Morphine + Vancomycin for Pain Control After Knee Replacement

Overseen By Devon Pekas, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Carilion Clinic

Must not be taking: Narcotics

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if injecting morphine directly into the bone during knee replacement surgery can reduce postoperative pain. It compares two groups: one receives morphine with antibiotics, and the other receives only antibiotics. Researchers will measure patients' pain levels and their need for pain medication after surgery. Individuals undergoing their first knee replacement surgery and comfortable with text messaging may be suitable candidates. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using a mix of morphine and vancomycin for pain relief after knee surgery yields promising results. Patients who received this mixture injected into their knee bone reported less pain post-surgery. This method is already common in some surgeries.

Regarding safety, studies have found that morphine can cause side effects like vomiting and drowsiness, but these are usually manageable. Vancomycin, an antibiotic, is generally safe when injected into the bone and is already a standard treatment.

Overall, while morphine can have some side effects, the combination with vancomycin has been used without major problems in similar surgeries. This suggests that the treatment is relatively safe and well-tolerated by patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pain control after knee replacement?

Researchers are excited about the combination of morphine and vancomycin for pain control after knee replacement because it introduces a novel delivery method. Unlike standard post-surgical pain treatments, which typically involve systemic administration of opioids like morphine, this approach delivers both morphine and the antibiotic vancomycin directly into the bone (intraosseously). This targeted delivery could potentially offer more effective pain relief while minimizing systemic side effects. Additionally, the use of vancomycin may help reduce the risk of infection, offering dual benefits in a single procedure.

What evidence suggests that this trial's treatments could be effective for pain control after knee replacement?

Research has shown that morphine effectively manages pain after knee replacement surgery. Studies have found that injecting morphine directly into the bone can significantly reduce pain for up to two weeks post-surgery. This method also decreases the need for additional pain medication, facilitating a smoother recovery. Although opioids like morphine can cause side effects, they remain a strong option for post-surgical pain control. In this trial, one group of participants will receive a combination of morphine and vancomycin injected into the bone to explore whether this combination improves pain relief after knee surgery. Another group will receive vancomycin without morphine as a control. ^{2 6 7 8 9}

Who Is on the Research Team?

Joseph T Moskal, MD

Principal Investigator

Carilion Clinic

Are You a Good Fit for This Trial?

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 have had a total knee replacement.

Participants must be able to consent for themselves

Capable and comfortable with text messaging

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Morphine

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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 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 97 patients undergoing total knee arthroplasty, adding morphine to spinal anesthesia significantly reduced rest pain and the need for additional analgesics in the first 12 hours post-surgery compared to other methods.

However, adding morphine to periarticular multimodal drug injection showed limited efficacy and did not enhance functional recovery, while also leading to more adverse effects like vomiting compared to the control group.

NCBI (Pubmed)

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. Miyamoto, S., Sugita, T., Aizawa, T., et al.[2019]

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]

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]

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 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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6819170/

Postoperative Pain Management in Total Knee Arthroplasty Although opioids are effective in pain management after TKA, there are some adverse effects associated with them, such as itchiness, nausea, ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2352344120302211

Randomized Double-Blind Controlled Trial Comparing 0.2 ... Conclusion. Postoperative pain control achieved with PI combined with ITM 0.1 mg after primary unilateral TKA was comparable to that achieved with ITM 0.2 mg.

3. houstonmethodist.org houstonmethodist.org/newsroom/a-new-way-to-control-pain-after-knee-replacement-surgery/

A new way to control pain after knee replacement surgery “By infusing pain medication intraosseously we're able to reduce postoperative pain for up to two weeks, reduce the number of pain pills ...

4. josr-online.biomedcentral.com josr-online.biomedcentral.com/articles/10.1186/s13018-024-05324-4

Advances in perioperative pain management for total knee ... This review aims to summarize current research on perioperative pain control in TKA and assess the effectiveness of different analgesic interventions.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03203967

Epidural Morphine for Postoperative Analgesia After Total ... Effectiveness of femoral nerve blockade for pain control after total knee arthroplasty. J Perianesth Nurs. 2006 Oct;21(5):311-6. doi: 10.1016/j.jopan ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3393054/

Long-acting morphine following hip or knee replacement The results yielded minimally improved pain scores and additional adverse effects (vomiting and oversedation). Published research in which long-acting opioids ( ...

7. read.houstonmethodist.org read.houstonmethodist.org/lessening-pain-after-knee-replacement-surgery

Lessening Pain After Knee Replacement Surgery Patients receiving a mixture of morphine and the antibiotic vancomycin injected into the tibia of their knee joint have lesser pain post-surgery.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0885392402003834

Efficacy and Safety of a Once-Daily Morphine Formulation ... Avinza and MS Contin reduced pain and improved several sleep measures versus placebo. Analgesic efficacy was comparable between Avinza and MS Contin ...

9. wmpllc.org wmpllc.org/ojs/index.php/jom/article/view/3079

Efficacy and safety of intrathecal morphine in total knee ... Conclusion: ITM reduces pain at 4 and 24 hours post-operatively with no effect on cumulative morphine consumption. The only feared side effect ...