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IRCT20240519061842N2 IRCT 2026-07-01 Iran University of Medical Sciences Investigating the Effect of 50% Nitrous Oxide on Opioid-Induced Hyperalgesia (OIH) in Patients Undergoing Septorhinoplasty Surgery 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 2026-07-21 anticipated 56 Recruiting https://irct.ir/trial/91296 interventional Randomization: Randomized, Blinding: Double blinded, Placebo: Not used, Assignment: Parallel, Purpose: Supportive, Randomization description: 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, Blinding description: 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. 2-3 Opioid-Induced Hyperalgesia following remifentanil in septorhinoplasty surgery. Intervention 1: Intervention group: Patients in this group receive a gas mixture of 50% nitrous oxide (N₂O) and 50% oxygen with a fresh gas flow of 2 L/min during maintenance of anesthesia. Anesthesia induction is performed with midazolam 0.02 mg/kg, fentanyl 0.02 µg/kg, propofol 2 mg/kg, atracurium 0.5 mg/kg, and lidocaine 1 mg/kg. Anesthesia is maintained with isoflurane (adjusted to maintain BIS between 40-60) and remifentanil at a fixed dose of 0.1 µg/kg/min as a continuous intravenous infusion. The surgeon injects 6 mL of 2% lidocaine with 1:100,000 epinephrine into the nasal area at the start of surgery, and at the end of surgery, all patients receive 1 gram of intravenous apotel (tranexamic acid). The nitrous oxide used (N₂O) is medical-grade gas with 99.9% purity, supplied by Darmangaz Co, in Iran. Intervention 2: Control group: Patients in this group receive only 100% oxygen with a fresh gas flow of 2 L/min during maintenance of anesthesia. Anesthesia induction, maintenance with isoflurane (BIS 40-60) and remifentanil 0.1 µg/kg/min, injection of 2% lidocaine with epinephrine by the surgeon at the start of surgery, and administration of apotel 1 g IV at the end of surgery are exactly the same as the intervention group. The only difference is that they do not receive nitrous oxide and breathe pure oxygen. Undecided - It is not yet known if there will be a plan to make this available Justification or reason for indecision in sharing IPD is There is no further information
public Taymaz Amiraslani
Iran University of Medical Sciences - Faculty of Medicine, Hemat Highway, next to Milad Tower, Tehran
Tehran Iran (Islamic Republic of) 1449614535 +98 21 86709 amiraslani.ta@iums.ac.ir Iran University of Medical Sciences scientific Taymaz Amiraslani
Iran University of Medical Sciences - Faculty of Medicine, Hemat Highway, next to Milad Tower, Tehran
Tehran Iran (Islamic Republic of) 1449614535 +98 21 2274 9252 amiraslani.ta@iums.ac.ir Iran University of Medical Sciences Iran (Islamic Republic of) 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 18 years 55 months Both History of chronic pain Substance or alcohol abuse Diagnosed psychiatric disorders Obesity (Body 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 R20.3 Hyperesthesia Treatment - Other Treatment - Other Intervention group: Patients in this group receive a gas mixture of 50% nitrous oxide (N₂O) and 50% oxygen with a fresh gas flow of 2 L/min during maintenance of anesthesia. Anesthesia induction is performed with midazolam 0.02 mg/kg, fentanyl 0.02 µg/kg, propofol 2 mg/kg, atracurium 0.5 mg/kg, and lidocaine 1 mg/kg. Anesthesia is maintained with isoflurane (adjusted to maintain BIS between 40-60) and remifentanil at a fixed dose of 0.1 µg/kg/min as a continuous intravenous infusion. The surgeon injects 6 mL of 2% lidocaine with 1:100,000 epinephrine into the nasal area at the start of surgery, and at the end of surgery, all patients receive 1 gram of intravenous apotel (tranexamic acid). The nitrous oxide used (N₂O) is medical-grade gas with 99.9% purity, supplied by Darmangaz Co, in Iran. Control group: Patients in this group receive only 100% oxygen with a fresh gas flow of 2 L/min during maintenance of anesthesia. Anesthesia induction, maintenance with isoflurane (BIS 40-60) and remifentanil 0.1 µg/kg/min, injection of 2% lidocaine with epinephrine by the surgeon at the start of surgery, and administration of apotel 1 g IV at the end of surgery are exactly the same as the intervention group. The only difference is that they do not receive nitrous oxide and breathe pure oxygen. Opioid-Induced Hyperalgesia. Timepoint: Before surgery and 5 minutes after PACU admission. Method of measurement: Pressure algometer (kg/cm²). Postoperative Shivering Intensity. Timepoint: 5 minutes after PACU admission. Method of measurement: The standard shivering scale ( Grade 0 indicated no shivering; Grade 1 referred to mild shivering localized to the face and neck; Grade 2 denoted visible shivering involving the trunk muscles; Grade 3 represented generalized shivering involving both the trunk and extremities; and Grade 4 indicated severe generalized shivering with an inability to cooperate). Morphine Consumption. Timepoint: During the recovery period. Method of measurement: Recorded from patient file (mg). Extubation Time. Timepoint: From end of surgery to extubation. Method of measurement: Recorded from patient file (minutes). Postoperative Nausea and Vomiting. Timepoint: During the recovery period. Method of measurement: Recorded by nurse (yes/no). Postoperative Pain Intensity. Timepoint: During the recovery period. Method of measurement: Numerical Rating Scale (NRS) from 0 to 10. Iran University of Medical Sciences Approved 2026-06-22 Ethics Committee of the Faculty of Medicine, Iran University of Medical Sciences Iran University of Medical Sciences, Shahid Hemmat Highway, between Sheikh Fazl-allah and Chamran Expressways, Tehran, Iran Tehran Tehran Iran (Islamic Republic of)