Liposomal Bupivacaine vs Nerve Catheters for Post-Amputation Pain

Overseen By Janelle M Richard

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ryan Mountjoy, MD

Must not be taking: Opioids

Disqualifiers: Allergy to anesthetics, Coagulopathy, Substance use disorder, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 72 hours

30 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on opioids over 90 MME/day, you cannot participate.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on more than 90 morphine milligram equivalents of opioids per day, you cannot participate.

What data supports the idea that Liposomal Bupivacaine vs Nerve Catheters for Post-Amputation Pain is an effective treatment?

The available research shows that liposomal bupivacaine may help reduce the need for opioids after surgery. In a study on below knee amputations, patients who received liposomal bupivacaine nerve blocks used less opioids compared to those who did not receive it (25.0 vs 50.5 in daily opioid use). However, other studies suggest that liposomal bupivacaine does not consistently provide better pain relief than standard treatments. For example, only a small percentage of trials showed significant improvement with liposomal bupivacaine compared to other anesthetics. Overall, the evidence does not strongly support using liposomal bupivacaine over other options for post-amputation pain. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Liposomal Bupivacaine for post-amputation pain?

Research shows that using liposomal bupivacaine in regional nerve blocks for below knee amputations can reduce the need for opioids after surgery, as patients who received it used fewer opioids compared to those who did not. ^{1 2 3 4 5}

What safety data exists for liposomal bupivacaine?

Liposomal bupivacaine (Exparel) is approved for postsurgical analgesia and has been studied in various clinical trials. It is generally considered safe for surgical infiltration and peripheral nerve blocks, though its effectiveness compared to standard anesthetics is mixed. Some studies have examined its use in off-label applications, such as peripheral nerve blocks and subarachnoid injections, with varying outcomes. Overall, while it is approved and used in certain settings, its superiority over traditional bupivacaine is not consistently supported by evidence. ^{3 6 7 8 9}

Is liposomal bupivacaine safe for use in humans?

Liposomal bupivacaine (Exparel) has been shown to be generally safe for use in humans, particularly for surgical site pain relief, and is approved by the FDA for this purpose. However, its safety in other uses, like nerve blocks, is still being studied, and some studies have shown mixed results regarding its effectiveness compared to other anesthetics. ^{3 6 7 8 9}

Is the drug Liposomal bupivacaine a promising treatment for post-amputation pain?

Liposomal bupivacaine, a drug used to manage pain after surgery, has shown mixed results in research. While it is safe and can reduce pain in some cases, most studies do not show it to be better than standard pain relief methods. Therefore, it may not be a promising treatment for post-amputation pain compared to other options. ^{1 2 3 4 10}

How is the drug liposomal bupivacaine different from other treatments for post-amputation pain?

Liposomal bupivacaine is unique because it is designed to provide prolonged pain relief by slowly releasing the anesthetic over time, unlike standard local anesthetics that act more quickly but wear off sooner. However, evidence suggests it may not be more effective than traditional nerve blocks with unencapsulated bupivacaine for post-amputation pain. ^{1 2 3 4 10}

What is the purpose of this trial?

Through this pilot prospective trial, we aim to obtain preliminary data investigating the effectiveness of perineural catheters and liposomal bupivacaine, both currently accepted as standard care at Maine Medical Center, for the management of post-limb amputation pain. We will use the data that we collect to inform the design of a larger, appropriately powered study.

Research Team

Ryan Mountjoy, MD

Principal Investigator

MaineHealth

Eligibility Criteria

This trial is for individuals scheduled for primary below-knee amputation or stump revision, who can understand and consent in English. They should not have a severe allergy to local anesthetics, infections where the needle will go, extreme obesity (BMI > 40), bleeding disorders, be on high-dose opioids (>90 MME/day), have substance use disorders, or need emergency amputations.

Inclusion Criteria

English speaking

You have a certain level of physical health, as classified by the American Society of Anesthesiologists.

You are planning to have a surgery to remove a limb or revise the remaining part of a limb.

Exclusion Criteria

You have been diagnosed with a substance use disorder.

Patients unable to cooperate or consent to the study

You are allergic to local anesthetics.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a continuous perineural popliteal nerve block catheter or a single shot perineural popliteal nerve block for pain management post-below knee amputation

72 hours

Follow-up

Participants are monitored for opioid consumption, length of stay, and phantom limb pain

30 days

Treatment Details

Interventions

• Bupivacaine Hydrochloride 0.5 % Injectable Solution
• Liposomal bupivacaine

Trial Overview The study compares two pain management methods after leg amputations: Liposomal bupivacaine versus continuous nerve catheters with Bupivacaine Hydrochloride. It's designed to gather initial data at Maine Medical Center to plan a larger future study.

Participant Groups

Group I: Continuous perineural popliteal nerve block catheter Active Control 1 Intervention

Placement of continuous perineural popliteal nerve block catheter with injection of 30cc 0.5% bupivacaine within one hour prior to surgery, followed by continuous infusion of 10cc 0.3% ropivacaine (current standard practice) for at least 72 hours following surgery. Saphenous single shot 20cc 0.2

Group II: Single Shot Perineural Popliteal Nerve Block Active Control 1 Intervention

Single shot perineural popliteal nerve block injection of 10cc 13.3% liposomal bupivacaine combined with 15cc 0.50% bupivacaine hydrochloride within one hour prior to surgery

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

Approved in United States as Exparel for:

• Postsurgical pain in adults

Approved in European Union as Exparel liposomal for:

• Local pain relief around small to medium-sized surgical wounds
• Regional pain relief in the surgery of the knee and around the shoulders

Who Is Running the Clinical Trial?

