ZYNRELEF for Postoperative Knee Pain

Overseen By Charles M Lawrie, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Baptist Health South Florida

Must not be taking: Antidepressants, Gabapentin, Pregabalin, others

Disqualifiers: Inflammatory arthritis, CKD, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 1

242 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new pain relief method for individuals undergoing total knee replacement surgery. Researchers aim to determine if Zynrelef, a combination of bupivacaine and meloxicam, better controls pain and reduces the need for opioids after surgery. Participants will either receive this new pain relief treatment or follow the usual pain management process post-surgery. This trial targets adults with knee osteoarthritis who plan to have knee replacement surgery and are expected to go home the same day. As a Phase 4 trial, this research seeks to understand how the already FDA-approved and effective treatment benefits a broader patient population.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications like amitriptyline, nortriptyline, gabapentin, pregabalin, duloxetine, des-venlafaxine, cyclobenzaprine, and baclofen to participate in this trial.

What is the safety track record for Zynrelef?

Research has shown that Zynrelef, a combination of bupivacaine and meloxicam, has been used safely in various surgeries. In one study, 1,627 patients undergoing different types of surgeries used Zynrelef, and it proved to be safe. The FDA has approved this treatment for surgeries like bunion removal and hernia repair, indicating its general safety. Another study demonstrated that people using Zynrelef experienced better pain relief than those using only bupivacaine, without major safety issues. Overall, evidence suggests that Zynrelef is well-tolerated. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about ZYNRELEF for postoperative knee pain because it combines Bupivacaine and Meloxicam into a single, extended-release injectable solution. Unlike standard treatments that often require multiple doses or types of medication for pain management, this combo aims to provide long-lasting relief with just one administration directly at the surgical site. This innovative delivery method could mean more effective pain control with fewer side effects and less reliance on oral painkillers.

What evidence suggests that Zynrelef might be an effective treatment for postoperative knee pain?

In this trial, participants in the intervention arm will receive Zynrelef, a combination of bupivacaine and meloxicam, to control pain after surgery. Research has shown that Zynrelef provides superior pain relief for up to 72 hours post-surgery compared to bupivacaine alone. This means Zynrelef can significantly reduce pain in the days following surgery. Additionally, evidence suggests that Zynrelef reduces the need for opioid pain medication after surgery, which helps avoid the side effects and risks associated with opioids. These findings support Zynrelef's effectiveness in managing pain after knee replacement surgery. Participants in the standard-of-care arm will receive the usual procedure for knee replacement and pain management. ^{1 2 4 5 6}

Who Is on the Research Team?

Juan C Suarez, MD

Principal Investigator

Baptist Health South Florida

Are You a Good Fit for This Trial?

This trial is for adults aged 35-70 with primary osteoarthritis planning a total knee replacement. Eligible participants must have a BMI under 40, be discharged the same day as surgery, and have certain limits on knee deformity. Exclusions include inflammatory arthritis, kidney disease, uncontrolled diabetes, liver disease, mental health disorders, allergies to specific drugs including NSAIDs and local anesthetics, prior significant knee surgeries or conditions that affect walking.

Inclusion Criteria

I have been diagnosed with primary osteoarthritis.

You are not extremely overweight.

Your leg is not bent inward by more than 10 degrees.

Exclusion Criteria

I am not allergic to local anesthetics, NSAIDs, or any components of the study drug.

My blood sugar levels are not well-controlled (HbA1c > 8.0%).

I have not used narcotics or tramadol in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgical Procedure and Treatment

Participants undergo total knee replacement surgery and receive either standard care or Zynrelef for pain management

1 day

1 visit (in-person)

Immediate Post-Surgery Monitoring

Participants are monitored for pain control and opioid consumption for 5 days following surgery

5 days

Follow-up

Participants are monitored for safety and effectiveness, including incidence of major complications, for 42 days following surgery

42 days

What Are the Treatments Tested in This Trial?

Interventions

• Bupivacaine
• Meloxicam

Trial Overview The study tests Zynrelef (a bupivacaine-meloxicam injectable solution) for pain management after total knee replacement surgery. It aims to see if Zynrelef can control pain better and reduce opioid use compared to standard care in the days following surgery. Participants are randomly assigned to receive either Zynrelef or usual postoperative care.

