ZYNRELEF for Pain Management in Total Knee Arthroplasty

A Randomized Controlled Trial of ZYNRELEF Versus Standard of Care for Pain Management Following Unilateral Total Knee Arthroplasty

The goal of this randomized controlled trial is to compare opioid medication consumption after surgery for patients who have a total knee replacement.

The main questions it aims to answer are:

• How well does the study drug control pain in the days after surgery?
• Does the study drug reduce the amount of opioid analgesic consumed after surgery?

Participants in the study group will undergo a total knee replacement as planned with their surgeon. In addition, be given the study drug, Zynrelef (combination of bupivacaine and meloxicam).

Researchers will compare the above to a control group who will have a total knee replace only according to usual standards to see if there are any differences in the amount of a type of pain medication (opioid analgesic) consumed in the days following surgery.

Study Overview

• Status: Terminated
• Conditions: Osteoarthritis, Knee; Post Operative Pain
• Intervention / Treatment: Drug: Bupivacaine-Meloxicam 400 Mg-12 Mg/14 mL Injectable Solution, Extended Release

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33146
      • Doctors Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult patients undergoing primary unilateral total knee arthroplasty [Current Procedural Terminology Code: 27447]
2. Patients with a diagnosis of primary osteoarthritis [ICD-10 codes: M17.0, M17.10, M17.11, M17.12]
3. Varus deformity less than 10 degrees
4. Flexion contracture less than 10 degrees
5. Age 35 - 70 years old
6. BMI < 40
7. Patients who are discharged on the same day after the unilateral total knee arthroplasty procedure

Exclusion Criteria:

1. Inflammatory arthritis
2. Post-traumatic arthritis
3. Valgus deformity
4. Severe varus (> 10 degrees)
5. Severe flexion contracture (> 10 degrees)
6. Overnight or longer hospital stay after surgery
7. Prior surgery on affected knee other than knee arthroscopy for meniscal or cartilage debridement/repair
8. Creatinine > 1.2
9. Chronic Kidney Disease (CKD) stage 3, 4, 5 or end stage renal disease
10. Uncontrolled Diabetes mellitus (Glycated Hemoglobin > 8.0%)
11. Current liver disease
12. Personal history of depression or anxiety disorder
13. Personal history of Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE)
14. Narcotic or tramadol use within 2 weeks of the planned procedure
15. Allergy to aspirin, NSAIDS, oxycodone, Tylenol, local anesthetics
16. Walking aid for anything other than the operative joint

17. Contraindication for use of the study drug (as specified by the manufacturer):

    • Known hypersensitivity to local amide anesthetics, NSAIDs or study drug components
    • History of asthma, urticaria or other allergic-type reactions to aspirin or other NSAIDs

18. Patients taking the following medications:

    • Amitriptyline
    • Nortriptyline
    • Gabapentin
    • Pregabalin
    • Duloxetine (SNRI)
    • Des-Venlafaxine (SNRI)
    • Cyclobenzaprine
    • Baclofen
19. Pregnant or lactating females
20. Patients unable to provide informed consent
21. Subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Bupivacaine-Meloxicam 400 Mg-12 Mg/14 mL Injectable Solution, Extended Release; Instillation of the drug into the knee joint capsule and surrounding tissues after placing the knee prosthesis and before close of the surgical wound; Other Names: Zynrelef
No Intervention: Standard-of-care; Usual standard of care procedure for knee replacement and pain management before, during and immediately following surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total opioid analgesic consumption	Amount of opioid analgesic consumed in the time frame calculated as Morphine Milligram Equivalent (MME).	5 days following surgical procedure
Change in pain assessment scores	Pain assessment scores using the pain Numeric Rating Scale for pain (NRS). The NRS scale is measured on a scale of 0 - 10, where 0 is no pain and 10 is the most severe pain.	Baseline and every 24 hours for 120 hours following surgical procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of major complications	Number of procedure-related adverse events and medication-related adverse events.	42 days following surgical procedure

Collaborators and Investigators

• Sponsor: Baptist Health South Florida
• Investigators: Principal Investigator: Juan C Suarez, MD, Baptist Health South Florida

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2023
• Primary Completion (Actual): December 19, 2025
• Study Completion (Actual): December 19, 2025

Study Registration Dates

• First Submitted: November 11, 2022
• First Submitted That Met QC Criteria: December 7, 2022
• First Posted (Actual): December 9, 2022

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Knee Arthroplasty; Postoperative pain management
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Musculoskeletal Diseases; Postoperative Complications; Pathologic Processes; Arthritis; Joint Diseases; Rheumatic Diseases; Osteoarthritis; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain, Postoperative; Osteoarthritis, Knee; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antirheumatic Agents; Anesthetics, Local; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Cyclooxygenase 2 Inhibitors; bupivacaine-meloxicam drug combination
• Other Study ID Numbers: 1891382

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes