Analgesic Regimens for Surgical Pain

(CARES for Kids Trial)

Recruiting at 3 trial locations

Overseen By Sarah Clark

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Michigan

Disqualifiers: Complex chronic conditions, Liver disease, Acute psychiatric instability, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

900 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you have no significant pain medication use before surgery. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

What data supports the effectiveness of the drug combination of tramadol and acetaminophen for surgical pain?

Research shows that the combination of tramadol and acetaminophen is effective for controlling postoperative pain, as it was found to be superior to tramadol alone in reducing pain after oral surgery. Additionally, using paracetamol (another name for acetaminophen) with tramadol in multimodal analgesia regimens provides a good analgesic effect without the need for narcotic drugs. ^{1 2 3 4 5}

Is the analgesic regimen for surgical pain generally safe for humans?

Paracetamol (acetaminophen) and NSAIDs (non-steroidal anti-inflammatory drugs) like ibuprofen are commonly used for mild-to-moderate pain, but NSAIDs can cause stomach issues and increase the risk of heart problems. Paracetamol combined with weak opioids like tramadol is considered effective and safe for managing moderate-to-severe pain. It's important to use the lowest effective dose for the shortest time to minimize risks. ^{6 7 8 9 10}

How does the drug regimen for surgical pain differ from other treatments?

This drug regimen for surgical pain is unique because it combines multiple types of pain relievers, including acetaminophen, NSAIDs, and opioids, to provide effective pain relief with fewer side effects. The use of a multimodal approach, which involves different drugs working through various mechanisms, helps achieve better pain control and minimizes the need for opioids, which can have adverse reactions. ^{2 11 12 13 14}

What is the purpose of this trial?

This trial is being completed to compare two commonly used options to treat pain after discharge from surgery. Participants that undergo tonsil removal, gallbladder removal, and knee scope will be eligible to enroll. Eligible participants will be randomized to prescription of 1 of 2 groups of medications (Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) plus acetaminophen or low dose opioids with the NSAIDs plus acetaminophen. The key question the study seeks to answer is which option will have the best outcomes and with the fewest side effects?

Research Team

Mark Bicket, MD

Principal Investigator

University of Michigan

Eligibility Criteria

This trial is for kids who've had tonsillectomies, gallbladder removals, or knee scopes. They'll be randomly assigned to one of two pain management groups after surgery: NSAIDs with acetaminophen or a low dose opioid combined with NSAIDs and acetaminophen.

Inclusion Criteria

I haven't used strong painkillers before surgery.

I am scheduled for elective tonsil, gallbladder, or knee surgery.

Exclusion Criteria

I expect to have another surgery within the next year.

Acute psychiatric instability (defined as current uncontrolled severe depression, severe post-traumatic stress disorder (PTSD), or suicidal ideation), substance use disorder not in remission or treatment, and history of diversion of controlled substances (opioids)

Anticipated life expectancy of less than 12 months

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo surgery and are randomized to receive either NSAIDs plus acetaminophen or low dose opioids with NSAIDs plus acetaminophen for pain management

2 weeks

Post-surgery follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including pain intensity and adverse medication-related symptoms

12 months

Regular follow-up assessments

Long-term monitoring

Participants are assessed for long-term outcomes such as chronic pain, opioid misuse, and healthcare utilization

Up to 12 months

Treatment Details

Interventions

• Acetaminophen
• Ibuprofen
• NSAID
• Opioid

Trial Overview The study compares the effectiveness and safety of two post-surgery pain treatments in children. One group will receive non-opioid drugs (NSAIDs plus acetaminophen), while the other will get a combination including a low-dose opioid.

Participant Groups

Group I: Acetaminophen/NSAID/Opioid regimen Experimental Treatment 3 Interventions

Group II: Acetaminophen/NSAID regimen Experimental Treatment 2 Interventions

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

Approved in United States as Tylenol for:

• Pain relief
• Fever reduction

Approved in European Union as Paracetamol for:

• Pain relief
• Fever reduction

Approved in Canada as Tylenol for:

• Pain relief
• Fever reduction

Who Is Running the Clinical Trial?

University of Michigan

Lead Sponsor

Trials

1,891

Recruited

6,458,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Findings from Research

In a multicenter trial involving 305 patients, tramadol combined with acetaminophen (APAP) was found to be significantly more effective than placebo for managing postsurgical pain, providing better total pain relief and lower pain intensity.

