GlyNAC for Postoperative Pain After Knee Replacement

Overseen By Gail Mayo, RN

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Vanderbilt University Medical Center

Disqualifiers: Neuropathy, Heart disease, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

148 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two antioxidants, glycine and N-acetyl-cysteine (GlyNAC), to determine if it can reduce oxidative stress and chronic pain after knee replacement surgery. Researchers aim to discover whether taking GlyNAC before and after surgery improves pain and function over a year. Participants will receive either GlyNAC or a placebo, a harmless pill resembling the real treatment. Individuals with osteoarthritis who experience significant knee pain and plan to undergo knee replacement surgery might be suitable for this trial. As a Phase 4 trial, this research involves an FDA-approved treatment and seeks to understand its benefits for more patients.

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.

What is the safety track record for GlyNAC?

Research shows that GlyNAC, a combination of glycine and N-acetyl-cysteine, is generally safe for people. N-acetyl-cysteine (NAC), one component of GlyNAC, already protects cells and treats acetaminophen overdose, indicating good tolerance.

Glycine, the other component, is a common amino acid found in many foods. Previous animal studies suggest that GlyNAC might protect tissues and aid recovery. While these animal studies are promising, human studies are needed to fully understand its safety.

Since this trial is in a later stage, earlier studies likely provided some evidence of GlyNAC's safety in humans. Overall, the data so far suggests that GlyNAC is safe, but ongoing research will continue to monitor its effects. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Most treatments for postoperative pain after knee replacement, such as opioids and NSAIDs, work by blocking pain signals or reducing inflammation. But GlyNAC works differently, targeting oxidative stress and inflammation at a cellular level. It combines glycine and N-acetylcysteine, which are antioxidants that might help speed up recovery and reduce pain by improving cellular health. Researchers are excited about GlyNAC because it has the potential to offer pain relief with fewer side effects compared to traditional painkillers.

What evidence suggests that GlyNAC might be an effective treatment for postoperative pain after knee replacement?

This trial will evaluate GlyNAC, a combination of glycine and N-acetylcysteine, for its potential to reduce stress on the body and chronic pain after knee replacement surgery. Researchers believe this antioxidant mix protects tissues and aids recovery. Animal studies have shown it supports the health of the spinal cord and muscles. Participants in this trial may receive GlyNAC, which could help reduce pain and improve movement by addressing stress linked to long-term pain. Although complete data from human studies is not yet available, these early results are promising for reducing pain after knee surgery. ^{1 2 3 6 7}

Who Is on the Research Team?

Stephen Bruehl, Ph.D.

Principal Investigator

Vanderbilt University Medical Center

Frederic T Billings, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• GlyNAC
• Placebo

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.

How Is the Trial Designed?

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.

GlyNAC is already approved in United States for the following indications:

Approved in United States as CelltrientTM Cellular Protect for:

• None specifically approved; used as a dietary supplement for various health conditions

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-4-osteoarthritis-knee-2-2024-fdccc

GlyNAC for Postoperative Pain After Knee Replacement 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06083480

NCT06083480 | Reducing Perioperative Oxidative Stress ... 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 ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06083480/reducing-perioperative-oxidative-stress-to-prevent-postoperative-chronic-pain-following-total-knee-arthroplasty

Reducing Perioperative Oxidative Stress to Prevent ... ... -acetyl-cysteine(GlyNAC)) reduces oxidative stress and chronic post surgical pain (CPSP) in patients undergoing total knee arthroplasty (TKA).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11074018/

The Effect of Glycine and N-Acetylcysteine on Oxidative Stress ... These findings suggested that GlyNAC can protect spinal cord tissue, delay skeletal muscle atrophy, and promote functional recovery in rats ...

5. trial.medpath.com trial.medpath.com/clinical-trial/593100d5c1c7f6b5/nct06083480-reducing-perioperative-oxidative-stress-prevent-postoperative-chronic-pain-total-knee

Reducing Perioperative Oxidative Stress to Prevent ... - MedPath 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 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06083480?term=gly%20200&viewType=Table&checkSpell=&rank=2

Reducing Perioperative Oxidative Stress to Prevent ... 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 ...

7. webmd.com webmd.com/vitamins/ai/ingredientmono-1018/n-acetyl-cysteine-nac

N-Acetyl Cysteine (Nac) – Uses, Side Effects, and More N-acetyl cysteine (NAC) comes from the amino acid L-cysteine. Amino acids are building blocks of proteins. NAC has many uses and is an FDA approved drug.