How Is the Trial Designed?

Group I: Intervention Experimental Treatment 1 Intervention

In addition to the standard-of-care arm description, single administration of Bupivacaine-Meloxicam 400 Mg-12 Mg/14 mL Injectable Solution, Extended Release in the surgical site before complete wound closure.

Group II: Standard-of-care Active Control 1 Intervention

Usual standard of care procedure for knee replacement and pain management before, during and immediately following surgery.

Who Is Running the Clinical Trial?

Baptist Health South Florida

Lead Sponsor

Trials

54

Recruited

8,100+

Published Research Related to This Trial

The combination of bupivacaine (BVC) and meloxicam (MLX) provides effective postoperative pain relief for up to 72 hours, reducing the need for opioids and managing pain better than BVC alone.

New spectrophotometric methods were developed for the simultaneous analysis of BVC and MLX, using eco-friendly solvents, which are user-friendly and require minimal data processing, marking a significant advancement in pharmaceutical analysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manipulation and Processing of Spectral Signals for the Assay of the Newly Authorized Mixture of Bupivacaine/Meloxicam Using Fully Green Solvents and a Comparative Green Evaluation Supporting the Greenness and Sustainability of the Developed Smart Spectrophotometric Methods. Bahgat, EA., Hashem, H., Saleh, H., et al.[2023]

Sustained-release buprenorphine (Bup-SR) and buprenorphine HCl (Bup HCl) effectively reduced both mechanical and thermal hypersensitivity in rats after surgery, indicating strong analgesic efficacy.

In contrast, sustained-release meloxicam (Melox-SR) and carprofen gel (CG) only alleviated mechanical hypersensitivity and did not affect thermal sensitivity, suggesting that not all analgesics are equally effective for different types of pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative Analgesia Due to Sustained-Release Buprenorphine, Sustained-Release Meloxicam, and Carprofen Gel in a Model of Incisional Pain in Rats (Rattus norvegicus). Seymour, TL., Adams, SC., Felt, SA., et al.[2018]

In a study of 128 knee osteoarthritis patients undergoing total knee arthroplasty, meloxicam significantly reduced postoperative pain at various time points (6h, 12h, D1, D2, D3) compared to a placebo, leading to higher patient satisfaction scores.

Meloxicam did not impact long-term knee function recovery or increase the risk of adverse events, indicating it is a safe and effective option for managing postoperative pain in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of analgesic effect, joint function recovery and safety of meloxicam in knee osteoarthritis patients who receive total knee arthroplasty: A randomized, controlled, double-blind study. Hu, F., Wu, G., Zhao, Q., et al.[2023]

In a study of 42 knee osteoarthritis patients undergoing total knee arthroplasty, periarticular injections with multimodal drugs significantly reduced post-operative pain, as indicated by lower visual analog scores (VAS) and reduced morphine usage compared to a control group.

The injection group also experienced significantly less blood loss post-operation (263.8 ml) compared to the control group (362.1 ml), demonstrating the efficacy of this pain management strategy without significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-op pain and blood loss in total knee arthroplasty: an RCT using periarticular injection with diclofenac-based multimodal drugs. [2018]

Intra-articular administration of Bupivacaine, Bupivacaine plus midazolam, and Bupivacaine plus fentanyl effectively reduced post-operative pain after knee arthroscopic surgery in a study of 35 patients.

While all combinations provided analgesia, the combination of Bupivacaine plus fentanyl resulted in the least need for additional pain relief, indicating it may offer superior pain management compared to Bupivacaine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesia Following Arthroscopy - a Comparison of Intra-articular Bupivacaine and/or Midazolam and or Fentanyl. Nahravani, M., Tekye, SM., Alipour, M., et al.[2022]

In a study involving 26 female dogs undergoing laparoscopic surgery, meloxicam was found to be more effective than robenacoxib in managing postoperative pain, with significantly lower pain scores at 24 hours post-surgery.

