Steroid-Enhanced Nerve Block vs Exparel for Knee Surgery 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: 54

Duration: Immediate post-surgery

66 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two methods for managing pain after knee replacement surgery. It compares a steroid-enhanced nerve block (Dexamethasone Sodium Phosphate-Methylprednisolone Acetate, or B-DEX-MPA) with a liposomal bupivacaine nerve block (Exparel, or B-LB) to determine which provides better pain relief and a smoother recovery. Participants will receive one treatment in each knee to directly compare their effects. Individuals with osteoarthritis planning a double knee replacement might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

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

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

Research has shown that liposomal bupivacaine is generally safe for knee surgery, but its effectiveness for pain relief varies. Some studies found it reduces pain and the need for opioid painkillers, while others found no improvement in recovery compared to regular bupivacaine. Importantly, studies have reported no major safety concerns.

For the steroid combination treatment, which includes dexamethasone and methylprednisolone, early safety data is encouraging. Research suggests this combination is safe and may enhance pain relief when applied directly to the pain site. Reports of significant side effects are absent, indicating good tolerance.

Both treatments have been tested in humans. While each has advantages and disadvantages, both are considered safe for further study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a potentially more effective way to manage pain after knee surgery. The study explores using a combination of bupivacaine, liposomal bupivacaine, dexamethasone sodium phosphate, and methylprednisolone acetate in nerve blocks. These treatments differ from the standard options like opioids and non-steroidal anti-inflammatory drugs (NSAIDs) by targeting pain directly at the nerve level, potentially reducing the need for systemic medications. The use of liposomal bupivacaine allows for extended-release of the anesthetic, which may provide longer-lasting pain relief. Additionally, the combination with steroids like dexamethasone and methylprednisolone could enhance anti-inflammatory effects, leading to better overall pain management.

What evidence suggests that this trial's treatments could be effective for knee surgery pain management?

This trial will compare the effectiveness of Liposomal Bupivacaine (LB) and Dexamethasone Sodium Phosphate with Methylprednisolone Acetate (DEX-MPA) for pain management after knee surgery. Research has shown that LB can reduce pain and the need for opioids, though its effectiveness compared to other methods remains debated. Some studies found that LB slightly decreases opioid use and shortens hospital stays for knee surgery patients. Meanwhile, using DEX-MPA in nerve blocks may improve pain management and reduce opioid use. These treatments aim to provide better pain control and a smoother recovery after knee surgery. ^{1 6 7 8 9}

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 who are scheduled for elective, primary, bilateral knee replacement surgery and can receive spinal anesthesia with bupivacaine. They should not be pregnant, have coagulopathy or severe liver/renal issues, use opioids recently, or have certain conditions like uncontrolled diabetes.

Inclusion Criteria

I am scheduled for knee replacement surgery under spinal anesthesia.

Exclusion Criteria

Refusal of consent

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

I have not used opioids or regularly used marijuana in the month before my surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nerve block treatments with B-LB and B-DEX-MPA during bilateral total knee arthroplasty

Immediate post-surgery

In-hospital stay up to 48 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment, including pain and functional assessments

3 months

Multiple assessments at baseline, 6 weeks, and 3 months

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 (B-DEX-MPA), while the other uses liposomal bupivacaine with plain bupivacaine (B-LB). It aims to see which provides better pain relief and recovery quality.

How Is the Trial Designed?

Group I: B-LB in right knee and B-DEX-MPA in left knee Experimental Treatment 2 Interventions

Participants in this arm will receive B-LB in their right knee and B-DEX-MPA in their left knee. Nerve block with (B-LB): A medication mixture of 40 ml (20 ml LB and 20 ml 0.25% plain bupivacaine) will be prepared, of which 20 ml will be used in Adductor canal block, 10 ml will be used in iPACK block and 5 ml each will be used in medial upper and lateral upper genicular nerve block, respectively. Nerve block with (B-DEX-MPA): A medication mixture of 40 ml (40 ml 0.25% plain bupivacaine, 10 mg DEX and 80 mg MPA) will be prepared, of which 20 ml will be used in Adductor canal block, 10 ml will be used in iPACK block and 5 ml each will be used in medial upper and lateral upper genicular nerve block, respectively.

