Authors: Min Zhang, Yi Liu, Jing Cao, Mengjie Liu, Xiaojun Gao, Na Guo, Chuansong Wei, Ye Zhu, Yongtao Sun, Jianbo Wu
Categories: Study Protocol, Oxycodone, Intercostal nerve block, Different ages, Thoracoscopic pulmonary surgery, Acute postoperative pain, Median effective dose
Source: BMC Anesthesiology
Authors: Min Zhang, Yi Liu, Jing Cao, Mengjie Liu, Xiaojun Gao, Na Guo, Chuansong Wei, Ye Zhu, Yongtao Sun, Jianbo Wu
Oxycodone is an effective drug for controlling acute postoperative pain (APP), especially visceral pain. However, the effective dose needed for controlling APP depends on the surgical method and the patient age. Therefore, through use of the Dixon up-and-down method, this study investigated the median effective dose (ED50) of oxycodone that could be combined with intercostal nerve block (INB) to effectively control APP after thoracoscopic pulmonary surgery in patients of different ages.
This is a prospective, interventional, dose-finding study. Patients undergoing thoracoscopic lobar and sublobar resections under general anaesthesia will be selected and divided into 4 groups according to age and surgical the elderly lobectomy group (aged ≥ 65 years), the nonelderly lobectomy group (aged < 65 years), the elderly sublobar resection group (aged ≥ 65 years), and the nonelderly sublobar resection group (aged < 65 years). The study will be performed simultaneously in four experimental groups via the Dixon up-and-down method. The initial dose for the first patient in each group will be set to 0.1 mg/kg; the dose for the next patient will be determined by the response of the previous patient. The primary outcome is the ED50 of oxycodone.
The results of this study are expected to provide an effective strategy for the management of APP following thoracoscopic pulmonary surgery and specifically to offer more accurate dose guidance for the use of oxycodone in older patients. This will not only improve the development of individualized pain management plans but also optimize the patient’s postoperative recovery, reduce unnecessary drug side effects, and increase the overall comfort and quality of life of patients.
This study was registered on clinicaltrials.gov (NCT06534801) on August 1, 2024.
While thoracoscopic surgery minimizes surgical trauma compared to thoracotomy, moderate-to-severe acute postoperative pain (APP) persists as a significant clinical challenge, adversely impacting complication rates, patient satisfaction, and long-term recovery outcomes [1–4]. Furthermore, APP is strongly associated with emergence agitation [5], elevating risks of unintended drainage tube dislodgement and complicating postoperative care.
Multimodal analgesia, combining pharmacological interventions and regional anesthesia, remains the optimal strategy for controlling acute postoperative pain (APP) by balancing analgesia efficacy with opioid-related side-effect mitigation [5–7]. Intercostal nerve block (INB), favored for its procedural simplicity and low complication profile, effectively alleviates somatic incision pain in thoracic surgery [8–10]; but lacks efficacy against visceral pain. Oxycodone, a dual μ/κ-opioid agonist, demonstrates superior efficacy against visceral and neuropathic pain with reduced risks of respiratory depression and nausea compared to μ-selective opioids [11–13]. While oxycodone dosing varies by surgical type [14–16], the effective analgesic dose for thoracoscopic pulmonary surgery remains undefined.
A significant proportion of patients undergoing thoracoscopic pulmonary surgery are aged ≥ 65 years, a population characterized by physiological decline, reduced organ reserve, and frequent comorbidities[17, 18]. These factors necessitate cautious intraoperative medication dosing to mitigate adverse effects. For opioids like oxycodone, age-related pharmacodynamic sensitivity further underscores the need for tailored dosing strategies. This study investigates the median effective dose (ED50) of oxycodone for acute postoperative pain management in thoracoscopic surgery, evaluating its variation across age groups (≥ 65 vs. < 65 years) and surgical methods (lobectomy vs. sublobar resection). The null hypothesis posits no difference in ED50 between these subgroups, aiming to establish evidence-based guidelines for safer opioid use in older adults and diverse surgical contexts.
This prospective, double-blind, dose-finding study will be conducted at the First Affiliated Hospital of Shandong First Medical University. The Ethics Committee of the First Affiliated Hospital of Shandong First Medical University approved the protocol on May 31, 2024 (YXLL-KY-2024(058)). The results will be published in peer-reviewed international journals. The protocol is written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)statement [19]. The checklist is shown in Supplementary Information.