Only 2 dogs treated with meloxicam required additional pain relief compared to 7 dogs treated with robenacoxib, indicating that meloxicam provides better pain control in this surgical context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meloxicam vs robenacoxib for postoperative pain management in dogs undergoing combined laparoscopic ovariectomy and laparoscopic-assisted gastropexy. Bendinelli, C., Properzi, R., Boschi, P., et al.[2019]

Intravenous (IV) meloxicam, a COX-2 inhibitor, has been shown to significantly reduce post-operative pain and decrease the need for opioids, based on recent clinical trials.

The review indicates that meloxicam IV is an effective and well-tolerated option for managing moderate to severe pain during the perioperative period, addressing limitations of oral formulations that have a slow onset of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meloxicam in the management of post-operative pain: Narrative review. Bekker, A., Kloepping, C., Collingwood, S.[2020]

In a study of 30 patients undergoing knee surgery, the addition of hyalase to a treatment regimen of ketorolac, marcaine, and triamcinolone resulted in approximately 30% better pain scores and significantly less pain over time, particularly from six to twelve months post-surgery.

Patients receiving hyalase also experienced a greater increase in range of motion during the same period, suggesting that hyalase not only improves pain control but may also enhance recovery outcomes after knee surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of intra-articular hyalase, Ketorolac, marcaine and triamcinolone, versus Ketorolac, marcaine and triamcinolone for reducing knee joint pain other than joint replacement. Daneshian, M., Montazemi, M., Abbaskhani Davanloo, A.[2022]

Bupivacaine/meloxicam PR (Zynrelef®) is an effective treatment for postoperative pain, significantly reducing pain and opioid consumption compared to bupivacaine hydrochloride and placebo in clinical trials involving surgeries like bunionectomy and total knee arthroplasty.

This combination medication, which releases its active ingredients over 72 hours, was generally well tolerated and associated with fewer opioid-related side effects, making it a promising non-opioid option for pain management after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupivacaine/Meloxicam Prolonged Release: A Review in Postoperative Pain. Blair, HA.[2021]

In a study of 63 patients undergoing knee arthroscopy, the combination of ropivacaine, morphine, and ketorolac provided significantly better pain relief compared to bupivacaine or ropivacaine alone, especially at 8 and 24 hours post-surgery.

The combination treatment not only reduced the need for additional pain medication but also improved patients' daily activities and satisfaction without increasing side effects, indicating a safer and more effective pain management strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of intra-articular bupivacaine, ropivacaine, or a combination of ropivacaine, morphine, and ketorolac on postoperative pain relief after ambulatory arthroscopic knee surgery: a randomized double-blind study. Ng, HP., Nordström, U., Axelsson, K., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40711999/

A Randomized Clinical Trial Showing Similar Efficacy in ... Results: Similar postoperative analgesia was observed, with an AUC for the adjusted NRS pain score up to 72 hours of 331 in the experimental ...

2. zynrelef.com zynrelef.com/efficacy-pain-reduction/

72 Hours of Postoperative Pain Relief ZYNRELEF patients experienced superior pain relief through 72 hours compared to patients receiving bupivacaine HCl solution.

3. sciencedirect.com sciencedirect.com/science/article/pii/S2352344125000913

A Novel Extended-Release Analgesic Without Periarticular ... PAI offered comparable immediate postoperative pain relief to the combination of PAI and the ER analgesic solution in both NRS Pain Intensity Scores (mean (SD) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11064821/

Safety and Efficacy of Zynrelef® in Combination with a Single ... This study provides evidence that the combination of a single unilateral or bilateral nerve block with Zynrelef is safe.

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/53/NCT05188053/Prot_SAP_000.pdf

Periarticular Bupivacaine + Meloxicam ER Solution Versus ... The purpose of this study is to examine the efficacy of a recent FDA approved medication: bupivacaine +low dose meloxicam extended release (ER) solution (HTX- ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2024/211988Orig1s013.pdf

211988Orig1s013 | FDA The safety of ZYNRELEF has been evaluated in a total of 1627 patients undergoing various surgical procedures across 14 clinical studies ...