Morphine + Vancomycin for Pain Control After Knee Replacement

Overseen By Devon Pekas, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Carilion Clinic

Must not be taking: Narcotics

Disqualifiers: Non-primary knee arthroplasty, Narcotic addiction, others

Prior Safety Data

Approved in 5 Jurisdictions

Trial Summary

What is the purpose of this trial?

Study investigators propose to investigate if a bony injection of pain medication during a knee replacement will help pain levels following primary knee replacement surgery. To investigate this, 86 patients will be enrolled. Half of the patients will receive a bony injection of antibiotics with morphine (pain medication) while the other half will receive a bony injection of antibiotics with placebo (no pain medication). Following surgery, patient pain levels and pain medication consumption will be measured. The injection is intraosseous meaning in the bone. The needle pierces the bone and the medication is injected into the bone. The site of injection is on the anterior (front) of the upper portion of the tibia. The medications are Vancomycin (antibiotic) and Morphine (pain medication) which are mixed in separate syringes and then injected. Intraosseous vancomycin is standard of care while intraosseous vancomycin with morphine is also standard of care, depending on operating surgeon.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have a history of chronic narcotic use or narcotic addiction, you may not be eligible to participate.

What data supports the effectiveness of the drug Morphine for pain control after knee replacement surgery?

Research shows that morphine, when added to spinal anesthesia, can improve pain relief for the first 24 hours after knee surgery. Additionally, morphine in various forms has been effective in managing pain after orthopedic surgeries, providing significant pain relief with manageable side effects. ^{1 2 3 4 5}

Is the combination of Morphine and Vancomycin safe for humans?

Morphine, including its controlled-release form MS Contin, has been studied for safety in humans. Some patients may experience side effects like respiratory depression (slowed breathing), but these are generally manageable with proper dosing and monitoring. Overall, morphine is considered safe when used as directed, though individual responses can vary. ^{6 7 8 9 10}

How does the drug combination of morphine and vancomycin differ from other pain control options after knee replacement?

The combination of morphine and vancomycin for pain control after knee replacement is unique because it potentially combines the pain-relieving effects of morphine with the antibacterial properties of vancomycin, which is not a standard approach for pain management in this context. Typically, morphine is used alone or in combination with other pain relievers, but not with antibiotics like vancomycin. ^{2 11 12 13 14}

Research Team

Joseph T Moskal, MD

Principal Investigator

Carilion Clinic

Eligibility Criteria

This trial is for patients undergoing primary knee replacement surgery due to osteoarthritis. Participants must be suitable for receiving intraosseous injections (directly into the bone) of medication during the procedure.

Inclusion Criteria

I am between 18 and 100 years old.

I have had a total knee replacement.

Participants must be able to consent for themselves

Exclusion Criteria

I am getting or have had a knee replacement that isn't my first.

Chronic narcotic use or history of narcotic addiction

Allergy to vancomycin

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo total knee arthroplasty with intraosseous injection of vancomycin with or without morphine

1 day

1 visit (in-person)

Postoperative Monitoring

Participants' pain levels and medication consumption are measured for 14 days postoperatively

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including patient-reported outcomes

6 weeks

Treatment Details

Interventions

• Morphine (Opioid)

Trial Overview The study tests if adding morphine to a standard bony injection of vancomycin, an antibiotic, can better manage pain after knee replacement surgery. Patients are randomly divided into two groups: one receives vancomycin with morphine and the other gets vancomycin with a placebo.

Participant Groups

Group I: Experimental (Intraosseous vancomycin with morphine) Experimental Treatment 2 Interventions

Control patients will receive 500 mg of vancomycin in 100 mL of normal saline + 10 mg of morphine in 10 mL of normal saline. Both with be injected intraosseously in the tibia.

Group II: Control (Intraosseous vancomycin with no morphine) Placebo Group 1 Intervention

Control patients will receive 500 mg of vancomycin in 100 mL of normal saline + 10 mL of normal saline (placebo). Both with be injected intraosseously in the tibia.

Who Is Running the Clinical Trial?

