Opioid-Free Pain Management for Prostate Cancer Surgery

Overseen by Ashok K Hemal, MD

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Wake Forest University Health Sciences

Must not be taking: Narcotics

Disqualifiers: Metastatic disease, Brain metastases, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The objective of this study is to conduct a randomized clinical trial to evaluate an opioid versus an opioid-free pathway of perioperative use of ketamine, ketorolac, and IV acetaminophen followed by the postoperative use of ketorolac, and oral acetaminophen for pain associated with robotic-assisted radical prostatectomy. Escalation to use of opioid treatment for the opioid-free constituents will be available if needed.

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

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you have a prescription for narcotics in the past 30 days or have chronic narcotic dependence. It's best to discuss your current medications with the trial team.

What data supports the idea that Opioid-Free Pain Management for Prostate Cancer Surgery is an effective treatment?

The available research shows that using drugs like ketorolac, which is part of opioid-free pain management, can be effective in managing pain. For example, ketorolac was found to be as effective as morphine in treating cancer pain, with fewer patients stopping its use due to side effects. Additionally, ketorolac has been shown to reduce the need for narcotic drugs, shorten hospital stays, and lower overall hospital costs. This suggests that opioid-free pain management can be a viable alternative to traditional opioid treatments, offering effective pain relief with fewer side effects and cost benefits. ^{1 2 3 4 5}

What safety data exists for opioid-free pain management in prostate cancer surgery?

The safety data for opioid-free pain management, particularly using ketorolac, shows that it is effective in reducing postoperative pain with minimal side effects. Ketorolac, a nonsteroidal anti-inflammatory drug (NSAID), has been shown to decrease the need for opioids by 40-45% in various studies, without increasing side effects. It is administered intramuscularly and is suitable for short-term use. However, more research is needed to fully understand its role and side effects in postoperative pain management. Additionally, studies have shown that combining ketorolac with other non-opioid analgesics like acetaminophen can provide effective pain relief in surgical settings. ^{1 6 7 8 9}

Is the drug combination of Acetaminophen, Ketamine, and Ketorolac a promising treatment for pain management after prostate cancer surgery?

Yes, the combination of Acetaminophen, Ketamine, and Ketorolac is promising for pain management after prostate cancer surgery. These drugs can help manage pain effectively without using opioids, which can have side effects like sedation and respiratory issues. This approach can reduce the need for opioids and their related side effects, making it a valuable option for patients. ^{1 10 11 12 13}

Research Team

Ashok K Hemal, MD

Principal Investigator

Atrium Health Wake Forest Baptist Comprehensive Cancer Center

Eligibility Criteria

Men aged 40-75 scheduled for robotic-assisted radical prostatectomy to treat localized prostate cancer can join. They must have normal liver and kidney function, no recent surgeries or narcotic prescriptions, and not be in prison. Participants with metastatic disease, unstable heart conditions, or chronic narcotic dependence are excluded.

Inclusion Criteria

I am a man aged 40-75 with prostate cancer, planning to undergo surgery.

My liver and kidney functions are within normal ranges.

I can understand and am willing to sign the consent form.

Exclusion Criteria

I have been prescribed narcotics in the last 30 days.

I have not had major surgery in my pelvis or abdomen in the last 6 months.

Participants with known allergies to any medication involved in the study or its excipients

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preoperative

Participants undergo preoperative assessments and preparation for surgery

1 day

1 visit (in-person)

Surgery and Immediate Postoperative

Participants undergo robotic-assisted radical prostatectomy and receive either opioid or non-opioid pain management

1 day

Inpatient stay

Postoperative Pain Management

Participants receive postoperative pain management with either opioid or non-opioid regimen

7-10 days

1 visit (in-person) for follow-up

Follow-up

Participants are monitored for safety and effectiveness after treatment

7-10 days

1 visit (in-person)

Treatment Details

Interventions

• Acetaminophen (Analgesic)
• Ketamine (Anaesthetic)
• Ketorolac (Analgesic)
• Opioid-Free Pain Control Regimen (Other)
• Oxycodone (Opioid)

Trial Overview The trial is testing pain management strategies post-prostate surgery: one group receives ketamine, ketorolac, and acetaminophen without opioids; the other uses traditional opioid-based treatment (oxycodone). If necessary, patients on the opioid-free path may receive opioids.

