HTX-011 for Pain Management in Total Knee Replacement

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Mayo Clinic

Must not be taking: Opioids, NSAIDs

Disqualifiers: Chronic pain, Severe renal, 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: Unknown

Duration: 1 week

209 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing HTX-011, a pain control medication, on patients having knee replacement surgery. The goal is to see if it provides better pain relief by numbing the surgical area for several days. HTX-011 is a dual-acting local anesthetic combining bupivacaine and meloxicam in an extended-release polymer, designed to provide prolonged pain relief and reduce opioid use.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have a history of prolonged daily opioid use or allergies to NSAIDs, you may not be eligible to participate.

What data supports the effectiveness of the drug HTX-011 for pain management in total knee replacement?

Research shows that ketorolac, a component of HTX-011, is effective in reducing postoperative pain and decreasing the need for narcotics after surgeries, including knee replacements. Studies have demonstrated that ketorolac, when used in combination with other pain management strategies, provides significant pain relief and reduces narcotic requirements. ^{1 2 3 4 5}

Is HTX-011 safe for use in humans?

Ketorolac, a component of HTX-011, has been used safely for managing postoperative pain, showing minimal side effects and reducing the need for narcotics. However, it may increase the risk of bleeding in neurosurgical patients, and its use is generally limited to short-term treatment due to potential kidney effects. ^{1 3 4 6 7}

How is HTX-011 different from other drugs for pain management in total knee replacement?

HTX-011 is unique because it combines bupivacaine and meloxicam in an extended-release form, providing longer-lasting pain relief and reducing the need for opioids after surgery. This dual-acting local anesthetic is applied without needles during surgery and has shown to be more effective than standard bupivacaine in managing postoperative pain. ^{8 9 10 11 12}

Research Team

Matthew P Abdel, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults over 18 years old needing a primary total knee replacement due to joint disease, who can consent and have an ASA classification I to III. It's not for those with severe health issues like kidney injury, high opioid use, extreme obesity (BMI > 45), allergies to NSAIDs, cognitive impairments, or major illnesses such as advanced heart or liver diseases.

Inclusion Criteria

I am getting a knee replacement due to arthritis.

I am able to understand and agree to the study's procedures and risks.

I am 18 or older with a health status that allows for safe surgery.

Exclusion Criteria

Your body mass index (BMI) is higher than 45, which means you are very overweight.

I have been taking strong painkillers daily for over a month.

I am unable to give my own consent for medical procedures.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo total knee arthroplasty and receive either HTX-011 or standard of care for perioperative analgesia

1 week

Inpatient surgery and monitoring

Follow-up

Participants are monitored for pain control and opioid consumption postoperatively

1 week

Postoperative monitoring and assessments

Treatment Details

Interventions

• Bupivacaine
• Epinephrine
• Ketorolac
• Meloxicam ER Solution
• Ropivacaine

Trial Overview The study tests HTX-011 against standard pain control practices after knee surgery. HTX-011 is FDA-approved and may offer better pain management within the first 72 hours post-surgery compared to the usual mix of ropivacaine, epinephrine, ketorolac in saline.

Participant Groups

Group I: HTX-011 Treatment Group Experimental Treatment 1 Intervention

Subjects undergoing a total knee arthroplasty will receive HTX-011 (Zynrelef) for perioperative analgesia

Group II: Standard Block Control Group Active Control 1 Intervention

Subjects undergoing a total knee arthroplasty will receive standard of care arthroplasty block for perioperative analgesia

Epinephrine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Approved in United States as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Approved in Canada as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

In a randomized study involving patients after extensive colonic resections, the combination of intramuscular ketorolac and patient-controlled intravenous morphine provided equal pain relief compared to morphine alone, without increasing side effects.

The use of ketorolac significantly reduced the need for narcotics by an average of 45%, making it a valuable option for patients at risk of narcotic-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac and patient controlled analgesia in the treatment of postoperative pain. Cataldo, PA., Senagore, AJ., Kilbride, MJ.[2013]

Ketorolac tromethamine is an effective nonsteroidal anti-inflammatory drug (NSAID) for managing moderate to severe postoperative pain, reducing the need for opioid analgesics, which can help minimize opioid-related side effects.

