The goal of this clinical trial is to learn if a non-opioid pain medicine called suzetrigine works to treat pain after total knee replacement surgery in adults. It will also learn about the safety of suzetrigine. The main questions it aims to answer are:

Does suzetrigine lower the amount of opioid pain medicine participants use after surgery?

Does suzetrigine have any effect on postoperative patient-reported outcomes, including pain scores, range of motion, length of stay, and KOOS/PROMIS surveys?

Researchers will compare suzetrigine to a placebo to see if suzetrigine works to treat pain after total knee replacement surgery.

Participants will:

Take suzetrigine or a placebo by mouth for 14 days after surgery

Receive standard pain care, including opioid pain medicine only if needed

Report their pain levels using short daily surveys

Attend routine follow-up visits after surgery

Post-operative pain management following total knee arthroplasty (TKA) continues to present significant challenges. Despite multimodal Enhanced Recovery After Surgery (ERAS) protocols, over 60% of patients still require opioid medications two weeks after surgery. Given the ongoing opioid epidemic, opioid prescribing is a priority for quality improvement in orthopaedic surgery. High opioid exposure is associated with constipation, nausea, increased risk of falls, hindered rehabilitation, and persistent opioid use. Furthermore, opioid use within the early postoperative period following TKA is associated with a dose-dependent increased risk of periprosthetic joint infection and venous thromboembolic events. With over 700,000 TKAs performed each year in the United States, these complications represent not only individual patient risks but also broader public health concerns.

Multimodal pain regimens consisting of alternative analgesics such as acetaminophen, NSAIDs, and gabapentinoids may only provide partial relief for patients, leaving opioids as the default choice for managing breakthrough pain, despite their undesirable side effect profile and addictive potential.[8] This ongoing challenge underscores the urgent need to identify safer and more effective pain management strategies.

Suzetrigine (Brand name: Journavx), a selective inhibitor of NaV1.7/NaV1.8 channels, has emerged as a promising candidate. Phase 3 clinical trials have shown that suzetrigine provides pain relief comparable to opioids, effectively reducing pain scores, with fewer adverse effects. Data from phase 2 bunionectomy studies further support its opioid-sparing capabilities. Unlike opioids, suzetrigine does not cause sedation, respiratory depression, or dependency. Its favorable pharmacokinetic properties, including renal-sparing metabolism and convenient oral twice-daily dosing, make it well-suited for integration into ERAS protocols.

The purpose of this randomized controlled trial is to assess whether suzetrigine can serve as an effective, opioid-sparing analgesic after TKA. If the results are successful, this could lead to expanded FDA labeling, wider adoption in orthopaedic practices, and a significant decrease in opioid prescriptions on a large scale.

Inclusion Criteria:

• Age 18 years or older
• Scheduled for elective, unilateral primary total knee arthroplasty
• Able to tolerate oral medications after surgery

Exclusion Criteria:

• Revision or bilateral total knee arthroplasty
• American Society of Anesthesiologists (ASA) physical status classification greater than 3
• Severe renal impairment (estimated glomerular filtration rate less than 15 mL/min/1.73 m²)
• Severe hepatic impairment (Child-Pugh Class C)
• Chronic opioid use of 30 morphine milligram equivalents per day or greater for more than 3 months
• Pregnancy or breastfeeding
• Seizure disorder or known hypersensitivity to suzetrigine
• Use of medications contraindicated with CYP3A metabolism
• Active gastrointestinal ulcer or bleeding

Individual participant data may not be shared outside the research team. The study includes sensitive health information collected under institutional review board approval, and participant consent does not include public data sharing. Data will be analyzed and reported in aggregate to protect participant privacy.