Ryan Mountjoy, MD

Lead Sponsor

Trials

1

Recruited

30+

MaineHealth

Collaborator

Trials

76

Recruited

43,800+

Findings from Research

In a study of 40 patients undergoing forefoot surgery, those who received liposomal bupivacaine consumed significantly fewer narcotic pills on the first two postoperative days compared to the control group, indicating its effectiveness in reducing opioid consumption.

Patients receiving liposomal bupivacaine reported lower pain scores during the first four days after surgery, and there were no increased wound complications, suggesting it is a safe and effective addition to postoperative pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal bupivacaine in forefoot surgery. Robbins, J., Green, CL., Parekh, SG.[2022]

In a study of 631 patients undergoing major lower-extremity amputation, peripheral nerve blockade significantly reduced opioid use in the first 72 hours post-surgery compared to those who received only general anesthesia.

The addition of liposomal bupivacaine to standard bupivacaine in nerve blocks did not result in a significant difference in opioid consumption compared to using standard bupivacaine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral Nerve Blockade with Combined Standard and Liposomal Bupivacaine in Major Lower-Extremity Amputation. Dumitrascu, CI., Warner, NS., Stewart, TM., 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 randomized controlled trial involving 57 patients undergoing midurethral sling placement, liposomal bupivacaine resulted in lower median pain scores on postoperative day 1 compared to a mixture of bupivacaine and lidocaine (20 mm vs 30 mm), indicating some efficacy in pain management.

Despite the initial lower pain scores, there were no significant differences in overall opioid and nonsteroidal anti-inflammatory drug consumption or in quality of recovery scores after 7 days, suggesting that liposomal bupivacaine may not provide a clinically significant advantage over traditional pain management methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Versus Bupivacaine Hydrochloride with Lidocaine during Midurethral Sling Placement: A Randomized Controlled Trial. Iwanoff, C., Salamon, C.[2020]

In a study of 69 patients who underwent below knee amputations, those who received liposomal bupivacaine (LB) nerve blocks consumed significantly less opioids post-surgery, averaging 25.0 oral morphine equivalents (OME) compared to 50.5 OME in the control group.

The use of LB nerve blocks not only reduced opioid consumption but also resulted in a higher percentage of patients using minimal opioids, suggesting that LB may be an effective alternative for pain management after amputation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Liposomal Bupivacaine in Regional Nerve Blocks for Below Knee Amputations. Allsbrook, AP., Gotsch, A., To, J., et al.[2023]

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 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]

In a pilot study involving 25 pigs, subarachnoid administration of liposomal bupivacaine resulted in a longer duration of pain relief compared to standard bupivacaine hydrochloride, with effects lasting up to 32 hours for higher doses.

No signs of neurotoxicity were observed in any treatment group, suggesting that liposomal bupivacaine may be a safe option for extended analgesia in the neuraxial space, warranting further studies for potential human use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological and histological outcomes after subarachnoid injection of a liposomal bupivacaine suspension in pigs: a pilot study. Zel, J., Hadzic, A., Cvetko, E., et al.[2019]

In a study of 34 patients undergoing breast augmentation, liposomal bupivacaine provided statistically significant lower pain scores compared to standard bupivacaine at multiple time points post-surgery, indicating it may offer better pain control.

Despite the statistical significance, the differences in pain relief were small, and 70% of patients felt the additional cost of liposomal bupivacaine was not justified by the benefits, suggesting limited clinical relevance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupivacaine Versus Liposomal Bupivacaine for Postoperative Pain Control after Augmentation Mammaplasty: A Prospective, Randomized, Double-Blind Trial. Nadeau, MH., Saraswat, A., Vasko, A., et al.[2022]

In a study of 90 patients undergoing immediate breast reconstruction, the use of liposomal bupivacaine (LB) significantly reduced postoperative pain scores compared to traditional pain management methods, indicating its efficacy as a pain reliever.

Patients receiving LB also had a shorter hospital stay (1.5 days) compared to those on narcotics (2.0 days), with no reported adverse events, highlighting its safety and potential benefits in postoperative recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative Pain and Length of Stay Lowered by Use of Exparel in Immediate, Implant-Based Breast Reconstruction. Butz, DR., Shenaq, DS., Rundell, VL., et al.[2022]

References

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

Liposomal bupivacaine in forefoot surgery. [2022]

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

Peripheral Nerve Blockade with Combined Standard and Liposomal Bupivacaine in Major Lower-Extremity Amputation. [2022]

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

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

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

Liposomal Bupivacaine Versus Bupivacaine Hydrochloride with Lidocaine during Midurethral Sling Placement: A Randomized Controlled Trial. [2020]

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

The Efficacy of Liposomal Bupivacaine in Regional Nerve Blocks for Below Knee Amputations. [2023]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Perineural dexamethasone attenuates liposomal bupivacaine-induced delayed neural inflammation in mice in vivo. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Neurological and histological outcomes after subarachnoid injection of a liposomal bupivacaine suspension in pigs: a pilot study. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Bupivacaine Versus Liposomal Bupivacaine for Postoperative Pain Control after Augmentation Mammaplasty: A Prospective, Randomized, Double-Blind Trial. [2022]

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

Postoperative Pain and Length of Stay Lowered by Use of Exparel in Immediate, Implant-Based Breast Reconstruction. [2022]