Enhanced Nerve Block for Total Knee Arthroplasty Pain Management

(Yale SEVEN Trial)

Recruiting at 1 trial location

Overseen By Jinlei Li, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must not be taking: Opioids, Marijuana

Disqualifiers: Pregnancy, Diabetes, Immune compromise, 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

Duration: Immediate post-surgery

250 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two pain relief methods for individuals undergoing total knee replacement. One method combines Dexamethasone and Methylprednisolone with a common anesthetic, bupivacaine. The other method uses a special form of bupivacaine, known as Bupivacaine-Liposomal Bupivacaine. The researchers aim to determine which method offers better pain control and recovery after surgery. Individuals planning a single knee replacement due to osteoarthritis and who can use the internet for follow-ups might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on opioids or have certain conditions like uncontrolled diabetes or severe liver or kidney issues.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using bupivacaine with liposomal bupivacaine is generally safe for managing pain after knee surgery. Studies have found that this combination can reduce pain and lessen the need for opioid painkillers, indicating good patient tolerance.

For the combination of Dexamethasone sodium phosphate (DEX) and Methylprednisolone acetate (MPA), early safety data is promising. One study found that using these steroid medications together did not cause major safety issues. Another study suggested that a single dose of DEX and MPA might reduce the need for local anesthetics, aiding patient recovery.

Overall, both treatment options in this trial have shown promising safety in past research. However, this trial will provide more detailed information on their safety and effectiveness for controlling pain after knee replacement surgery. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore enhanced pain management techniques for total knee arthroplasty. Unlike traditional nerve blocks that rely solely on bupivacaine, one treatment arm combines bupivacaine with dexamethasone and methylprednisolone acetate. This combination could provide longer-lasting pain relief by using steroids to reduce inflammation and prolong the effects of the nerve block. The other treatment arm uses liposomal bupivacaine, which is designed to release the drug slowly over time, potentially extending pain relief beyond what standard bupivacaine offers. These innovations aim to improve patient comfort and reduce the need for opioid medications post-surgery.

What evidence suggests that this trial's treatments could be effective for post-surgical pain control in total knee arthroplasty?

Research has shown that adding Dexamethasone sodium phosphate (DEX) and Methylprednisolone acetate (MPA) to nerve blocks can reduce the need for opioids after knee surgery. In this trial, one group of participants will receive this combination with bupivacaine to improve pain control after knee replacement surgery. Another group will receive Liposomal Bupivacaine (LB), which has shown mixed results in studies. Some studies found that LB reduces pain and opioid use, while others did not find it more effective than traditional methods. This trial explores both treatments to determine which provides better pain relief after knee surgery. ^{6 7 8 9 10}

Who Is on the Research Team?

Jinlei Li, MD PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults with good overall health status (ASA I-III) who are scheduled for a single knee replacement surgery and can receive spinal anesthesia. They must not have used opioids in the last month, have no allergies to study drugs, uncontrolled diabetes, severe liver or kidney issues, weigh at least 60 kg, and be able to complete online questionnaires.

Inclusion Criteria

I am scheduled for knee surgery with spinal anesthesia.

Exclusion Criteria

Conditions making the patient unable to fill out questionnaire online, through email or over the phone including with cognitive dysfunction, psychiatric disorder, or non-English speaking patients, or lack of internet access which would prevent post discharge follow-up electronically

Pregnancy

I am having a knee replacement for reasons other than wear and tear arthritis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nerve blockade with either B-DEX-MPA or B-LB for post-surgical pain control during unilateral total knee arthroplasty

Immediate post-surgery

1 visit (in-person)

Postoperative Monitoring

Participants are monitored for postoperative pain, opioid consumption, and recovery quality for up to 48 hours post-surgery

48 hours

In-hospital stay

Follow-up

Participants are monitored for knee functional status, pain, and recovery quality at 6 weeks and 3 months post-surgery

3 months

Multiple visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Bupivacaine-Liposomal Bupivacaine
• Dexamethasone sodium phosphate-Methylprednisolone acetate

Trial Overview The study compares two pain control methods after knee surgery: one combines Dexamethasone and Methylprednisolone with bupivacaine; the other uses Liposomal Bupivacaine with bupivacaine. It aims to see which provides better pain relief and postoperative recovery.

How Is the Trial Designed?

Group I: Bupivacaine -Dexamethasone Sodium Phosphate-Methylprednisolone Acetate (B-DEX-MPA) Experimental Treatment 1 Intervention

Nerve blockade administration will be carried out per standard of care. All patients will receive single injection under ultrasound guidance with adductor canal block comprised of 30 ml 0.25% plain bupivacaine + 5 mg DEX (0.5 ml) and 40 mg MPA (1 ml); 20 ml 0.25% plain bupivacaine + 5 mg DEX (0.5 ml) and 40 mg MPA (1 ml) will be administered through an iPACK block.