Patients will be stratified by age (≥ 65 vs. < 65 years) and surgical method (lobectomy vs. sublobar resection) to account for age-dependent pharmacokinetic variability and procedural differences in tissue trauma, which may independently influence postoperative pain intensity and oxycodone requirements. Patients scheduled for elective video-assisted thoracoscopic (VATS) lung resection will be divided into the elderly lobectomy group (aged ≥ 65 years), the nonelderly lobectomy group (aged < 65 years), the elderly sublobar resection (wedge/pulmonary segment) group (aged ≥ 65 years), and the nonelderly sublobar resection group (aged < 65 years). The recruitment period for the study participants for the trial will span from January 2025 to December 2026. The flowchart of the trial design and study assessment procedures and timetable are shown in Fig. 1 and Table 1, respectively.Table 1Study assessment procedures and timetableNBP noninvasive blood pressure, HR Heart rate, NRS numerical rating scale. T1, baseline vital signs. T2, the timepoint of anaesthesia induction. T3, 1 min before oxycodone injection. T4, the timepoint of oxycodone injection. T5, 3 min after oxycodone injection. T6, 5 min after oxycodone injection. T7, 3 min after extubation. T8, 30 min after extubation
Fig. 1Flowchart of the trial design. NRS, numerical rating scale
Plan to undergo the initial unilateral VATS lobectomy or sublobar resection under general anesthesia utilizing either a single-port or two-port approach;Age between 18 and 80 years;American Society of Anaesthesiologists (ASA) physical status I-III;Body mass index (BMI) between 18 and 30.0 kg/m^2^;Voluntary participation in this study and signing of an informed consent form.
Allergy or hypersensitivity to oxycodone;History of chronic pain;Severe heart, lung, liver, or kidney disease;Intraoperative conversion to thoracotomy (unplanned open thoracotomy during VATS);Use of > 2 chest drainage tubes;Participation in other relevant clinical studies within three months;Unable to cooperate due to illness or other reasons.
Recruitment should be completed 1 day before surgery by professional researchers. After the subject or his or her legal representatives has gained a full understanding of the methods, purpose, and potential benefits and risks of the trial, they are to sign an informed consent form alongside trained researchers. If a patient refuses to participate, they will be assured that the quality of their perioperative management will not be affected.
This is a dose-finding study that includes only one allocation group, that is, individuals who will be intravenously administered a predetermined dose of oxycodone for analgesia; therefore, there is no need for subject randomization. In this study, the patients, anaesthesiologists, and data collectors will be blinded. A predetermined dose of oxycodone will be drawn by a member of the medical staff who will not participate in the clinical observation. We plan to have three researchers be responsible for data collection. To prevent them from extrapolating the predetermined dose of oxycodone, one person will be randomly selected to collect the data each time.
According to the Dixon up-and-down method, once the seven turning points, that is, from effective analgesia to ineffective analgesia or from ineffective analgesia to effective analgesia, are reached, the sample size will be considered sufficient. According to previous studies [15, 20], the sample size should be approximately 20–40 individuals per group.
None of the patients will receive pre-anaesthesia medication, and all patients will be instructed about the use of the numeric rating scale (NRS) prior to arrival at the operating room. After entering the room, standard monitoring, including electrocardiography (ECG), pulse oxygen saturation (SpO2) monitoring, noninvasive blood pressure (NBP) monitoring, end-expiratory carbon dioxide pressure (PETCO2) monitoring, and determination of the bispectral index (BIS), will be performed. The NBP and heart rate (HR) will be measured after 10 and 15 mins of rest, and the average of the two measurements will be considered the baseline.
