Pain Control for Ankle Fracture

Recruiting at 2 trial locations

Overseen By Jillian Kazley, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Massachusetts, Worcester

Must not be taking: Chronic opioids

Disqualifiers: Neurologic condition, Polytrauma, Pregnant, 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: 1

Duration: Immediate perioperative period

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This project is a multicenter, three armed, prospective randomized control trial studying the effectiveness of a long-acting local anesthetic "cocktail" in patients undergoing operative fixation of ankle fractures.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be able to take the standard post-operative pain regimen, which includes gabapentin, oxycodone, acetaminophen, and ibuprofen.

What data supports the effectiveness of the drug liposomal bupivacaine for pain control in ankle fractures?

Liposomal bupivacaine, a slow-releasing form of bupivacaine, has been shown to be effective for managing postsurgical pain, providing relief for up to 72 hours with a single application. However, a comprehensive review of trials found that liposomal bupivacaine often does not outperform standard local anesthetics like unencapsulated bupivacaine or ropivacaine, especially when used in peripheral nerve blocks. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Liposomal bupivacaine, a long-acting form of bupivacaine, has been shown to be safe for pain management in surgeries like breast augmentation and third molar extraction. However, there have been severe adverse reactions, including fatalities, associated with bupivacaine and etidocaine, highlighting the importance of being aware of potential risks. ^{1 6 7 8 9}

How is the drug used for pain control in ankle fractures different from other treatments?

The drug, liposomal bupivacaine, is unique because it provides long-lasting pain relief for up to 72 hours with just a single injection, unlike standard treatments that may require more frequent dosing. ^{1 2 10 11 12}

Research Team

Eric Swart, MD

Principal Investigator

Lahey Hospital & Medical Center

Eligibility Criteria

This trial is for adults with a specific type of ankle fracture (bimalleolar) that requires surgery using medial and lateral incisions. It's not for those with certain other fractures, open injuries, chronic opioid use, or who can't consent. Pregnant women, non-English speakers without translator access, and people on certain medications are also excluded.

Inclusion Criteria

You have only one injury and no other health problems.

I have a specific type of ankle fracture that requires surgery with cuts on both sides of my ankle.

I have a three-part ankle fracture and won't have surgery on the back part.

Exclusion Criteria

You have an open wound or injury.

I have been treated with a device outside my body to stabilize bones.

I have a broken ankle and only one side will be surgically fixed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a long-acting local anesthetic cocktail, regional anesthesia, or traditional care for pain control during operative fixation of ankle fractures

Immediate perioperative period

1 visit (in-person for surgery)

Postoperative Monitoring

Participants are monitored for pain control and narcotic use for 72 hours post-surgery

72 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Long-Acting Local Anesthesia
• Regional Anesthesia

Trial Overview The study compares the pain control effectiveness of a long-acting local anesthetic 'cocktail' versus regional anesthesia in patients having surgery to fix their broken ankles. Participants will be randomly assigned to one of three groups in different medical centers.

Participant Groups

Group I: Regional Anesthesia Experimental Treatment 1 Intervention

Single injection perioperative peripheral nerve block + followed by administration of oral narcotics on a need-based system

Group II: Long-Acting Local Anesthesia Experimental Treatment 1 Intervention

Subcutaneous local cocktail injection + followed by administration of oral narcotics on a need-based system

Group III: Traditional Pain Control Care Active Control 1 Intervention

Standard of care post-operative pain control with oral narcotics

Long-Acting Local Anesthesia is already approved in European Union, United States for the following indications:

Approved in European Union as Bupivacaine for:

• Pain relief for surgical procedures
• Postoperative pain management

Approved in United States as Bupivacaine for:

• Pain relief for surgical procedures
• Postoperative pain management
• Regional anesthesia

Approved in United States as Liposomal Bupivacaine for:

• Single-dose infiltration into the surgical site to produce postsurgical analgesia

Approved in European Union as Ropivacaine for:

• Pain relief for surgical procedures
• Postoperative pain management
• Regional anesthesia

Approved in United States as Ropivacaine for:

• Pain relief for surgical procedures
• Postoperative pain management
• Regional anesthesia

Approved in European Union as Etidocaine for:

• Pain relief for surgical procedures
• Postoperative pain management
• Regional anesthesia

Approved in United States as Etidocaine for:

• Pain relief for surgical procedures
• Postoperative pain management
• Regional anesthesia

Who Is Running the Clinical Trial?

University of Massachusetts, Worcester

Lead Sponsor

Trials

372

Recruited

998,000+

Lahey Clinic

Lead Sponsor

Trials

74

Recruited

245,000+

Findings from Research

Liposomal bupivacaine offers effective and safe pain management after surgery, providing long-lasting local analgesia for up to 72 hours with a single injection.

This slow-releasing formulation enhances patient satisfaction by reducing the need for additional pain medications following procedures like total ankle arthroplasties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration technique of liposomal bupivacaine for total ankle arthroplasty. Matsumoto, T., Parekh, SG.[2017]

In a study of 76 patients undergoing surgery for ankle fractures, the use of liposomal bupivacaine significantly reduced postoperative pain scores compared to a placebo, with effects lasting up to 2 weeks after surgery.

Patients receiving liposomal bupivacaine required less Percocet for pain management in the first 4 hours post-surgery, indicating its efficacy in improving pain control immediately after the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Liposomal Bupivacaine Administered With Standard Bupivacaine in Ankle Fractures Requiring Open Reduction Internal Fixation: A Single-Blinded Randomized Controlled Trial. Davidovitch, R., Goch, A., Driesman, A., et al.[2018]

In a study of 50 patients undergoing vaginal reconstructive surgery, liposomal bupivacaine (LB) did not show any significant advantage over plain bupivacaine in terms of postoperative pain control, narcotic use, or length of hospital stay.