Participant Groups

Group I: Opioid Control Cohort Active Control 2 Interventions

Participants will receive standard general anesthesia and receive local anesthesia medication (bupivacaine) during surgery per the investigator's surgical protocol. AFTER surgery participants will be administered oxycodone and acetaminophen.

Group II: Experimental Non-Opioid Cohort Active Control 3 Interventions

Participants will receive standard general anesthesia and receive local anesthesia medication (bupivacaine) during surgery per the investigator's surgical protocol. BEFORE and AFTER surgery participants will be administered Ketamine; DURING surgery Ketorolac and acetaminophen.

Acetaminophen is already approved in Canada for the following indications:

Approved in Canada as Tylenol for:

• Pain relief
• Fever reduction

Who Is Running the Clinical Trial?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

Dr. L. Ebony Boulware

Wake Forest University Health Sciences

Chief Medical Officer since 2022

MD from Duke University School of Medicine, MPH from Johns Hopkins Bloomberg School of Public Health

Dr. Julie Ann Freischlag

Wake Forest University Health Sciences

Chief Executive Officer since 2020

BS from University of Illinois, MD from Rush University

Findings from Research

Adding nefopam to a multimodal analgesia regimen that included paracetamol, ketoprofen, and ketamine did not significantly improve pain relief after total hip arthroplasty, as both groups had similar morphine consumption and pain scores.

However, the nefopam group experienced significantly lower rates of nausea, vomiting, pruritus, and visual disturbances compared to the control group, suggesting nefopam may help reduce side effects associated with morphine use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nefopam after total hip arthroplasty: role in multimodal analgesia. Remérand, F., Le Tendre, C., Rosset, P., et al.[2022]

Ketorolac tromethamine (KT) demonstrated high efficacy in managing pain after surgery, with 83% effectiveness reported after a single injection, making it comparable to opioid analgesics.

The combination of KT with morphine allowed for a significant reduction in morphine dosage by 40-50%, while side effects were relatively low, occurring in only 15% of patients, primarily involving mild symptoms like fever and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Methods of the use of ketorolac tromethamine in patients during the early postoperative period]. Lebedeva, RN., Maiachkin, RB., Nikoda, VV., et al.[2013]

In a study involving 51 patients with moderate to severe cancer pain, ketorolac tromethamine and morphine showed no significant difference in overall analgesic efficacy, indicating that ketorolac can be an effective alternative for pain management.

While 57% of patients on ketorolac and 74% on morphine changed their analgesic, significantly more patients discontinued ketorolac due to inadequate pain relief, whereas more patients stopped morphine due to side effects like nausea, suggesting ketorolac has a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative-study of intramuscular ketorolac tromethamine and morphine in patients experiencing cancer pain. Jameel, A., Stein, R., Rawson, N., et al.[2019]

In a study of 50 patients undergoing major gynecological cancer surgery, a single intravenous dose of 100 mg ketoprofen significantly reduced the need for tramadol, a common pain medication, by lowering its consumption compared to a placebo group.

Despite the reduction in tramadol use, there were no significant differences in pain scores, side effects, or patient satisfaction between the ketoprofen and placebo groups, indicating that ketoprofen is effective in reducing opioid requirements without compromising overall pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding ketoprofen to intravenous patient-controlled analgesia with tramadol after major gynecological cancer surgery: a double-blinded, randomized, placebo-controlled clinical trial. Tuncer, S., Pirbudak, L., Balat, O., et al.[2020]

In a study of 229 patients treated with ketorolac for postoperative pain management, it was found that ketorolac significantly reduced the length of hospital stay by an average of 1.15 days compared to a matched cohort of 821 patients who did not receive the drug.

Ketorolac also led to lower usage of narcotics and fewer adverse drug events, resulting in overall reduced hospital costs, highlighting its effectiveness as a narcotic-sparing analgesic in postoperative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the financial impact of ketorolac tromethamine therapy in hospitalized patients. Burke, JP., Pestotnik, SL., Classen, DC., et al.[2019]

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 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]

In a study of 115 patients with bone cancer pain, dexketoprofen trometamol (25 mg) was found to be as effective as ketorolac (10 mg) in reducing pain, with a significant improvement in the pain rating index for dexketoprofen (8.5 vs. 9.7, P=0.04).