General anaesthesia will be induced with 0.05 mg/kg midazolam, 0.2–0.3 mg/kg etomidate, 0.6–1.0 mg/kg rocuronium bromide, and 1 µg/kg remifentanil. When the BIS reaches 40–60, a dual-lumen bronchial catheter will be inserted, and the anaesthesia device will be connected to perform volume-controlled ventilation. If the BIS will remain outside the target range (40–60) after initial drug administration, the propofol infusion rate will be adjusted in increments of 0.5 mg/kg/h, and remifentanil will be titrated by 0.05 µg/kg/min every 3 mins until the BIS reached 40–60. The respiratory parameters will include a tidal volume of 6–8 mL/kg, ventilation frequency of 10–14 breaths/min, inspiration-to-exhalation ratio of 1.5–2, airway pressure of < 30 mmHg, and PETCO2 of 35–45 cmH2O. After anaesthesia induction, ultrasound-guided INB will be performed at the upper, middle and lower points of the thoracoscopic incision via injections of 5 mL of 0.375% ropivacaine at each point. During the operation, propofol will be continuously pumped at 2 to 10 mg/kg/h, remifentanil at 0.2 to 1.0 μg/kg/min, and rocuronium at 5 to 6 μg/kg/min to maintain a BIS of 40–60. Vasoactive drugs will be used to treat hypotension or hypertension, bradycardia (HR < 50 bpm) will be treated with atropine (0.5 mg IV), and tachycardia (HR > 100 bpm) will be treated with β-blockers only after excluding hypovolemia, pain, or hypercapnia via clinical evaluation. Patients will receive one or two chest tubes unless the complexity of the surgery necessitates additional drainage, in which case they will be excluded if more than two tubes are required. A predetermined dose of oxycodone (20 mL) will be administered intravenously approximately 30 mins prior to the conclusion of the surgery. Additionally, 8 mg of ondansetron will be administered at the completion of the surgery, following the placement of the final stitch. All surgeries will be performed by the same team of surgeons.
After surgery, the patient will be transferred to the post-anaesthesia care unit (PACU). The tracheal tube will be removed when the patient fully wakes, can respond to calls, can swallow, can demonstrate a cough reflex, and has a satisfactory breathing recovery rate (VT > 6 mL/kg). The NRS score will be used to evaluate the degree of resting pain of the patient within 30 min after the removal of the tracheal tube, in which 0 points will indicate no pain at all and 10 points will indicate the worst pain imaginable. An NRS score ≥ 4 would indicate unsatisfactory analgesia; these patients would be administered oxycodone (0.5 mg) as rescue analgesia. After leaving the PACU, patient-controlled intravenous analgesia (PCIA, Fornia, Zhuhai, China, WZ-6523C-4), consisting of 1.0 mg/kg oxycodone, 50 mg flurbiprofen, and 16 mg ondansetron diluted to 100 mL with normal saline. PCIA will be administered with a bolus dose of 0.5 mL (equivalent to 0.005 mg/kg oxycodone), a lockout interval of 15 mins, and a maximum hourly limit of 4 boluses (2 mL/h). No background infusion was used.
The Dixon up-and-down method will be used in this study for sequential allocation [21]. The trial will be performed simultaneously for the four surgical groups. In accordance with the results of previous clinical studies [14, 22, 23], the initial dose of oxycodone will be set to 0.1 mg/kg, and the dose gradient will be set to 0.01 mg/kg. If the analgesia of the previous subject is considered satisfactory, the dose of oxycodone for the next subject will be reduced by 0.01 mg/kg; if the analgesia effect of previous last subject is considered unsatisfactory, the dose of oxycodone for the next subject will be increased by 0.01 mg/kg. The subject just prior to the first turning point will be included in the group as the first case, and the trial will be terminated once seven 7 turning points have been reached. If the analgesic effect of the previous subject is ambiguous, the next subject would receive the same dose as the previous subject.
The primary outcome indicator of this study is the ED50 of oxycodone in the management of APP following thoracoscopic pulmonary surgery.
The 95% effective dose (ED95) of oxycodone for managing APP after thoracoscopic pulmonary surgery.HR and NBP, measured at the following time baseline (T0), 1 min prior to dosing with oxycodone (T1), 3 min (T2) and 5 min after oxycodone dosing (T3) and 3 min (T4), and 30 min after removal of the tracheal tube (T5).Adverse reactions during emergence from anaesthesia, including emergence agitation and delirium, respiratory depression, delayed emergence, postoperative chills, and postoperative nausea and vomiting.
All the subjects will have the right to withdraw from the study at any stage, and if they decide to do so, they will be assured that the effect of perioperative treatment will not be affected. If the subject has a serious clinical event, further participation in the study will be terminated.
We will design a case report form (CRF) for each subject. Data will be reviewed by two researchers to ensure consistency, and any modifications and deletions will be preserved. After the study is completed and the general manager of the project provides approval, the CRFs will be given to the researcher in charge of data management to confirm the quality of the data. Data management will always be under the supervision of the ethics committee.