Despite LB's higher cost, the results indicate that it is not more effective than plain bupivacaine for managing pain after surgery, suggesting a need for further research to find the best pain management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal versus plain bupivacaine for pain control following vaginal reconstruction. Jensen, S., Amasyali, AS., Keheila, M., et al.[2023]

In a study of 105 patients undergoing posterior spinal surgery, the use of liposomal bupivacaine (LB) significantly reduced patient-reported pain levels at 24 hours and 48-72 hours post-surgery compared to a control group, indicating its efficacy as a local analgesic.

Patients receiving LB also experienced a shorter average length of hospital stay (1.85 days) compared to those who did not receive LB (2.68 days), suggesting that LB may contribute to improved recovery outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal bupivacaine in posterior spine surgery: A piece of the puzzle for postoperative pain. Forrester, DA., Miner, H., Shirazi, C., 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 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]

Bupivacaine and etidocaine, long-acting local anesthetics introduced in the 1980s, have been associated with severe adverse reactions, including fatalities, even with small doses, highlighting their potential risks.

Animal studies indicate that bupivacaine and etidocaine have higher systemic toxicity compared to lidocaine, leading to serious central nervous system and cardiovascular issues, which can result in life-threatening conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic systemic reactions of bupivacaine and etidocaine. Bacsik, CJ., Swift, JQ., Hargreaves, KM.[2019]

A systematic review of 13 randomized controlled trials found that liposomal bupivacaine may provide longer pain relief compared to conventional local anesthetics in certain regional anesthesia techniques, particularly in transversus abdominis plane (TAP) blocks, with 3 out of 5 studies showing extended analgesia.

However, the evidence is not consistent across all studies, as some techniques did not demonstrate significant differences in analgesic duration, indicating that more research is needed to establish the efficacy of liposomal bupivacaine compared to standard bupivacaine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Liposomal Bupivacaine and Conventional Local Anesthetic Agents in Regional Anesthesia: A Systematic Review. Jin, Z., Ding, O., Islam, A., et al.[2023]

In a phase 3 study involving 150 subjects undergoing third molar extraction, liposomal bupivacaine (LB) showed a significant reduction in pain scores compared to placebo in the per-protocol population, indicating its potential efficacy as a pain management option.

Despite the promising results, the primary efficacy analysis did not show significant differences due to protocol violations, suggesting that further studies are needed to confirm LB's effectiveness and ensure adherence to study protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal Bupivacaine Use in Third Molar Impaction Surgery: INNOVATE Study. Lieblich, SE., Danesi, H.[2018]

In a study involving 52 patients undergoing wrist surgeries, liposomal bupivacaine and standard bupivacaine HCl provided similar pain control and opioid usage in the first four postoperative days.

There were no significant differences in pain scores or opioid requirements between the two anesthetics, indicating that liposomal bupivacaine does not offer a clear advantage over bupivacaine HCl for early postoperative pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupivacaine Extended-Release Liposomal Injection Versus Bupivacaine HCl for Early Postoperative Pain Control Following Wrist Operations: A Prospective, Randomized Control Trial. Dale, EL., Kluemper, CT., Cowart, SJ., et al.[2021]

Patients receiving bupivacaine liposome (Exparel) reported significantly lower pain levels and consumed fewer opioid pills on the day of surgery compared to those receiving standard bupivacaine (Marcaine).

However, the benefits of Exparel in reducing pain and opioid use were not sustained beyond the day of surgery, as no significant differences were observed in pain levels or total opioid consumption in the following days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective Randomized Study Comparing Bupivacaine Hydrochloride Versus Bupivacaine Liposome for Pain Management After Distal Radius Fracture Repair Surgery. Alter, TH., Liss, FE., Ilyas, AM.[2018]

Instilling 0.5% bupivacaine directly into the surgical wound before closure is a safe and effective method for significantly reducing postoperative foot pain.

This technique offers a practical alternative to oral narcotics and parenteral agents, minimizing side effects and the need for complex administration methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative pain relief using local anesthetic instillation. Bourne, MH., Johnson, KA.[2019]

References

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

Administration technique of liposomal bupivacaine for total ankle arthroplasty. [2017]

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

The Use of Liposomal Bupivacaine Administered With Standard Bupivacaine in Ankle Fractures Requiring Open Reduction Internal Fixation: A Single-Blinded Randomized Controlled Trial. [2018]

3. Canada pubmed.ncbi.nlm.nih.gov

Liposomal versus plain bupivacaine for pain control following vaginal reconstruction. [2023]

4. India pubmed.ncbi.nlm.nih.gov

Liposomal bupivacaine in posterior spine surgery: A piece of the puzzle for postoperative pain. [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

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

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

Toxic systemic reactions of bupivacaine and etidocaine. [2019]

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

Comparison of Liposomal Bupivacaine and Conventional Local Anesthetic Agents in Regional Anesthesia: A Systematic Review. [2023]

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

Liposomal Bupivacaine Use in Third Molar Impaction Surgery: INNOVATE Study. [2018]

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

Bupivacaine Extended-Release Liposomal Injection Versus Bupivacaine HCl for Early Postoperative Pain Control Following Wrist Operations: A Prospective, Randomized Control Trial. [2021]

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

A Prospective Randomized Study Comparing Bupivacaine Hydrochloride Versus Bupivacaine Liposome for Pain Management After Distal Radius Fracture Repair Surgery. [2018]

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

Postoperative pain relief using local anesthetic instillation. [2019]