Dexketoprofen had a better safety profile, with fewer patients withdrawing due to adverse effects (16% for dexketoprofen vs. 24% for ketorolac), indicating it is a well-tolerated option for managing bone cancer pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain. Rodríguez, MJ., Contreras, D., Gálvez, R., et al.[2019]

In a study of 100 patients undergoing gynecologic surgeries, both acetaminophen and ketorolac provided similar levels of post-operative pain relief, as measured by visual analogue scales and total morphine usage.

Patients receiving ketorolac experienced less reliance on dilaudid for pain control and returned to normal bowel function faster than those receiving acetaminophen, although overall length of hospital stay and blood transfusion rates were comparable between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective randomized trial of intravenous ketorolac vs. acetaminophen administered with opioid patient-controlled analgesia in gynecologic surgery. Rakowski, JA., Holloway, RW., Ahmad, S., et al.[2019]

Craniotomy pain is often severe and can be challenging to manage due to the need to balance effective pain relief with the risk of adverse effects from opioids, such as sedation and respiratory depression.

Non-opioid analgesics, including regional scalp blocks, paracetamol, and non-steroidal anti-inflammatory drugs, are effective for managing post-craniotomy pain and may be used in combination with newer analgesics like dexmedetomidine and ketamine, although further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Craniotomy Pain Management: Beyond Opioids. Dunn, LK., Naik, BI., Nemergut, EC., et al.[2018]

The review of 13 randomized-controlled trials on NSAIDs and paracetamol for cancer pain management indicates that their role remains controversial, with no clear evidence supporting their use as initial treatments alongside opioids.

While paracetamol appears to offer little benefit at standard doses, ketorolac may provide an additional analgesic effect when used with opioids, suggesting that NSAIDs could be beneficial for some patients in managing cancer pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The long and winding road of non steroidal antinflammatory drugs and paracetamol in cancer pain management: a critical review. Mercadante, S., Giarratano, A.[2018]

Non-opioid analgesics like paracetamol, NSAIDs, and gabapentinoids significantly reduce post-operative morphine requirements, with gabapentinoids showing the highest reduction of ≥13 mg morphine per 24 hours when used alone.

The evidence for the effectiveness of glucocorticoids in reducing opioid use is less convincing, and there is a need for more research on the benefits of combination regimens of these non-opioid drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review. Dahl, JB., Nielsen, RV., Wetterslev, J., et al.[2022]

In a study of 154 patients undergoing total hip arthroplasty, ketamine significantly reduced morphine consumption in the first 24 hours post-surgery, demonstrating its effectiveness as part of a multimodal analgesia approach.

Ketamine not only aided in immediate pain management but also reduced the incidence of chronic pain at rest in the operated hip up to 6 months after surgery, indicating its potential long-term benefits for postoperative recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. Remérand, F., Le Tendre, C., Baud, A., et al.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

Nefopam after total hip arthroplasty: role in multimodal analgesia. [2022]

2. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Methods of the use of ketorolac tromethamine in patients during the early postoperative period]. [2013]

3. Greece pubmed.ncbi.nlm.nih.gov

Comparative-study of intramuscular ketorolac tromethamine and morphine in patients experiencing cancer pain. [2019]

4. Singapore pubmed.ncbi.nlm.nih.gov

Adding ketoprofen to intravenous patient-controlled analgesia with tramadol after major gynecological cancer surgery: a double-blinded, randomized, placebo-controlled clinical trial. [2020]

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

Evaluation of the financial impact of ketorolac tromethamine therapy in hospitalized patients. [2019]

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

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

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

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

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

Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain. [2019]

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

A prospective randomized trial of intravenous ketorolac vs. acetaminophen administered with opioid patient-controlled analgesia in gynecologic surgery. [2019]

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

Post-Craniotomy Pain Management: Beyond Opioids. [2018]

11. Netherlands pubmed.ncbi.nlm.nih.gov

The long and winding road of non steroidal antinflammatory drugs and paracetamol in cancer pain management: a critical review. [2018]

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

Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review. [2022]

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

The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. [2022]