Tramadol plus APAP was better tolerated than codeine plus APAP, with fewer adverse events like constipation and vomiting, making it a safer alternative for pain management after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination tramadol plus acetaminophen for postsurgical pain. Smith, AB., Ravikumar, TS., Kamin, M., et al.[2013]

In a study involving 50 adult patients undergoing surgery, Tramadol (100 mg IM) provided better pain control than Ketorolac (30 mg IM) at all assessed post-operative time points, indicating its efficacy as a pain management option.

Both Tramadol and Ketorolac significantly reduced pain intensity post-surgery, but Tramadol was associated with better tolerance and only mild side effects, suggesting it may be a safer choice for managing moderate to severe pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tramadol versus ketorolac in the treatment of postoperative pain following maxillofacial surgery. Shankariah, M., Mishra, M., Kamath, RA.[2022]

In a study of 54 children aged 1-15 years, IV ketoprofen significantly improved postoperative pain management when used alongside epidural sufentanil, leading to a reduced need for sufentanil and allowing for earlier discontinuation of the epidural infusion.

The ketoprofen group experienced lower pain scores during activity and fewer adverse effects, such as desaturation and fever, compared to the placebo group, indicating that ketoprofen is a safe and effective adjuvant for pain relief after major surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of intravenous ketoprofen on postoperative epidural sufentanil analgesia in children. Kokki, H., Tuovinen, K., Hendolin, H.[2019]

In a study of 456 patients with moderate-to-severe pain after oral surgery, tramadol/acetaminophen (APAP) was found to be significantly more effective than tramadol alone or placebo in providing pain relief, with better scores on all efficacy measures.

Tramadol/APAP not only provided faster pain relief onset compared to tramadol and placebo, but it also had a lower incidence of adverse effects like nausea and dizziness, making it a safer option for post-surgical pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain. Fricke, JR., Hewitt, DJ., Jordan, DM., et al.[2021]

In a study of 53 patients who underwent surgeries on the aorta and lower extremities, various combinations of non-narcotic analgesics were evaluated for effective postoperative pain relief, showing that multimodal regimens can provide good analgesia without narcotics.

The combination of paracetamol with tramadol not only led to a quicker onset of pain relief but also reduced the need for tramadol, making it a safer option for patients at high risk for complications from non-steroidal anti-inflammatory drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Systemic multimodality postoperative analgesia in vascular surgery]. Kazennov, VV., Shishkin, MN., Amerov, DB.[2019]

Chronic pain affects up to 50% of the European population, leading to a growing need for safe and effective pain management strategies, especially among the elderly with complex health issues.

While traditional pain relievers like NSAIDs and paracetamol are effective, they carry risks such as gastrointestinal issues and cardiovascular events, prompting a shift towards safer alternatives like fixed-dose combinations of paracetamol with weak opioids, such as tramadol, for managing moderate-to-severe pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pain management today - what have we learned? Langford, RM.[2022]

Paracetamol and codeine are identified as safe alternative pain relievers for patients who cannot tolerate traditional analgesics.

Recent selective COX-2 inhibitors, including nimesulide, meloxicam, and rofecoxib, are also considered safe options for pain management in these patients, particularly in the context of their recent marketing in Turkey.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of nimesulide, meloxicam and rofecoxib as alternative analgesics. Karakaya, G., Kalyoncu, AF.[2018]

Tramadol/paracetamol (TRM+P) has the highest reporting rate of adverse drug reactions (ADRs) among the three weak opioid analgesics studied, with a rate of 44.5 per 100,000 person-years, compared to 24.9 for dextropropoxyphene/paracetamol (DXP+P) and 12.5 for codeine/paracetamol (COD+P).

Dextropropoxyphene/paracetamol (DXP+P) is associated with a higher frequency of hepatobiliary ADRs and a worse safety profile compared to codeine/paracetamol (COD+P), despite having a lower overall reporting rate of ADRs than tramadol/paracetamol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reporting rate of adverse drug reactions to the French pharmacovigilance system with three step 2 analgesic drugs: dextropropoxyphene, tramadol and codeine (in combination with paracetamol). Tavassoli, N., Lapeyre-Mestre, M., Sommet, A., et al.[2021]

A study of 576 participants in southwestern France revealed that while 76.2% recognized paracetamol as the first-line analgesic, knowledge about the maximum daily doses was low, with only 58.3% knowing the correct dose for paracetamol.

