Intraosseous Morphine for ACL Injury

Overseen By Haley Goble

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: The Methodist Hospital Research Institute

Must not be taking: Chronic pain medication

Disqualifiers: Substance abuse, BMI >= 35, 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 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: Immediate (surgical procedure)

84 Participants Needed

Trial Summary

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

The trial excludes patients who have been on chronic pain medication within the last 6 months. If you are on such medication, you may not be eligible to participate.

What data supports the idea that Intraosseous Morphine for ACL Injury is an effective drug?

The available research shows that intra-articular morphine is effective for pain relief after ACL surgery. In one study, patients who received morphine had significantly lower pain scores compared to those who did not. Another study found that patients who received intra-articular morphine required less additional pain medication after surgery. This suggests that intra-articular morphine can effectively reduce pain and the need for other painkillers after ACL surgery. ^{1 2 3 4 5}

What safety data exists for intraosseous morphine treatment?

The provided research does not contain specific safety data for intraosseous morphine, morphine sulfate, or morphine hydrochloride. The studies focus on anaphylactoid reactions related to cyclosporine and the excipient Cremophor EL, as well as safety evaluations of polysorbate 20 and histological changes from percutaneous applications. None of these directly address the safety of intraosseous morphine. ^{6 7 8 9 10}

Is the drug Intraosseous Morphine a promising treatment for ACL injury?

Yes, Intraosseous Morphine is a promising drug for ACL injury because it provides effective pain relief after surgery, reduces the need for additional pain medication, and has fewer side effects compared to traditional methods. ^{1 2 4 5 11}

What is the purpose of this trial?

The purpose of this study is to determine if intraosseous (IO) morphine decreases pain and post-operative opioid use in patients undergoing anterior cruciate ligament (ACL) reconstruction.

Research Team

Robert Jack, MD

Principal Investigator

The Methodist Hospital Research Institute

Eligibility Criteria

This trial is for individuals undergoing anterior cruciate ligament (ACL) reconstruction. Specific eligibility criteria are not provided, but typically participants would need to be in good health aside from their ACL injury and able to comply with the study requirements.

Inclusion Criteria

My ACL surgery will be done by an approved surgeon using my own bone graft.

Exclusion Criteria

Vulnerable populations

I am having ACL surgery with a graft type that is not bone-tendon-bone.

Patients with a history of substance abuse

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo ACL reconstruction with either standard care or intraosseous morphine administration

Immediate (surgical procedure)

1 visit (in-person)

Post-operative Monitoring

Participants' pain levels, opioid use, activity level, and range of motion are monitored post-surgery

12 weeks

3 visits (in-person) at 2, 6, and 12 weeks postop

Follow-up

Participants are monitored for long-term outcomes and recovery progress

4 weeks

Treatment Details

Interventions

• Intraosseous Morphine

Trial Overview The study is testing whether giving morphine directly into the bone (intraosseous) can reduce pain and lessen the need for other opioids after ACL surgery.

Participant Groups

Group I: Intraosseous Injection of Morphine Experimental Treatment 1 Intervention

The intervention group will receive an intraosseous (IO) injection of 10mg of morphine mixed with up to 100mg of saline into the tibial tubercle during a standard ACL reconstruction.

Group II: Standard of Care Morphine Administration Active Control 1 Intervention

The control group will receive the standard of care treatment, which is no IO injection during a standard ACL reconstruction.

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

Approved in United States as Morphine for:

• Pain management
• Acute pain
• Chronic pain

Approved in European Union as Morphine for:

• Severe pain
• Acute pain
• Chronic pain

Approved in Canada as Morphine for:

• Pain management
• Acute pain
• Chronic pain

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

Findings from Research

In a study involving 40 athletes undergoing arthroscopic knee surgery, the use of 15 mg of intra-articular morphine significantly improved pain relief and extended the duration of analgesia compared to lower doses and saline.

No drowsiness or significant side effects were reported in any of the groups within the first 24 hours, indicating that 15 mg of morphine is a safe option for post-surgery pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic efficacy of intra-articular morphine after arthroscopic knee surgery in sport injury patients. Yari, M., Saeb, M., Golfam, P., et al.[2022]

Intraarticular morphine significantly reduced the total morphine consumption in the first 24 hours after anterior cruciate ligament repair, indicating its effectiveness in managing postoperative pain.

While the study group reported lower pain scores compared to the control group, the difference was not statistically significant, suggesting that while intraarticular morphine is beneficial, further research may be needed to confirm its impact on pain levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of intraarticular morphine on analgesic requirements after anterior cruciate ligament repair. Joshi, GP., McCarroll, SM., McSwiney, M., et al.[2013]

In a randomized, double-blind study of 20 patients undergoing ACL repair, those who received intra-articular morphine experienced significantly lower pain scores in the first 24 hours post-surgery compared to the saline control group.

Patients receiving morphine also required fewer additional pain medications, indicating that intra-articular morphine effectively reduces postoperative pain and improves pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intra-articular morphine for pain relief after anterior cruciate ligament repair. Joshi, GP., McCarroll, SM., Brady, OH., et al.[2022]

Intraarticular administration of morphine (1 mg and 5 mg) significantly reduced pain scores for up to 24 hours post-surgery compared to a control group receiving saline, indicating effective pain relief after ACL surgery.