During the entire study, we will constantly implement subject safety monitoring. Perioperative adverse events, such as severe allergies and respiratory depression, will be recorded on the CRF, explained to the participants or their legal representatives in a timely manner, and reported to the hospital’s adverse event registration system according to the severity of the event. Participants will receive free treatment for any adverse events, and all relevant information will be reported to the hospital ethics committee.
Data analysis will be performed with SPSS 25.0 software. Normally distributed data will be expressed as the means ± standard deviations (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \overline{x }
### Amendments to the protocol The protocol will be strictly followed V.1.0 of the study. Any behaviours that violate the protocol will be recorded, and the protocol will subsequently be reviewed again by the hospital Ethics Committee and updated in the clinical trial registration form. ### Patient and public involvement Patient and public comments are not included in the design, recruitment, intervention, reporting, or dissemination plan of the study. ### Dissemination policy The study data will be analysed and summarized after the completion of the study. The study results, whether positive or negative, will be submitted to international peer-reviewed medical journals for publication. ### Data sharing The data, original informed consent forms, CRFs and other materials obtained from the subjects will be retained by the study group for at least 5 years, and inspection by relevant regulatory agencies will be guaranteed. The data will be safely retained by the researchers and will not be shared with others without proper authorization. ## Discussion While previous studies have established the utility of oxycodone in pain management following VATS, critical gaps remain in defining its optimal dosing stratified by age and procedural trauma. Kampe et al. [24] demonstrated oxycodone’s efficacy in VATS but utilized a fixed dose of 0.1 mg/kg without exploring dose–response relationships or addressing age-specific requirements. Similarly, Wang et al. [25] focused on patient-controlled analgesia (PCA) rather than APP management, leaving the immediate postoperative dosing paradigm unresolved. Notably, no prior thoracic studies have employed the Dixon up-and-down method to quantify both the median (ED~50~) and 95% effective dose (ED~95~) of oxycodone—a robust approach for precise dose-finding in heterogeneous populations. Our study uniquely addresses this gap by incorporating dual stratification (age ≥ 65 vs. < 65 years; lobectomy vs. sublobar resection) to account for age-related pharmacodynamic sensitivity and procedural differences in tissue trauma. This approach provides granular insights into individualized dosing, enabling clinicians to balance analgesia efficacy with opioid-sparing benefits, particularly in elderly patients and those undergoing extensive resections. Post-thoracoscopic pain arises from heterogeneous neuropathic components from intercostal nerve traction (38%), visceral contributions from pleural/parenchymal manipulation (52%), and nociceptive triggers from chest tube irritation (23%) [26, 27]. Post-thoracoscopic pain arises from heterogeneous neuropathic components from intercostal nerve traction (38%), visceral contributions from pleural/parenchymal manipulation (52%), and nociceptive triggers from chest tube irritation (23%). Crucially, lobectomy induces greater tissue disruption—involving bronchovascular division and hilar dissection—compared to sublobar resection’s localized excision. This procedural dichotomy likely modulates opioid requirements through differential activation of κ-opioid receptor pathways (predominant in visceral pain mediation). Our stratification by surgical approach (lobectomy vs. sublobar) specifically targets these mechanistically distinct pain profiles to quantify oxycodone ED~50~ variations. Aging alters opioid pharmacodynamics through neuroanatomical decreased μ-opioid receptor density (↓28% in thalamus) and impaired blood–brain barrier permeability increase CNS drug sensitivity [28]. Specifically, oxycodone’s volume of distribution rises by 40% in patients > 65 years due to reduced lean mass and altered protein binding [29, 30]. This study pioneers age-stratified ED~50~ quantification for thoracoscopic APP management, addressing a critical gap in geriatric analgesia—where current guidelines extrapolate from younger cohorts despite known PK/PD disparities. By defining age-specific oxycodone requirements, we aim to establish biologically grounded dosing thresholds that balance efficacy with avoidance of opioid-induced neurocognitive sequelae in older adults. This study protocol has several limitations. First, we only plan to collect data from the patients in the PACU and not while they are in the ward or after they have been discharged; thus, the analgesic effect of oxycodone during these times will not be known. Second, we will only include patients undergoing unilateral VATS, but we will not limit the patients according to the number of lung lobes that will be surgically treated, which could affect the study results. Third, secondary outcome indicators such as the ED~95~ could offer greater guidance in the rational use of the drug than the primary outcome indicator ED~50~. Fourth, the outcomes of this study may not be suitable for patients over 80 years of age. In subsequent studies, we plan to further divide the target older patient population into finer age groups.