Carilion Clinic

Lead Sponsor

Trials

85

Recruited

15,400+

Findings from Research

In a study involving 10 patients with chronic moderate-to-severe pain, the once-daily extended-release morphine formulation (MSER) showed a 19% lower maximum concentration and a 66% higher minimum concentration compared to the twice-daily controlled-release morphine (CRM), indicating a more stable drug level throughout the day.

Both MSER and CRM had similar overall bioavailability and safety profiles, but MSER maintained effective morphine levels longer and with less fluctuation, suggesting it may provide more consistent pain control for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steady-state pharmacokinetic comparison of a new, extended-release, once-daily morphine formulation, Avinza, and a twice-daily controlled-release morphine formulation in patients with chronic moderate-to-severe pain. Portenoy, RK., Sciberras, A., Eliot, L., et al.[2022]

In a study involving 10 patients over 6 days, MS Contin (morphine sulfate in a wax cellulose matrix) demonstrated comparable analgesic efficacy to continuous intravenous morphine for treating burn pain.

MS Contin's oral dosing and extended duration of action make it a promising option for managing burn pain, similar to traditional intravenous morphine infusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of morphine sulfate (MS Contin) in patients with burns: a pilot study. Alexander, L., Wolman, R., Blache, C., et al.[2019]

In a study of 100 patients post-orthopedic surgery, MS Contin (MSC) 60 mg demonstrated superior analgesic efficacy compared to Oramorph SR (OSR) 60 mg, achieving significant pain relief within the first three hours after administration.

MSC 60 mg not only provided faster pain relief but also resulted in fewer adverse effects, with the OSR group experiencing nearly double the number of side effects, including increased somnolence and dizziness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic efficacy and safety of two oral controlled-release morphine preparations in orthopedic postoperative pain. Cooper, SA., Fitzmartin, R., Slywka, J., et al.[2013]

In a study comparing oral sustained-release morphine sulfate (MST) and intramuscular (IM) morphine in patients after total hip arthroplasty, both methods effectively managed pain with no significant difference in pain scores between the two groups.

Oral MST was found to be a viable alternative to IM morphine, with similar efficacy and a manageable side effect profile, making it an attractive option for postoperative pain management under regional anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of regularly administered sustained release oral morphine with intramuscular morphine for control of postoperative pain. Bourke, M., Hayes, A., Doyle, M., et al.[2019]

A patient with severe neuralgia experienced respiratory depression after taking a single 20 mg dose of controlled release morphine sulfate (MS Contin), highlighting a potential safety concern with this medication.

The immediate reversal of respiratory depression was achieved with nalorphine chloride, demonstrating the effectiveness of this intervention in managing opioid-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Respiratory depression following controlled-release morphine sulfate tablets]. Hoogslag, PA., van Dijk, B., Vinks, AA.[2013]

In a study involving 66 patients, adherence to established guidelines for titrating MS Contin (controlled-release morphine) resulted in effective pain management, with about 75% of patients reporting no or slight pain by the end of the study.

Only 5% of patients discontinued due to drug-related side effects, indicating that MS Contin is generally well-tolerated; however, there is a need for better management of side effects and consideration of patient-controlled titration to optimize pain relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of dosing guidelines for the use of oral controlled-release morphine (MS Contin tablets). Warfield, CA.[2019]

The 200 mg MS Contin tablet provides the same absorption rate and effectiveness as taking two 100 mg tablets, ensuring consistent pain relief.

This new higher strength formulation allows for easier dosing for patients needing larger morphine doses, giving doctors more options for managing pain effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Morphine at gramme doses: kinetics, dynamics and clinical need. Smith, KJ., Miller, AJ., McKellar, J., et al.[2013]

In a study of 23 adult cancer patients, both oral morphine sulfate solution (MSS) and controlled-release morphine sulfate tablets (MS Contin) provided effective pain control, with no significant differences in pain scores or side effects between the two formulations.

The study found that while both medications had similar bioavailability, MS Contin took longer to reach maximum morphine concentration (Tmax) compared to MSS, indicating that MSS may provide quicker pain relief, but both were well tolerated and effective for managing chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. Thirlwell, MP., Sloan, PA., Maroun, JA., et al.[2019]

The controlled-release morphine sulfate tablet (MS-contin) demonstrated a slower absorption rate and fewer side effects compared to the immediate-release morphine preparation, making it a safer option for patients.

