The goal of this clinical trial is to determine whether treating pain after surgery with ketamine is more effective when administered intravenously as a continuous infusion or through a patient-controlled analgesia (PCA) pump. This study focuses on adult volunteers following major orthopedic surgery. We have two main questions to address:

• Is a continuous intravenous infusion of ketamine as effective as ketamine administered through a PCA pump for managing pain after major orthopedic surgery.
• Does a continuous intravenous infusion of ketamine result in lower opioid requirements compared to ketamine delivered through a PCA pump for pain management after major orthopedic surgery?

Participants will be divided into two groups. One group will receive ketamine via continuous infusion, while the other will receive it through a PCA pump. Both groups will also receive a placebo (a substance that looks like the drug but contains no active ingredients), ensuring that neither group knows whether they are receiving ketamine through the PCA pump (which always contains a painkiller) or as a continuous infusion.

Participants will be assigned to one of the two groups and will receive their assigned treatment for 48 hours while hospitalized. Researchers will visit participants during their first three days in the hospital to assess their pain levels and monitor for any side effects.

Managing postoperative pain is a primary concern for patients undergoing major surgery, especially in major orthopedic surgery. Effective pain management is crucial, as uncontrolled postoperative pain can lead to prolonged hospital stays, decreased patient satisfaction, and various complications, including pulmonary and gastrointestinal issues.

Current pain management strategies emphasize multimodal analgesia, which involves using multiple medications with different mechanisms of action to minimize side effects. Ketamine has been investigated in this context and has been found effective for treating postoperative pain following major surgeries while reducing the need for opioids. However, there is still some uncertainty regarding the optimal method for administering ketamine after surgery. The aim of this trial is to compare the effectiveness of intravenous ketamine in terms of pain control, measured by numerical pain scores, and opioid consumption within the first 24 hours postoperatively using two different strategies: continuous infusion versus patient-controlled analgesia (PCA) in adults undergoing non-cardiac surgery.

For this research, two hypotheses are proposed, as the objective involves two types of outcomes related to the analgesic effectiveness of intravenous ketamine: pain measured by a numerical pain scale and opioid consumption equivalent to oral morphine.

Based on data from previous studies, it is highly likely that continuous ketamine infusion will provide similar pain control efficacy at 24 hours compared to PCA ketamine. However, the data suggests that continuous infusion may result in lower opioid consumption than PCA. Therefore, the hypotheses are as follows:

**First Hypothesis** Continuous ketamine infusion is not inferior to PCA ketamine for pain control, as measured by a numerical pain scale at 24 hours postoperatively in patients undergoing major orthopedic surgery with a high risk of severe acute pain.

**Second Hypothesis** Continuous ketamine infusion is superior to PCA ketamine in reducing opioid consumption at 24 hours postoperatively in patients undergoing major orthopedic surgery at high risk of severe acute pain.

This trial will be a triple-blind, parallel-group, pragmatic, non-inferiority controlled clinical trial focused on pain management and superiority regarding opioid use, along with other secondary outcomes.

Inclusion Criteria:

• Patients over 18 years of age
• Elective major orthopedic surgery.
• ASA (American Association of Anesthesiology) classification 1, 2 or 3.

Exclusion Criteria:

• Patients with a diagnosis of perioperative kidney injury or hepatic failure
• Patients with active cardiac conditions
• Patients with any cognitive impairment that disables the patient from operating the PCA pump or impedes the postoperative interview
• Patients with scheduled ICU admission with invasive ventilatory support
• Patients with known hypersensitivity to opioid medications
• Patients with past medical history of severe adverse reactions to opioids or ketamine.
• Pregnant patients
• Patients undergoing continuous regional anesthetic techniques including peripheral nerve catheters or continuous epidural catheters
• Patient refusal to participate in the study

It was not approved by our Institutional Research Board.

Treating Anesthesiologist: The anesthesiologist responsible for the case and intraoperative management will be blinded to the assigned intervention. The assignment will be carried out by another anesthesiologist who is not involved in the case. This external anesthesiologist will be present in the operating room, and after opening the envelope, will inform the nursing staff regarding which drug mixtures to prepare.

Data Collection and Analysis Staff: Data will be collected during the hospital stay, up to three days, by two researchers. The researchers will be blinded to the assignment and will not have access to information about the prepared drug mixtures.