The goal of this clinical trial is to find out which type of steroid medicine, when added to a standard pain-control injection during total knee replacement surgery, works best at reducing pain, limiting opioid use, and improving recovery in adults undergoing surgery for severe knee arthritis or injury.

The main questions it aims to answer are:

Does adding a steroid to the injection improve pain control and reduce opioid use after surgery? Is the newer extended-release steroid (Zilretta) more effective and safer-especially for patients with diabetes-than the traditional steroid (methylprednisolone)?

Researchers will compare:

Standard pain-control injection alone Standard injection plus methylprednisolone Standard injection plus Zilretta to see which option provides better pain relief, less opioid use, and improved knee function.

(Patients with diabetes or prediabetes will only be in the standard injection or Zilretta groups so researchers can study whether Zilretta is safer for blood sugar control.)

Participants will:

Be randomly assigned to one of the study groups during their total knee replacement surgery Receive the assigned pain-control injection around the knee joint

Be followed after surgery to measure:

Pain levels Opioid pain medication use Knee movement (range of motion) Whether another procedure (such as manipulation under anesthesia) is needed if the knee becomes too stiff Patient-reported outcome surveys about pain and function

Total knee replacement surgery (also called total knee arthroplasty, or TKA) is a common procedure for people with severe knee arthritis or injury. While the surgery often leads to significant pain relief and improved mobility, the days and weeks afterward can be uncomfortable. Managing pain during recovery is important-not just to make patients feel better, but also to help them move their knee sooner, avoid excessive use of opioid medications, and get back to normal activities faster.

One common pain management tool is called a pericapsular injection (PAI). This is a mixture of medications injected around the knee joint during surgery to help control pain after the operation. PAIs usually include a long-lasting numbing medicine, an anti-inflammatory drug, and sometimes other medications that improve pain relief. Corticosteroids-powerful anti-inflammatory drugs-are sometimes added, but the best type of steroid and the ideal way to give it is still debated among doctors.

Why This Study Is Being Done This study will compare two types of corticosteroids, methylprednisolone (a traditional steroid) and Zilretta (a newer, extended-release form of the steroid triamcinolone), to see which works better when added to the standard PAI. Zilretta releases medication slowly over time, which may lead to longer-lasting pain control and fewer side effects such as temporary increases in blood sugar-something especially important for people with diabetes.

How the Study Works

Patients having total knee replacement will be randomly placed into one of three groups:

1. Standard PAI only - This mixture includes a long-acting numbing medicine, an anti-inflammatory (ketorolac), a small dose of adrenaline (epinephrine), clonidine (to help with pain control), and sterile saline.
2. Standard PAI + methylprednisolone - The same standard mixture with the addition of 40 mg of methylprednisolone.
3. Standard PAI + Zilretta - The same standard mixture with 32 mg of Zilretta, the extended-release steroid.

People with diabetes or prediabetes will only be placed in groups 1 or 3 so researchers can compare how Zilretta affects them compared to no steroid at all.

What Will Be Measured

The researchers will check patients' progress at several points after surgery to investigate:

• Pain levels
• Opioid pain medication use (measured in morphine-equivalent doses)
• Knee movement (range of motion)
• Need for further procedures (such as manipulation under anesthesia, or MUA, if the knee becomes too stiff)
• Patient-reported outcome surveys (including the Knee Injury and Osteoarthritis Outcome Score and the Single Assessment Numeric Evaluation) Expected Findings

The team believes that adding a corticosteroid to the PAI will:

• Improve pain control
• Reduce the need for opioid medications
• Lower the risk of needing a manipulation procedure to improve range of motion They also expect that Zilretta, because it lasts longer, will work better than methylprednisolone-especially in people with diabetes, by offering pain relief without causing as much temporary increase in blood sugar.

Why This Matters Past research shows that PAIs can help reduce pain and the need for opioids after knee replacement surgery, without raising the risk of infection or other serious complications. But doctors still don't know which steroid is best to use. If Zilretta works better and causes fewer side effects, it could become the preferred option for many patients-particularly those with other health issues like diabetes.

The results of this study could help guide surgeons toward the safest and most effective pain control strategies for people recovering from knee replacement surgery, ultimately leading to better recoveries, fewer complications, and improved quality of life.

Inclusion Criteria:

• Patients within the MHS who are DEERS eligible undergoing primary TKA at Walter Reed National Military Medical Center (WRNMMC), Surgery Center of Chevy Chase or District Surgery Center
• Age 18 or older
• successful surgical intervention

Exclusion Criteria:

• Unicompartmental knee arthroplasty (UKA)
• Revision total knee arthroplasty (rTKA)
• Females who are pregnant or nursing
• Allergic to ingredients in PAI or previous adverse reaction to steroids being used in this study
• Diabetics will be excluded from Group 2 (standard PAI + methylprednisolone)

Research participants will be randomized to one of three groups unless they are diabetic or pre-diabetic then they will be randomized to one of 2 groups (Group 1 or Group 3). Participants will not know to which group they were randomized to.

The groups that participants will be randomized to are:

Group 1: Standard PAI: 30 mg Toradol/ketorolac (30mg/ml), 49.25ml 0.5% ropivacaine (5mg/ml), and 0.5 mg epinephrine (1mg/ml), 0.8 ml clonidine (0.1mg/ml) and 8.45 ml 0.9% sodium chloride Group 2: Standard PAI + 40mg methylprednisolone (diabetics and pre-diabetics will not be randomized to this group) Group 3: Standard PAI + 32mg Zilretta (triamcinolone acetonide extended release injectable suspension)