Group II: Bupivacaine-Liposomal Bupivacaine (B-LB) Active Control 1 Intervention

Nerve blockade administration will be carried out per standard of care. All patients will receive single injection under ultrasound guidance with adductor canal block comprised of 20 ml 0.25% plain bupivacaine + 10 ml LB (133 mg) with the total volume of 30 ml; 10 ml 0.25% plain bupivacaine + 10 ml LB (133 mg) with the total volume of 20 ml will be administered through an Interspace between the popliteal artery and capsule of the posterior knee (iPACK) block.

Bupivacaine-Liposomal Bupivacaine is already approved in United States, European Union for the following indications:

Approved in United States as Exparel for:

• Postsurgical local analgesia
• Interscalene brachial plexus nerve block
• Adductor canal block
• Sciatic nerve block in the popliteal fossa

Approved in European Union as Exparel for:

• Postsurgical local analgesia

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Department of Anesthesiology Faculty Development Fund

Collaborator

Trials

2

Recruited

320+

Published Research Related to This Trial

Patients who received an intra-operative pericapsular injection of bupivacaine liposome suspension reported significantly lower pain levels and required less morphine compared to those who received a concentrated multi-drug cocktail after total knee arthroplasty, indicating better pain management.

The bupivacaine liposome group also experienced higher satisfaction with pain control and overall experience, along with fewer adverse events, suggesting it may be a safer and more effective option for postoperative pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving total knee arthroplasty perioperative pain management using a periarticular injection with bupivacaine liposomal suspension. Snyder, MA., Scheuerman, CM., Gregg, JL., et al.[2020]

In a study of 88,830 patients undergoing total knee arthroplasties, liposomal bupivacaine was used in 21.2% of cases but did not lead to a clinically meaningful reduction in inpatient opioid prescriptions or length of hospital stay.

The use of liposomal bupivacaine did not decrease the odds of opioid-related complications, suggesting it may have limited clinical impact in modern pain management settings that include peripheral nerve blocks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Does Not Reduce Inpatient Opioid Prescription or Related Complications after Knee Arthroplasty: A Database Analysis. Pichler, L., Poeran, J., Zubizarreta, N., et al.[2019]

Liposomal bupivacaine (LB) was found to be noninferior to continuous nerve block with a pain pump for managing pain after total knee arthroplasty, showing no significant differences in average pain scores or readmission rates among 2,378 patients studied.

The use of LB not only matched the efficacy of the pain pump but also resulted in an estimated cost savings of $95 per patient, totaling approximately $155,800 over the study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Versus Continuous Nerve Block: Liposomal Bupivacaine May be Non-inferior and More Cost Effective. Lonza, GC., Yuan, F., Pham, FM., et al.[2023]

In a study involving 59 patients undergoing total knee arthroplasty, liposomal bupivacaine did not show a significant clinical advantage over standard bupivacaine in terms of postoperative recovery, as measured by the number of physical therapy sessions needed for discharge.

The use of liposomal bupivacaine was associated with higher medication charges, raising concerns about its cost-effectiveness compared to standard care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Versus Standard Periarticular Injection in Total Knee Arthroplasty With Regional Anesthesia: A Prospective Randomized Controlled Trial. Hyland, SJ., Deliberato, DG., Fada, RA., et al.[2019]

In a study involving 32 patients undergoing knee arthroplasty, both liposomal bupivacaine (EXP) and a combination of ropivacaine, epinephrine, ketorolac, and clonidine (ROP) provided similar pain relief, with no significant differences in pain scores during the first two days post-surgery.

Patients did not perceive any difference in functional recovery between the two injection types, indicating that the more expensive liposomal bupivacaine does not offer additional benefits over the standard ROP formulation for pain management after knee surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Periarticular Ropivacaine Cocktail Is Equivalent to Liposomal Bupivacaine Cocktail in Bilateral Total Knee Arthroplasty. Danoff, JR., Goel, R., Henderson, RA., et al.[2019]

In a study of 96 total knee arthroplasty patients, liposomal bupivacaine did not show any significant advantage over ropivacaine in managing postoperative pain, as measured by narcotic use and pain scores.

Both treatment groups had similar outcomes in terms of narcotic consumption, time to ambulate, and length of hospital stay, indicating that liposomal bupivacaine may not provide additional benefits in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Bupivacaine Liposome Injectable Suspension for Postoperative Pain Control in Total Knee Arthroplasty: A Prospective, Randomized, Double Blind, Controlled Study. DeClaire, JH., Aiello, PM., Warritay, OK., et al.[2018]

In a retrospective analysis of 575 subjects across 6 clinical trials, liposome bupivacaine showed a similar safety profile to both bupivacaine HCl and normal saline, with 76% of liposome bupivacaine recipients experiencing adverse events (AEs).