Group II: B-LB in left knee and B-DEX-MPA in right knee Experimental Treatment 2 Interventions

Participants in this arm will receive B-LB in their left knee and B-DEX-MPA in their right knee. Nerve block with (B-LB): A medication mixture of 40 ml (20 ml LB and 20 ml 0.25% plain bupivacaine) will be prepared, of which 20 ml will be used in Adductor canal block, 10 ml will be used in iPACK block and 5 ml each will be used in medial upper and lateral upper genicular nerve block, respectively. Nerve block with (B-DEX-MPA): A medication mixture of 40 ml (40 ml 0.25% plain bupivacaine, 10 mg DEX and 80 mg MPA) will be prepared, of which 20 ml will be used in Adductor canal block, 10 ml will be used in iPACK block and 5 ml each will be used in medial upper and lateral upper genicular nerve block, respectively.

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

EXPAREL® (bupivacaine liposome injectable suspension) has been shown to effectively reduce postoperative pain and opioid use in patients undergoing hip and knee arthroplasty, offering a safer alternative to traditional peripheral nerve blocks.

In a pilot study, patients receiving EXPAREL® reported lower pain scores and experienced significant cost savings of $411 for total knee arthroplasty and $348 for total hip arthroplasty compared to those receiving nerve blocks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transition from nerve blocks to periarticular injections and emerging techniques in total joint arthroplasty. Springer, BD.[2022]

In a study involving 98 mice, liposomal bupivacaine (Exparel®) provided a longer duration of pain relief compared to standard bupivacaine, with motor block lasting up to 180 minutes and thermoalgesic block lasting up to 420 minutes.

The addition of dexamethasone, either perineurally or systemically, significantly reduced neural inflammation caused by bupivacaine, and perineural dexamethasone also helped reduce inflammation from Exparel®, suggesting a protective effect against nerve damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perineural dexamethasone attenuates liposomal bupivacaine-induced delayed neural inflammation in mice in vivo. Ferré, F., Krin, A., Sanchez, M., et al.[2020]

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 three cases of total hip arthroplasty using liposomal bupivacaine (Exparel®), patients experienced temporary loss of function in the sciatic nerve area for 24 to 72 hours post-surgery, likely due to the medication being injected too close to the nerve.

These neurological deficits have not been previously reported in the literature, highlighting the need for careful administration of liposomal bupivacaine to prevent such complications during orthopedic procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unanticipated transient sciatic nerve deficits from intra-wound liposomal bupivacaine injection during total hip arthroplasty. Bronson, WH., Doran, JP., Slover, J., et al.[2020]

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 of 100 patients undergoing total knee arthroplasties, liposomal bupivacaine (Exparel) used in adductor canal blocks significantly reduced hospital stay length (36.3 hours vs. 49.7 hours) and decreased inpatient opioid use (40.9 MME/d vs. 47.3 MME/d).

Patients receiving Exparel reported better pain relief at all postoperative time points and showed greater improvements in their WOMAC scores, indicating enhanced recovery and pain management compared to those receiving ropivacaine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine in Adductor Canal Blocks Before Total Knee Arthroplasty Leads to Improved Postoperative Outcomes: A Randomized Controlled Trial. Malige, A., Pellegrino, AN., Kunkle, K., 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]

Citations

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

Efficacy of Liposomal Bupivacaine and ... To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement.

2. josr-online.biomedcentral.com josr-online.biomedcentral.com/articles/10.1186/s13018-023-03699-4

Liposomal bupivacaine administration is not superior to ... It is inconclusive whether LB offers better efficacy than traditional periarticular injection (TPAI) following total knee arthroplasty (TKA).

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02274870

Liposomal Bupivacaine for Post Operative Pain After Knee ... Outcomes measured included pain at rest, movement and quadriceps muscle strength on the first and second postoperative day. It is hypothesized that Liposome ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5551634/

Postoperative Pain Management With Liposomal ... Use of liposomal bupivacaine produced a modest decrease in opioid use among knee patients and a decreased length of stay in both knee and hip patients.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0883540314006597

The Use of Exparel (Liposomal Bupivacaine) to Manage ... Local Infiltration Analgesia With Liposomal Bupivacaine Improves Early Outcomes After Total Knee Arthroplasty: 24-Hour Data From the PILLAR Study. The ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40701284/

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 ...

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 ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03303794

Study Details | NCT03303794 | 0.25% Bupivacaine Versus ... The primary outcome of this study is the proportion of patients "fit to discharge" on postoperative day one. Recently, liposomal bupivacaine (LB) (Exparel) was ...

9. 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 ...