Administered intramuscularly, ketorolac reaches peak plasma levels in about 45 to 50 minutes and has a low incidence of side effects, making it a promising option for both inpatient and outpatient pain management, although further research is needed to fully understand its role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac: a new parenteral nonsteroidal anti-inflammatory drug for postoperative pain management. Lassen, K., Epstein-Stiles, M., Olsson, GL.[2013]

In a study involving 155 patients, ketorolac tromethamine was found to provide better pain relief than morphine sulfate at lower doses (30 and 90 mg) for moderate to severe postoperative pain, especially after the first hour.

Ketorolac demonstrated a favorable safety profile, with no serious side effects reported, while morphine was associated with somnolence in 8% of patients, highlighting ketorolac as a safe and effective alternative for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. O'Hara, DA., Fragen, RJ., Kinzer, M., et al.[2022]

In a study of 4086 patients undergoing elective neurosurgery, those who received ketorolac had a significantly lower incidence of symptomatic intracranial hemorrhage (ICH) at 0.5% compared to 1.3% in those who did not receive the drug, suggesting a potential protective effect against bleeding.

Despite the lower observed risk of ICH in patients taking ketorolac, the adjusted odds ratio was close to 1, indicating that the findings may not be conclusive enough to definitively establish the safety of ketorolac in this surgical context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial hemorrhage requiring surgery in neurosurgical patients given ketorolac: a case-control study within a cohort (2001-2010). Magni, G., La Rosa, I., Melillo, G., et al.[2022]

The intranasal formulation of ketorolac tromethamine, known as SPRIX, provides a similar pharmacokinetic profile to intramuscular administration, making it an effective option for treating moderately severe acute pain.

Toxicology studies in rats and rabbits indicate that SPRIX has a safety profile comparable to other administration routes, with no adverse effects observed on the nasal passages or respiratory system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation. Boyer, KC., McDonald, P., Zoetis, T.[2013]

In a study of 51 patients undergoing total knee arthroplasty (TKA), the dual-acting local anesthetic HTX-011, combined with a multimodal analgesic (MMA) regimen, significantly reduced postoperative pain and opioid consumption compared to previous treatments.

The majority of patients reported mild pain levels, with 39% being discharged without an opioid prescription, indicating that HTX-011 with MMA is both effective and well-tolerated, with no additional safety risks observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HTX-011 in Combination with Multimodal Analgesic Regimen Minimized Severe Pain and Opioid Use after Total Knee Arthroplasty in an Open-Label Study. Lee, GC., Berkowitz, R., Hacker, S., et al.[2023]

HTX-011, an extended-release local anesthetic, effectively reduced postoperative pain and opioid use in bunionectomy patients, with 77% of participants remaining opioid-free during recovery.

The combination of HTX-011 with scheduled ibuprofen and acetaminophen maintained mild pain levels (NRS <4) for 72 hours post-surgery, demonstrating its safety and efficacy as part of a multimodal analgesia regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opioid-Free Recovery from Bunionectomy with HTX-011, a Dual-Acting Local Anesthetic Combining Bupivacaine and Meloxicam, as the Foundation of Non-Opioid Multimodal Analgesia. Pollak, R., Cai, D., Gan, TJ.[2021]

References

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

Population Pharmacokinetics of Periarticular Ketorolac in Adult Patients Undergoing Total Hip or Total Knee Replacement Surgery. [2023]

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

Efficacy of multimodal perioperative analgesia protocol with periarticular medication injection in total knee arthroplasty: a randomized, double-blinded study. [2022]

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

Ketorolac and patient controlled analgesia in the treatment of postoperative pain. [2013]

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

Ketorolac: a new parenteral nonsteroidal anti-inflammatory drug for postoperative pain management. [2013]

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

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. [2022]

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

Intracranial hemorrhage requiring surgery in neurosurgical patients given ketorolac: a case-control study within a cohort (2001-2010). [2022]

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

A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

HTX-011 in Combination with Multimodal Analgesic Regimen Minimized Severe Pain and Opioid Use after Total Knee Arthroplasty in an Open-Label Study. [2023]

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

Opioid-Free Recovery from Bunionectomy with HTX-011, a Dual-Acting Local Anesthetic Combining Bupivacaine and Meloxicam, as the Foundation of Non-Opioid Multimodal Analgesia. [2021]

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

Opioid-free recovery after herniorrhaphy with HTX-011 as the foundation of a multimodal analgesic regimen. [2020]

11. England pubmed.ncbi.nlm.nih.gov

HTX-011 (bupivacaine and meloxicam) for the prevention of postoperative pain - clinical considerations. [2021]

12. England pubmed.ncbi.nlm.nih.gov

HTX-011 effectively reduces postoperative pain intensity and opioid use in the elderly. [2022]