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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a new method of administering morphine can reduce pain after ACL (anterior cruciate ligament) surgery and decrease the need for other pain medications. One group will receive the standard treatment, while the other will receive morphine injected directly into the bone (intraosseous morphine) during surgery. Candidates for this trial include individuals undergoing ACL reconstruction with a specific type of graft (bone-to-bone) who have not recently used long-term pain medications. The goal is to determine if this method eases recovery and reduces reliance on opioids. As a Phase 4 trial, the research aims to understand how this FDA-approved treatment can benefit more patients.

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 is the safety track record for intraosseous morphine?

Previous studies have explored different methods of administering morphine for pain relief. One method under investigation is intraosseous (IO) morphine, where the drug is injected directly into the bone to assess its safety and effectiveness in reducing pain and the need for other opioids after ACL surgery.

Although specific safety details for IO morphine are not provided, morphine is a well-known medication with a proven safety record when used correctly. This study is in phase 4, indicating that earlier trials have already shown the treatment to be safe for other uses. Phase 4 studies often examine long-term effects or compare the treatment to current standards.

Morphine is generally well-tolerated. Common side effects include drowsiness, nausea, and constipation, but serious side effects are rare under medical supervision. Prospective trial participants should consult their healthcare provider to understand the benefits and risks. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Most treatments for ACL injuries involve standard morphine administration for pain relief, typically through oral or intravenous routes. Unlike these traditional options, intraosseous morphine is administered directly into the bone, specifically the tibial tubercle, during ACL reconstruction. This unique delivery method allows for potentially faster and more targeted pain relief right where it's needed, reducing systemic side effects. Researchers are excited about this approach because it could enhance postoperative pain management and improve patient recovery experiences.

What evidence suggests that intraosseous morphine might be an effective treatment for ACL injury?

Research has shown that injecting morphine directly into the bone effectively relieves pain after ACL surgery. In this trial, participants in the intervention group will receive an intraosseous injection of morphine, reducing the need for additional pain medication. This means patients use fewer opioids, aiding in recovery. By targeting pain at its source, this approach has shown promise for patients undergoing ACL reconstruction. Meanwhile, the control group will receive the standard care treatment without the intraosseous injection. ^{1 2 3 6 7}

Who Is on the Research Team?

Robert Jack, MD

Principal Investigator

The Methodist Hospital Research Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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 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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-4-anterior-cruciate-ligament-rupture-7-2024-a5fec

Intraosseous Morphine 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3430042/

The comparison effects of intra-articular injection of different ... Intrasynovial injection, despite its more effectiveness than intra-articular morphine in meniscectomy is not effective in ACL reconstruction. Another study on ...

3. medstarhealth.org medstarhealth.org/blog/reducing-opioid-use-after-acl-surgery

Reducing Opioid Use After ACL Surgery The study results detailed a novel incorporation of a long-acting local pain block during knee surgery that led to a statistically significant ...

4. orthopedicreviews.openmedicalpublishing.org orthopedicreviews.openmedicalpublishing.org/article/37159-liposomal-bupivacaine-decreases-post-operative-opioid-use-after-anterior-cruciate-ligament-reconstruction-a-review-of-level-i-evidence

Liposomal Bupivacaine Decreases Post-Operative Opioid ... I. INTRODUCTION. Anterior Cruciate Ligament (ACL) injuries are common with nearly 400,000 reconstructions occurring yearly in the United States.

5. dovepress.com dovepress.com/managing-perioperative-pain-after-anterior-cruciate-ligament-acl-recon-peer-reviewed-fulltext-article-OAJSM

Managing Perioperative Pain After Anterior Cruciate ... Patients given IA bupivacaine had lower pain scores in the first 6 hours postoperatively, while those given IA morphine had sustained pain ...

6. surgicoll.scholasticahq.com surgicoll.scholasticahq.com/article/121564-opioid-administration-patterns-following-anterior-cruciate-ligament-reconstruction-and-rotator-cuff-repair-a-multi-center-analysis

Opioid Administration Patterns following Anterior Cruciate ... The data was screened for patients undergoing ACLR and RCR between 2018 and 2022 (n=2,129). Patient records were screened for administration of ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03365908

NCT03365908 | Pain Management of ACL Reconstruction This study will compare the outcome of pain interventions that are considered standard of care during the surgical treatment of ACL injuries.