Title : Investigating the Effect of 50% Nitrous Oxide on Opioid-Induced Hyperalgesia (OIH) after Isoflurane-Remifentanil Administration or Quantitative Sensory Testing (QST) in Patients Undergoing Septorhinoplasty Surgery

To determine the effect of 50% nitrous oxide on reducing opioid-induced hyperalgesia (OIH) following isoflurane-remifentanil administration in patients undergoing septorhinoplasty surgery.

This was a phase 2–3, randomized, double-blind, parallel-group, controlled clinical trial conducted on 56 patients. Randomization was performed using the RAND function in Excel.

Double-blind RCT at Rasoul Akram Hospital, Tehran, on 56 patients aged 18-55, ASA I, septorhinoplasty. Block randomization (size 4, Excel) into intervention (50% N₂O+50% O₂) and control (100% O₂). Induction: midazolam, fentanyl, propofol, atracurium, lidocaine. Maintenance: isoflurane (BIS 40-60) + remifentanil 0.1 µg per kg per minute. Pressure pain threshold measured by algometer at nose, cheek, forearm before and 5 min post-PACU. Shivering, morphine use, extubation time, PONV recorded. Blinding: patients and outcome assessor; anesthesiologist aware.

Inclusion Criteria: Patients with ASA physical status I Age between 18 and 55 years Candidates for elective septorhinoplasty surgery under general anesthesia Provision of written informed consent to participate in the study Exclusion Criteria: History of chronic pain Substance or alcohol abuse Diagnosed psychiatric disorders Obesity (Bodu mass index more than 30) Use of any analgesic or opioid within 48 hours prior to surgery Known allergy or contraindication to any study medication Any contraindication to nitrous oxide including: proven or suspected pneumothorax, bowel obstruction, middle ear disease (e.g., acute infection or barotrauma), increased intracranial pressure, or history of allergy to N₂O

Intervention Group: Receives 50% N₂O + 50% O₂ at 2 L per minute during maintenance. Control Group: Receives 100% O₂ at 2 L per minute.

Opioid-Induced Hyperalgesia

Patient randomization in this clinical trial is performed using block randomization with a block size of 4 and an allocation ratio of 1:1. The unit of randomization is individual. The random sequence is generated using Microsoft Excel with the RAND function. For each patient, a random number between 0 and 1 is generated using the RAND function; patients are then sorted in ascending order based on these values and allocated into blocks of four to groups A (intervention) and B (control). For allocation concealment, the generated sequence is placed by an individual independent of the research into opaque, sealed, sequentially numbered envelopes from 1 to 56. After tracheal intubation and before initiating maintenance anesthesia, the attending anesthesiologist opens the corresponding envelope and adjusts the respiratory gases according to the allocation inside. The anesthesiologist is the only individual aware of the group assignment, while the outcome assessor performing QST measurements remains completely blinded to group allocation.

This study is designed as a double-blind trial, meaning that two main groups of individuals are unaware of the patient's group allocation: the patients and the outcome assessor. Blinding of patients: All patients are enrolled without knowing which type of respiratory gas they receive. Since maintenance anesthesia is initiated after tracheal intubation while the patient is already unconscious, patients are naturally unaware of the gas composition. During the recovery period, patients also have no information about their group assignment. Blinding of the outcome assessor: The researcher performing QST measurements using a pressure algometer at T₀ (before surgery) and T₁ (5 minutes after PACU admission) is completely blinded to patient group allocation. This researcher is not present in the operating room and has no access to allocation documents. Additionally, the recovery room nurse who records shivering intensity, nausea/vomiting, and morphine consumption is also blinded to group assignment. Practical blinding in the operating room: To ensure uniform appearance, the respiratory gas circuits and ventilators are covered so that the type of gas (presence or absence of N₂O) cannot be identified by the device's appearance or sound. The anesthesiologist responsible for adjusting the gases is the only individual aware of the allocation and is instructed not to disclose group information to other team members, the surgeon, or especially the outcome assessor. No group indicators are recorded on data collection forms; only the patient's identification code is used.