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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates which pain relief method works best after surgeries such as tonsil removal, gallbladder removal, or knee scopes. It compares two groups: one taking NSAIDs (a type of pain reliever) with acetaminophen, and the other taking the same medications plus a low dose of opioids (a class of strong pain relievers). The study aims to determine which option provides better results with fewer side effects. It suits individuals who have undergone one of the mentioned surgeries and do not regularly use pain medication. As a Phase 4 trial, this research involves treatments that are already FDA-approved and proven effective, aiming to understand how they benefit more patients.

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 is the safety track record for these treatments?

Past studies have shown that using acetaminophen with NSAIDs effectively relieves pain. Research indicates that combining these two can reduce the need for stronger painkillers like opioids while still providing effective pain control. This combination is well-tolerated with few side effects.

Studies have demonstrated that combining acetaminophen, NSAIDs, and opioids offers strong pain relief. However, opioids can cause more side effects than using just NSAIDs and acetaminophen, such as drowsiness or nausea. Despite this, the combination still shows promise for effective pain management.

Both treatment options have been studied for safety and are generally considered safe when used as directed. Following the doctor's instructions is important to minimize any potential risks. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these analgesic regimens for surgical pain because they explore combinations of acetaminophen, NSAIDs, and opioids in innovative ways. Unlike traditional methods that may rely heavily on opioids alone, these regimens aim to optimize pain relief while potentially reducing opioid dependency and associated side effects. The combination of acetaminophen and NSAIDs offers a multi-modal approach that targets different pain pathways, potentially enhancing pain control and recovery time. By integrating opioids more strategically, these regimens have the potential to deliver effective pain management with a lower risk of opioid-related complications.

What evidence suggests that this trial's treatments could be effective for surgical pain?

Research has shown that taking acetaminophen and NSAIDs (non-steroidal anti-inflammatory drugs) together can effectively reduce pain. This combination often proves more effective than taking each drug alone, particularly for post-surgical pain, such as after dental work. In this trial, one group of participants will receive an acetaminophen/NSAID regimen. Some studies suggest that combining acetaminophen with NSAIDs might reduce the need for opioids, which are strong painkillers with more side effects. Another group in this trial will receive an acetaminophen/NSAID/opioid regimen, as adding small amounts of opioids to acetaminophen and NSAIDs may provide even better pain relief for some people, especially after surgery. Both combinations effectively manage surgical pain, but the best choice depends on balancing pain relief with side effects. ^{2 6 7 8 9}

Who Is on the Research Team?

Mark Bicket, MD

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

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

Anticipated life expectancy of less than 12 months

Patients with legal guardians (due to special permission to enroll in trials)

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)

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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 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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11878654/

Comparative effect of paracetamol, NSAIDs or their ... Results: NSAIDs were clearly more effective in dental surgery, whereas the efficacy of NSAIDs and paracetamol seemed without substantial differences in major ...

2. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2724188

Effect of Combination of Paracetamol (Acetaminophen ... This randomized clinical trial compares the effects of combination paracetamol (acetaminophen) and ibuprofen at full vs half strength vs ...

3. bmj.com bmj.com/content/375/bmj.n2321

Effectiveness and safety of non-steroidal anti-inflammatory ... Evidence was found of an increased risk of any adverse event for 14 of 47 (29.8%) NSAIDs, 0 of 9 (0%) topical NSAIDs, 17 of 19 (89.5%) opioids, ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S075333222500263X

Pharmacological bases of combining nonsteroidal ... Clinical evidence (77 studies) confirms that in many cases efficacy is enhanced by paracetamol + NSAID combinations, but quite a few studies show no added ...

5. bmcanesthesiol.biomedcentral.com bmcanesthesiol.biomedcentral.com/articles/10.1186/s12871-020-01147-y

Efficacy of non-opioid analgesics to control postoperative pain Among abdominal procedures, MIV was associated with significantly greater pain reductions versus acetaminophen, ketorolac, other medications, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6439592/

Effect of Combination of Paracetamol (Acetaminophen) and ... This trial demonstrated that a combination of paracetamol 1000 mg and ibuprofen 400 mg resulted in a clinically relevant reduction in morphine ...

7. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/10.1002/bcp.70180

Combination vs. single‐drug nonprescription analgesics for ... In single-dose studies, combination therapy with paracetamol 500 mg/ibuprofen 250 mg provided significantly greater pain relief vs. ibuprofen ...

8. tandfonline.com tandfonline.com/doi/full/10.1080/00325481.2024.2382671

Ibuprofen/acetaminophen fixed-dose combination as an ... A fixed-dose combination (FDC) of ibuprofen and acetaminophen (IBU/APAP) has shown promise as an alternative to opioids in a range of pain management scenarios.

9. academic.oup.com academic.oup.com/painmedicine/article/12/6/961/1848715

Perioperative Intravenous Acetaminophen and NSAIDs Intravenous APAP is safe, effective for mild-to-moderate postoperative pain, well-tolerated, and has a very favorable side effect profile.