The most common AEs for liposome bupivacaine included nausea and hypesthesia, and serious AEs occurred in 8% of subjects, indicating that the side effects are likely related to the surgical procedure rather than the medication itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Side Effect Profile of Liposome Bupivacaine (Exparel) in Peripheral Nerve Blocks. Ilfeld, BM., Viscusi, ER., Hadzic, A., et al.[2022]

A review of 76 randomized controlled trials found that only 11% showed a significant benefit of liposomal bupivacaine over standard bupivacaine or ropivacaine for postoperative pain control.

The majority of trials indicated that unencapsulated bupivacaine provided better pain relief than liposomal bupivacaine, suggesting that routine use of liposomal bupivacaine may not be justified based on current evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Effectiveness of Liposomal Bupivacaine Administered by Infiltration or Peripheral Nerve Block to Treat Postoperative Pain. Ilfeld, BM., Eisenach, JC., Gabriel, RA.[2021]

In a study of 100 total knee arthroplasty patients, adding methylprednisolone acetate (MPA) to adductor canal and iPACK blocks significantly reduced cumulative opioid consumption compared to using dexamethasone (DEX) alone, with a median difference of -45.3 mg morphine equivalent.

Patients receiving DEX/MPA also reported lower pain scores on postoperative day 2, indicating better pain management, while other outcomes like knee joint range of motion and length of hospital stay remained similar between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perineural Methylprednisolone Depot Formulation Decreases Opioid Consumption After Total Knee Arthroplasty. Del Toro-Pagán, NM., Dai, F., Banack, T., et al.[2023]

Liposomal bupivacaine infiltration offers comparable postoperative pain relief to femoral nerve block after total knee arthroplasty, based on a meta-analysis of 1289 participants from various studies.

Liposomal bupivacaine significantly reduces morphine consumption in the first two days post-surgery without increasing the risk of adverse effects like nausea or vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal bupivacaine infiltration versus femoral nerve block for pain control in total knee arthroplasty: A systematic review and meta-analysis. Ma, J., Zhang, W., Yao, S.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05736549

Yale Steroid Enhanced Versus Exparel Nerveblock TKA ... The primary objective of this study is to investigate the efficacy of Dexamethasone sodium phosphate (DEX) plus Methylprednisolone acetate (MPA) in combination ...

2. withpower.com withpower.com/trial/phase-2-total-knee-replacement-surgery-3-2022-0332b

Enhanced Nerve Block for Total Knee Arthroplasty Pain ... Some studies suggest that adding methylprednisolone acetate to nerve blocks can reduce opioid use after knee surgery, but the effectiveness of liposomal ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05736549/yale-steroid-enhanced-versus-exparel-nerveblock-tka-part-2

Yale Steroid Enhanced Versus Exparel Nerveblock TKA ... The primary objective of this study is to investigate the efficacy of Dexamethasone sodium phosphate (DEX) plus Methylprednisolone acetate (MPA) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10661633/

A single center retrospective study - PMC Total-knee arthroplasty (TKA) is a highly effective orthopedic surgery used to improve pain control and functional status in patients with severe end-stage knee ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05279092

Yale Steroid Enhanced Versus Exparel Nerveblock TKA ... The primary objective of this phase 2 study is to investigate the efficacy of Dexamethasone sodium phosphate (DEX) plus Methylprednisolone acetate (MPA) in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8988023/

Efficacy of Liposomal Bupivacaine and ... This randomized clinical trial assesses the efficacy and cost-effectiveness of liposomal bupivacaine plus bupivacaine hydrochloride compared ...

7. arthroplastyjournal.org arthroplastyjournal.org/article/S0883-5403(25)00893-9/fulltext

A Phase 3 Active-Controlled Trial of Liposomal ... Liposomal bupivacaine administered via adductor canal block for total knee arthroplasty was associated with concurrent reductions in pain and opioid consumption ...

8. aetna.com aetna.com/cpb/medical/data/900_999/0941.html

Bupivacaine Liposome (Exparel) - Medical Clinical Policy ... Exparel was administered via a femoral nerve block in patients undergoing total knee arthroplasty (TKA) in two placebo-controlled studies. The results of these ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03303794

Study Details | NCT03303794 | 0.25% Bupivacaine Versus ... This is an assessor-blinded randomized controlled trial evaluating the efficacy of liposomal bupivacaine (Exparel) in patients undergoing Total Knee ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6599357/

The efficacy of liposomal bupivacaine compared with ... The efficacy of postoperative pain management is an important factor that influences the final outcome of total knee arthroplasty (TKA).