Participants showed significant gaps in understanding precautions and contraindications, particularly regarding ibuprofen and aspirin use during pregnancy and interactions with anticoagulants, indicating a need for better education on nonprescription medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients' Knowledge About Analgesic-Antipyretic Medications Purchased in Community Pharmacies: A Descriptive Study. Grézy-Chabardès, C., Fournier, JP., Dupouy, J., et al.[2017]

The review emphasizes that while analgesics, both non-opioid (like paracetamol and NSAIDs) and opioid medications, are commonly used for pain management, they carry significant risks of adverse drug reactions (ADRs) that can often be prevented.

Recognizing and understanding the safety issues associated with analgesics is crucial for healthcare professionals to ensure effective pain treatment while minimizing risks, highlighting the importance of careful patient monitoring and consideration of individual medical factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety issues of current analgesics: an update. Cazacu, I., Mogosan, C., Loghin, F.[2022]

A multimodal approach to postoperative pain management, which combines various drugs and techniques, is essential for effective pain relief while minimizing opioid use and their associated side effects.

Local anesthesia, higher doses of paracetamol, and the use of selective COX-2 inhibitors are highlighted as effective alternatives to opioids, with the potential for fewer side effects and improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-opioid postoperative analgesia. Dahl, V., Raeder, JC.[2022]

In a study of 60 patients undergoing major head and neck surgery, both ketoprofen and metamizole provided similar pain relief during the first 48 hours post-surgery.

However, ketoprofen was found to be more effective than metamizole in reducing pain on the 3rd postoperative day, indicating its potential for better long-term analgesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketoprofen is superior to metamizole in relieving postoperative pain after head and neck tumor operation. Jovic, R., Dragicevic, D., Komazec, Z., et al.[2015]

In a study involving cancer patients undergoing extensive surgeries, administering ketoprofen (ketonal) as a preventive measure significantly reduced postoperative pain, achieving adequate pain relief in 47% of patients.

The use of ketoprofen allowed for lower reliance on stronger opioids, with only 2 patients requiring a potent opioid (buprenorfin) for pain management, highlighting its efficacy and potential to minimize opioid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ketoprofen (ketonal): a drug for preventing and treating postoperative pain]. Osipova, NA., Beresnev, VA., Vetsheva, MS., et al.[2013]

A multimodal analgesic approach, including preoperative steroids, local anesthetics, NSAIDs or COX2-inhibitors, and paracetamol, is recommended to effectively manage early pain after laparoscopic cholecystectomy.

Surgical technique adjustments, such as using lower insufflation pressure and smaller trocars, along with providing patients with information about expected pain, can enhance pain relief following the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of pain after laparoscopic cholecystectomy]. Bisgaard, T.[2013]

References

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

Combination tramadol plus acetaminophen for postsurgical pain. [2013]

2. India pubmed.ncbi.nlm.nih.gov

Tramadol versus ketorolac in the treatment of postoperative pain following maxillofacial surgery. [2022]

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

The effect of intravenous ketoprofen on postoperative epidural sufentanil analgesia in children. [2019]

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

A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain. [2021]

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

[Systemic multimodality postoperative analgesia in vascular surgery]. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Pain management today - what have we learned? [2022]

7. Singapore pubmed.ncbi.nlm.nih.gov

Safety of nimesulide, meloxicam and rofecoxib as alternative analgesics. [2018]

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

Reporting rate of adverse drug reactions to the French pharmacovigilance system with three step 2 analgesic drugs: dextropropoxyphene, tramadol and codeine (in combination with paracetamol). [2021]

9. England pubmed.ncbi.nlm.nih.gov

Patients' Knowledge About Analgesic-Antipyretic Medications Purchased in Community Pharmacies: A Descriptive Study. [2017]

10. Romania pubmed.ncbi.nlm.nih.gov

Safety issues of current analgesics: an update. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Non-opioid postoperative analgesia. [2022]

12. Cyprus pubmed.ncbi.nlm.nih.gov

Ketoprofen is superior to metamizole in relieving postoperative pain after head and neck tumor operation. [2015]

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

[Ketoprofen (ketonal): a drug for preventing and treating postoperative pain]. [2013]

14. Denmark pubmed.ncbi.nlm.nih.gov

[Treatment of pain after laparoscopic cholecystectomy]. [2013]