Acetylcysteine (NAC) significantly reduced pain ratings and laser-evoked potentials in healthy volunteers, indicating its potential to inhibit pain transmission in humans, although it did not change thermal-pain thresholds.

In animal studies, NAC effectively reduced nociceptive responses to heat, and its pain-relieving effects were linked to the activation of mGlu2/3 receptors, suggesting a mechanism that could be explored for treating chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive transmission in humans. Truini, A., Piroso, S., Pasquale, E., et al.[2018]

In a clinical trial with 20 patients suffering from mild to moderate knee osteoarthritis, intra-articular N-acetyl cysteine (NAC) was found to be as effective as hyaluronic acid (HA) in reducing pain and improving function, as measured by the WOMAC and VAS scores.

NAC showed superior effectiveness in lowering specific cartilage degradation markers (C-6S and CTX-II) compared to HA, suggesting it could be a more cost-effective treatment option for knee OA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Intra-articular Injection of Hyaluronic Acid and N-Acetyl Cysteine in the Treatment of Knee Osteoarthritis: A Pilot Study. Ozcamdalli, M., Misir, A., Kizkapan, TB., et al.[2022]

A systematic review of nine studies involving 863 participants found that N-acetylcysteine did not significantly reduce pain intensity or improve functional outcomes in chronic pain conditions, suggesting limited efficacy.

Due to inconsistent reporting of adverse events, the safety profile of N-acetylcysteine in chronic pain management remains unclear, highlighting the need for larger randomized controlled trials to better assess its role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review and Meta-Analysis. Mohiuddin, M., Pivetta, B., Gilron, I., et al.[2022]

In a study of 75 patients aged 50-85 undergoing total knee arthroplasty, the adductor-canal-blockade using ropivacaine significantly reduced morphine consumption in the first 24 hours post-surgery (40 mg vs. 56 mg for placebo, P=0.006).

Patients receiving the adductor-canal-blockade also experienced significantly less pain during knee flexion and were able to ambulate faster in the Timed-Up-and-Go test (36 seconds vs. 50 seconds for placebo, P=0.03), indicating improved recovery outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty: a randomized study. Jenstrup, MT., Jæger, P., Lund, J., et al.[2022]

In a study of 60 patients undergoing total knee arthroplasty, computer-assisted cryotherapy (CAC) at 10-12 °C significantly reduced pain levels and opioid consumption compared to a warmer control group during the first 4 postoperative days.

Patients in the Cold-group used an average of 47 opioid tablets, while those in the Warm-group used 83, indicating that CAC can effectively enhance pain management following knee surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced opiate use after total knee arthroplasty using computer-assisted cryotherapy. Thijs, E., Schotanus, MGM., Bemelmans, YFL., et al.[2020]

In a study of 53 patients recovering from total knee arthroplasty, the lidocaine patch 5% did not provide significant additional pain relief compared to a control group, although it was well-received by patients with 94% reporting satisfaction.

While the control group showed better pain relief on day 3 post-surgery, both groups experienced similar overall pain improvements by the end of their hospital stay, indicating that the lidocaine patch may not enhance postoperative pain management significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating pain with the lidocaine patch 5% after total knee arthroplasty. Khanna, M., Peters, C., Singh, JR.[2013]

The adductor canal block using ropivacaine significantly reduced pain during knee flexion at 4 hours post-surgery compared to placebo, with a mean difference of 19 mm in pain scores (P = 0.04).

Despite the reduction in pain during flexion, there were no significant differences in pain at rest, morphine consumption, or morphine-related side effects between the ropivacaine and placebo groups, indicating that while the block may help with movement pain, it does not affect overall pain management or opioid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adductor canal block for postoperative pain treatment after revision knee arthroplasty: a blinded, randomized, placebo-controlled study. Jæger, P., Koscielniak-Nielsen, ZJ., Schrøder, HM., et al.[2019]

The adductor-canal-blockade using ropivacaine significantly reduced pain during knee flexion in the early post-operative period after total knee arthroplasty, as shown by a lower area under the curve for pain scores compared to placebo.

While there were no significant differences in pain at rest or overall morphine consumption, the ropivacaine group did experience less nausea, indicating potential benefits in managing side effects related to pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of adductor-canal-blockade on established, severe post-operative pain after total knee arthroplasty: a randomised study. Jaeger, P., Grevstad, U., Henningsen, MH., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of acetadote for acetaminophen toxicity. [2013]

2. Austria pubmed.ncbi.nlm.nih.gov

Analysis of the dose-response of N-acetylcysteine in the prevention of sensory neuronal loss after peripheral nerve injury. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive transmission in humans. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Comparison of Intra-articular Injection of Hyaluronic Acid and N-Acetyl Cysteine in the Treatment of Knee Osteoarthritis: A Pilot Study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review and Meta-Analysis. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty: a randomized study. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Reduced opiate use after total knee arthroplasty using computer-assisted cryotherapy. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Treating pain with the lidocaine patch 5% after total knee arthroplasty. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Adductor canal block for postoperative pain treatment after revision knee arthroplasty: a blinded, randomized, placebo-controlled study. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Effect of adductor-canal-blockade on established, severe post-operative pain after total knee arthroplasty: a randomised study. [2022]