The study found low levels of morphine and its metabolite morphine-6-glucuronide in the bloodstream after intraarticular injection, suggesting that morphine may work through a peripheral mechanism rather than systemic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraarticular morphine after arthroscopic ACL reconstruction: a double-blind placebo-controlled study of 40 patients. Brandsson, S., Karlsson, J., Morberg, P., et al.[2016]

In a study of 60 patients undergoing anterior cruciate ligament reconstruction, adding 10 mg of morphine to an intra-articular injection of bupivicaine significantly reduced the need for systemic opiate pain relief post-surgery.

Patients who received the morphine-bupivicaine combination required less oral morphine (27 mg) compared to those who received bupivicaine alone (50 mg), without any complications from the intra-articular analgesic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intra-articular morphine and bupivicaine for post-operative analgesia in anterior cruciate ligament reconstruction: a prospective randomised controlled trial. Senthilkumaran, S., Tate, R., Read, JR., et al.[2022]

In a phase I/II trial of high-dose intravenous cyclosporine (CsA) therapy involving 21 children, 5 experienced severe anaphylactoid reactions, which were linked to improper mixing of the vehicle Cremophor EL used in the infusion.

The study found that suboptimal mixing techniques led to uneven distribution of Cremophor EL, causing concentrated doses to trigger anaphylactoid reactions; this issue can be easily prevented with proper preparation, highlighting the importance of correct infusion techniques.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of Cremophor EL. Theis, JG., Liau-Chu, M., Chan, HS., et al.[2017]

CicloMulsion®, a new Cremophor® EL-free lipid emulsion of ciclosporin, is bioequivalent to the existing Sandimmune® formulation, showing similar pharmacokinetics in a study with 52 healthy volunteers.

CicloMulsion® demonstrated a significantly better safety profile, with no serious adverse events reported, while Sandimmune® was associated with serious hypersensitivity reactions, including anaphylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence and tolerability assessment of a novel intravenous ciclosporin lipid emulsion compared to branded ciclosporin in Cremophor ® EL. Ehinger, KH., Hansson, MJ., Sjövall, F., et al.[2021]

A four-week toxicity study in 66 rats and an irritation study in 18 rabbits showed that polysorbate 20, a non-human-derived excipient, is safe for intramuscular administration, with no observed systemic or local toxicities.

Polysorbate 20 demonstrated a safety profile comparable to human serum albumin (HSA), supporting its use as a reliable alternative in Botulinum toxin products, addressing concerns related to HSA's potential risks and supply issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits. Kim, J., Kwak, S., Park, MS., et al.[2022]

Histological evaluations of control animals (dogs, rabbits, and rats) revealed that various application procedures and vehicles caused significant skin changes, such as inflammation and acanthosis, indicating that these procedures can lead to skin injury.

The study identified that the type of application method influenced the degree of skin changes, with ointments and tapes causing more damage compared to lotions and creams, highlighting the importance of careful selection of application techniques in toxicity studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histological dermal changes caused by preparation and application procedures in percutaneous dose toxicity studies in dogs, rabbits and rats. Mitsuishi, M., Oshikata, T., Kumabe, S., et al.[2020]

Three patients experienced acute anaphylactoid reactions immediately after starting intravenous cyclosporine infusions post-organ transplantation, with symptoms including shortness of breath and flushing, but they recovered quickly after stopping the infusion.

The reactions are likely linked to Cremophor EL, an emulsifying agent in the intravenous formulation, and using slower infusion rates or premedicating with antihistamines may allow continued use of intravenous cyclosporine without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anaphylactoid reactions associated with parenteral cyclosporine use: possible role of Cremophor EL. Howrie, DL., Ptachcinski, RJ., Griffith, BP., et al.[2019]

Intra-articular injection of tenoxicam and morphine both effectively reduced postoperative pain after ACL reconstruction compared to a control group, indicating their analgesic efficacy.

While pain scores were similar between the tenoxicam and morphine groups shortly after surgery, patients receiving tenoxicam required significantly less additional analgesia 3-6 hours postoperatively, suggesting it may offer a more favorable pain management profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of analgesic effects of intra-articular tenoxicam and morphine in anterior cruciate ligament reconstruction. Guler, G., Karaoglu, S., Velibasoglu, H., et al.[2022]

References

1. Iran pubmed.ncbi.nlm.nih.gov

Analgesic efficacy of intra-articular morphine after arthroscopic knee surgery in sport injury patients. [2022]

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

Effects of intraarticular morphine on analgesic requirements after anterior cruciate ligament repair. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Intra-articular morphine for pain relief after anterior cruciate ligament repair. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Intraarticular morphine after arthroscopic ACL reconstruction: a double-blind placebo-controlled study of 40 patients. [2016]

5. Germany pubmed.ncbi.nlm.nih.gov

Intra-articular morphine and bupivicaine for post-operative analgesia in anterior cruciate ligament reconstruction: a prospective randomised controlled trial. [2022]

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

Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of Cremophor EL. [2017]

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

Bioequivalence and tolerability assessment of a novel intravenous ciclosporin lipid emulsion compared to branded ciclosporin in Cremophor ® EL. [2021]

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

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

Histological dermal changes caused by preparation and application procedures in percutaneous dose toxicity studies in dogs, rabbits and rats. [2020]

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

Anaphylactoid reactions associated with parenteral cyclosporine use: possible role of Cremophor EL. [2019]

11. Germany pubmed.ncbi.nlm.nih.gov

Comparison of analgesic effects of intra-articular tenoxicam and morphine in anterior cruciate ligament reconstruction. [2022]