Enhanced Nerve Block for Total Knee Arthroplasty Pain Management

(Yale SEVEN Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Jinlei Li, MD PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Yale University

Must not be taking: Opioids, Marijuana

Disqualifiers: Pregnancy, Diabetes, Immune compromise, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The objective of this phase 2 study is to investigate the efficacy of Dexamethasone sodium phosphate (DEX) plus Methylprednisolone acetate (MPA) in combination with plain bupivacaine (B) compared with Liposomal Bupivacaine (LB) in combination with plain bupivacaine on post-surgical pain control among patients undergoing unilateral total knee arthroplasty (TKA) to asses if perineural B-DEX-MPA will result in superior analgesia efficacy as compared to B-LB. This study will also assess if perineural B-DEX-MPA results in improved quality of postoperative recovery as compared to B-LB.

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.

What data supports the effectiveness of the drug Bupivacaine-Liposomal Bupivacaine, Exparel, Bupivacaine Liposome, Liposomal Bupivacaine, Dexamethasone sodium phosphate-Methylprednisolone acetate, Dexamethasone sodium phosphate-Methylprednisolone acetate, DEX-MPA for pain management in total knee arthroplasty?

Some studies suggest that adding methylprednisolone acetate to nerve blocks can reduce opioid use after knee surgery, but the effectiveness of liposomal bupivacaine for pain control is mixed, with limited evidence supporting its routine use over standard anesthetics. ^{1 2 3 4 5}

Is the enhanced nerve block using liposomal bupivacaine safe for humans?

Liposomal bupivacaine (Exparel) has been studied in various clinical trials and is generally considered safe for use in humans, with fewer adverse events reported compared to some multi-drug cocktails used for pain management in knee surgery. ^{2 5 6 7 8}

How is the drug for knee surgery pain management different from other treatments?

This drug combines liposomal bupivacaine, a long-acting local anesthetic, with steroids like dexamethasone and methylprednisolone, which may provide extended pain relief and reduce inflammation compared to standard treatments. It is designed to be more cost-effective and potentially as effective as continuous nerve blocks, offering a unique combination of pain management and anti-inflammatory effects. ^{1 2 7 9 10}

Research Team

Jinlei Li, MD PhD

Principal Investigator

Yale University

Eligibility Criteria

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.

Trial Timeline

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)

Treatment Details

Interventions

• Bupivacaine-Liposomal Bupivacaine (Local Anesthetic)
• Dexamethasone sodium phosphate-Methylprednisolone acetate (Corticosteroid)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

Department of Anesthesiology Faculty Development Fund

Collaborator

Trials

2

Recruited

320+

Findings from Research

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 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 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]

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]

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 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]

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]

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]

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]

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]

References

1. United States 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. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Periarticular Ropivacaine Cocktail Is Equivalent to Liposomal Bupivacaine Cocktail in Bilateral Total Knee Arthroplasty. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Does Not Reduce Inpatient Opioid Prescription or Related Complications after Knee Arthroplasty: A Database Analysis. [2019]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Perineural Methylprednisolone Depot Formulation Decreases Opioid Consumption After Total Knee Arthroplasty. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical Effectiveness of Liposomal Bupivacaine Administered by Infiltration or Peripheral Nerve Block to Treat Postoperative Pain. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Safety and Side Effect Profile of Liposome Bupivacaine (Exparel) in Peripheral Nerve Blocks. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Versus Standard Periarticular Injection in Total Knee Arthroplasty With Regional Anesthesia: A Prospective Randomized Controlled Trial. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Improving total knee arthroplasty perioperative pain management using a periarticular injection with bupivacaine liposomal suspension. [2020]

9. United States 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. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Versus Continuous Nerve Block: Liposomal Bupivacaine May be Non-inferior and More Cost Effective. [2023]