Evaluation of Ketoprofen, Paracetamol, and Nefopam in Managing Postoperative Pain Following Cardiac Surgery: A Multicenter, Randomized, Placebo-Controlled Trial

The primary objective of this study is to demonstrate that the use of **nonsteroidal anti-inflammatory drugs (NSAIDs)** reduces pain 24 hours after cardiac surgery. This is clinically relevant as effective management of **postoperative pain** can significantly improve patient recovery and reduce the risk of complications associated with inadequate pain control.

Secondary objectives include:

• Assessing postoperative pain during physiotherapy within 48 hours after cardiac surgery.
• Evaluating the evolution of pain during the first 7 days after surgery.
• Measuring total cumulative opioid consumption during the 48 hours following surgery.
• Comparing the incidence of nausea and vomiting in the 48 hours following surgery.
• Comparing the incidence of postoperative pulmonary complications in the 28 days following surgery.
• Comparing the incidence of chronic postoperative pain 3 months after surgery.
• Comparing the incidence of neuropathic pain at 48 hours and 3 months after surgery.
• Comparing the change in quality of life before and 3 months after surgery.

The clinical trial focuses on individuals experiencing **postoperative pain after cardiac surgery**. The study population includes both male and female participants aged 18 years and older, who are admitted for elective cardiac surgery under extracorporeal circulation. Participants are required to have signed informed consent. The trial does not specifically target a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection of the trial population is based on the inclusion criteria, which emphasize the age and surgical procedure of the participants. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial details.

The clinical trial is designed to evaluate the efficacy of **nonsteroidal anti-inflammatory drugs (NSAIDs)** in managing postoperative pain following cardiac surgery. This study is a multicenter, randomized, placebo-controlled trial, ensuring a robust methodology to assess the primary and secondary endpoints. The trial is expected to commence on February 17, 2024, and conclude by May 5, 2027. Participants will be randomly assigned to receive either the test drug, **ketoprofen**, or a placebo, with auxiliary medications such as **nefopam**, **paracetamol**, **tramadol**, and **sodium chloride** used as needed. The trial will employ a double-blind design to minimize bias, with neither participants nor investigators aware of the treatment allocations.

Study visits will follow a structured sequence, beginning with an inclusion visit where eligibility criteria are confirmed, including age (18 years or older) and informed consent. The primary endpoint will be assessed 24 hours post-surgery using a numerical rating scale (NRS) for pain at rest. Secondary endpoints include pain assessment during chest physiotherapy, daily pain evaluation from day 1 to day 7, and chronic pain assessment at 48 hours and 3 months post-surgery. Additional assessments will include nausea, postoperative pulmonary complications, neuropathic pain, and quality of life at 3 months using the EQ-5D-5L questionnaire.

Participants will be involved in the study for a maximum treatment period of 2 days, with follow-up visits scheduled to monitor outcomes and adverse events. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial's design and procedures are meticulously structured to ensure the collection of high-quality data while safeguarding participant well-being throughout the study duration.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their efficacy in managing postoperative pain after cardiac surgery. The primary experimental medication is **NEFOPAM**, which is provided in the form of a solution for injection. The maximum daily dose of NEFOPAM is 60 mg, with a total maximum dose of 120 mg over a treatment period of 2 days. The administration route is via infusion, and participant compliance will be monitored throughout the trial.

**PARACETAMOL** is used as an auxiliary treatment in the study. It is administered as a solution for infusion, with a maximum daily dose of 4000 mg and a total maximum dose of 8000 mg over the same 2-day period. The infusion route ensures controlled delivery, and adherence to the dosing schedule will be closely observed.

**KETOPROFEN** serves as the test medication in this trial. It is delivered as a solution for injection, with a maximum daily dose of 200 mg and a total maximum dose of 400 mg. The treatment period is limited to 2 days, and the administration is conducted via injection to ensure precise dosing.

**TRAMADOL** is included as an auxiliary medication, provided in the form of an injection. The maximum daily dose is 200 mg, with a total maximum dose of 400 mg over 2 days. The administration is performed through infusion, and compliance with the dosing regimen is monitored.

**SODIUM CHLORIDE** is utilized as a placebo in the trial. It is available as a solution for injection and can be administered via IV injection or IV infusion. The maximum daily dose is 200 mg, with a total maximum dose of 400 mg over the 2-day treatment period. The placebo administration is designed to mimic the experimental treatments, ensuring blinding of the study.

The efficacy of the clinical trial titled "Effect of nonsteroidal anti-inflammatory drugs in the management of postoperative pain after cardiac surgery: A multicentre, randomised, placebo-controlled trial" will be assessed using both primary and secondary endpoints. The primary endpoint involves evaluating postoperative pain at rest 24 hours after cardiac surgery using a numerical rating scale (NRS) graded from 0 to 10. This scale provides a quantitative measure of pain intensity, allowing for a standardized assessment across participants.

Secondary endpoints include several additional measures to comprehensively evaluate the efficacy of the intervention. Postoperative pain during chest physiotherapy will be assessed using the same NRS as the primary endpoint. Daily postoperative pain from the 1st to the 7th day will also be measured, with a focus on the pain trajectory between day 3 and day 7. Nausea will be recorded using a verbal scale categorized as none, moderate, or severe. Postoperative pulmonary complications will be monitored for the first 7 days following surgery, adhering to European consensus definitions. Chronic pain will be assessed at 48 hours and at 3 months post-surgery using the DN4 scale, a concise pain questionnaire. Neuropathic pain will be evaluated at 48 hours, and quality of life at 3 months will be assessed using the EQ-5D-5L questionnaire, compared to pre-surgery assessments.