Cancer patients using MS-contin experienced improved pain management with a longer dosing interval and a reduced total daily morphine requirement, enhancing their quality of life without significant development of tolerance over an average duration of 20.5 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled-release oral morphine sulfate in the treatment of cancer pain with pharmacokinetic correlation. Khojasteh, A., Evans, W., Reynolds, RD., et al.[2017]

In a study of 57 patients undergoing total knee arthroplasty, both intrathecal morphine and periarticular multimodal drug injection provided similar levels of postoperative pain control, indicating that neither method is superior in managing pain after surgery.

However, patients receiving intrathecal morphine experienced significantly more side effects, such as nausea and itching, compared to those who received the multimodal injection, suggesting that the latter may be a safer option with fewer adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is pain after TKA better with periarticular injection or intrathecal morphine? Tammachote, N., Kanitnate, S., Manuwong, S., et al.[2021]

In a study involving 53 patients undergoing simultaneous bilateral total knee arthroplasty, adding morphine to periarticular injections did not significantly improve postoperative pain relief, range of motion, or swelling compared to injections without morphine.

The findings suggest that the addition of morphine to the multimodal cocktail for knee injections is ineffective for local pain management, indicating that alternative strategies may be needed to address postoperative discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local Efficacy of Periarticular Morphine Injection in Simultaneous Bilateral Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Trial. Iwakiri, K., Ohta, Y., Kobayashi, A., et al.[2018]

In a study of 24 patients undergoing total knee arthroplasty, the intraosseous infusion of a multimodal pain management regimen combining morphine and ketorolac significantly reduced immediate postoperative pain and the need for additional opioid medication compared to a historical control group that received morphine alone.

While the multimodal approach showed benefits in the first four hours post-surgery, there were no significant differences in pain levels, opioid consumption, or nausea between the groups after this initial period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multimodal intraosseous infusion of morphine and ketorolac decreases early postoperative pain and opioid consumption following total knee arthroplasty. McNamara, CA., Laurita, J., Lambert, BS., et al.[2023]

In a study of 102 patients undergoing total knee arthroplasty, adding morphine to a multimodal pain relief injection did not improve pain relief, swelling, or range of motion compared to the injection without morphine.

Patients receiving morphine experienced significantly more nausea and vomiting, indicating that while morphine is commonly used for pain management, it may lead to adverse effects without providing additional benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Periarticular Morphine Injection for Total Knee Arthroplasty: A Randomized, Double-Blind Trial. Iwakiri, K., Minami, Y., Ohta, Y., et al.[2018]

References

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

Steady-state pharmacokinetic comparison of a new, extended-release, once-daily morphine formulation, Avinza, and a twice-daily controlled-release morphine formulation in patients with chronic moderate-to-severe pain. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

The effect of morphine added to periarticular multimodal drug injection or spinal anesthesia on pain management and functional recovery after total knee arthroplasty. [2019]

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

Use of morphine sulfate (MS Contin) in patients with burns: a pilot study. [2019]

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

Analgesic efficacy and safety of two oral controlled-release morphine preparations in orthopedic postoperative pain. [2013]

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

A comparison of regularly administered sustained release oral morphine with intramuscular morphine for control of postoperative pain. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

[Respiratory depression following controlled-release morphine sulfate tablets]. [2013]

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

Evaluation of dosing guidelines for the use of oral controlled-release morphine (MS Contin tablets). [2019]

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

Morphine at gramme doses: kinetics, dynamics and clinical need. [2013]

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

Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. [2019]

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

Controlled-release oral morphine sulfate in the treatment of cancer pain with pharmacokinetic correlation. [2017]

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

Is pain after TKA better with periarticular injection or intrathecal morphine? [2021]

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

Local Efficacy of Periarticular Morphine Injection in Simultaneous Bilateral Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Trial. [2018]

13. Netherlands pubmed.ncbi.nlm.nih.gov

A multimodal intraosseous infusion of morphine and ketorolac decreases early postoperative pain and opioid consumption following total knee arthroplasty. [2023]

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

Effect of Periarticular Morphine Injection for Total Knee Arthroplasty: A Randomized, Double-Blind Trial. [2018]