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Abstract
Introduction Postoperative pain is a main component influencing the recovery of patients with lung cancer. The combination of patient-controlled intravenous analgesia (PCIA) and paravertebral nerve block for postoperative analgesia in patients undergoing thoracoscopic lobectomy for lung cancer can achieve a satisfactory analgesic effect and promote early rehabilitation of patients. The objective is to investigate the optimal dose of oxycodone for PCIA combined with paravertebral nerve block, to achieve effective multimodal analgesia management in patients undergoing thoracoscopic lung cancer lobectomy.
Methods and analysis This prospective, double-blind, single-centre, parallel-group, superiority study from 7 April 2023 to 31 December 2024 will include 160 participants scheduled for thoracoscopic lobectomy for lung cancer. Participants will be randomly assigned to four groups in a 1:1:1:1 ratio: OCA group (oxycodone: 0.5 mg/kg), OCB group (oxycodone: 1.0 mg/kg), OCC group (oxycodone: 1.5 mg/kg) and one sufentanil group (sufentanil: 2 µg/kg). Flurbiprofen 50 mg and ondansetron 16 mg are added to each group. All the drugs are diluted with 0.9% saline in a 100 mL volume, with a background infusion rate of 2 mL/hour, a bolus dose of 0.5 mL and a lockout interval of 15 min. The primary outcome is pain scores at rest and dynamic at 24 hours after surgery using a Numeric Rating Scale (NRS). Dynamic NRS scores are defined as NRS when coughing. NRS scores will be assessed at 2, 4, 12, 24 and 48 hours postoperatively. The secondary outcomes include the following variables: (1) NRS score at rest and dynamic at 2, 4, 12 and 48 hours postoperatively; (2) total dose of sufentanil or oxycodone consumption in PCIA; (3) the times of patient-controlled analgesia; (4) Ramsay Sedation Score (RSS) at 2, 4, 12, 24 and 48 hours after the surgery; (5) extubation time; (6) serum C-reactive protein and interleukin six levels; (7) incidence of postoperative nausea and vomiting; (8) incidence of itching; (9) incidence of respiratory depression and (10) gastrointestinal recovery (exhaust time).
Ethics and dissemination The First Affiliated Hospital of Shandong First Medical University’s Ethics Committee granted consent for this study (approval number: YXLL-KY-2022(116)). To enable widespread use of the data gathered, we plan to publish the trial’s findings in an appropriate scientific journal after it is complete.
Trial registration number NCT05742256.
- Pain management
- Aging
- Adult anaesthesia
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This study employs strict screening criteria, a randomised allocation scheme and a standardised analgesic protocol for four groups.
This study presents a rigorous method to compare the analgesic effect of different concentrations of oxycodone in patients who will receive thoracoscopic lobectomy for lung cancer.
Patients of the study are administered a multimodal analgesic regimen consisting of thoracic paravertebral nerve block combined with oxycodone.
This study is conducted at a single centre, and the findings may not be applicable to a wider population.
Introduction
With the ageing of society and worsening environmental conditions, the incidence of cancer in China is gradually increasing. Lung cancer incidence is the highest among cancers in males and is second only to breast cancer in females, according to a global study on cancer.1 2 At present, lung cancer treatment involves comprehensive methods, of which surgical resection is the preferred intervention.3
Postoperative pain in lung cancer is a common type of acute pain observed in clinical practice.4 5 Both open-heart and thoracoscopic surgeries can produce severe pain,6 which affects patient recovery and reduces patient satisfaction with medical care. Poor postoperative pain control restricts deep breathing, eventually leading to atelectasis, pneumonia and respiratory failure.7 Of additional concern is that a postoperative hypercoagulable state caused by the stress response to poor analgesia, as well as limited patient activity, can cause deep vein thrombosis and pulmonary embolism. In the absence of adequate analgesia, acute postoperative pain may transform into chronic postoperative pain.8 Aggressive pain management, however, may lessen the incidence of chronic postoperative pain.9 Thus, effective postoperative analgesia is essential for good patient prognosis and recovery.
Thoracoscopic surgical incisions are relatively short, usually only 1–2 cm long, avoiding excessive detachment of the muscles of the chest wall, bracing or cutting of the ribs. In these situations, the intercostal incision is the primary site of acute postoperative pain.10 Somatic pain stimuli from surgical procedures, such as skin incisions, muscle separation, compression by rib spacers, use of lumpectomy instruments and stimulation by chest drains, are transmitted through the intercostal nerves to the ipsilateral dorsal horn of the spinal cord, where they are then combined and transmitted to the cerebral cortex and limbic system.11 The vagus nerve receives injury-related stimuli from the lungs, mediastinum and mediastinal pleura, which are the primary origins of visceral pain. Surgical trauma causes the release of inflammatory mediators, such as prostaglandins, bradykinin, histamine and potassium ions, which activate and sensitise peripheral injury receptors. Sustained peripheral sensitisation leads to hyperexcitability of spinal dorsal horn neurons, which release glutamate and activate spinal N-methyl-D-aspartic acid receptors, thereby causing secondary central sensitisation and persistent pain.12 In addition, stimulation of the phrenic nerve from the patient’s surgical position and intraoperative manipulation often causes shoulder entrapment pain. This complexity necessitates the use of multimodal analgesia for postoperative pain.
The optimal multimodal analgesic protocol for thoracoscopic lung cancer surgery has not yet been clearly defined.13 With the recent widespread use of ultrasound in clinical practice, the thoracic paravertebral block has become easier, more accurate and safer.14 This, in turn, leads to fewer complications, provides good analgesia to patients and reduces the use of opioid drugs, which significantly benefits patients. However, the duration of analgesia with local anaesthetics in single-site or multisegment paravertebral nerve blocks is relatively short, and patients still require clinical pain management after the block wears off. Therefore, patient-controlled intravenous analgesia (PCIA) is an important multimodal analgesia treatment modality.
Sufentanil is a powerful opioid-receptor agonist that is currently utilised in PCIA due to its significant analgesic effects, quick action, prolonged duration and minimal impact on haemodynamics. However, patients frequently develop severe, dose-related side effects when sufentanil is used alone in PCIA, including nausea, vomiting, respiratory depression, postoperative delirium and skin itching.15 16 Older patients are prone to accumulation of sufentanil in the body, which increases the risk of respiratory depression and excessive sedation.
Oxycodone is a semisynthetic opioid agonist of μ and κ receptors and has the characteristics of easily crossing the blood–brain barrier, having a rapid onset and moderate duration of action and having mild immunosuppressive effects. This effectively lowers patients’ postoperative pain and reduces the incidence of respiratory depression, nausea and vomiting. Currently, it is widely used for cancer pain treatment, pathological pain treatment and postoperative analgesia.17–19
Oxycodone combined with other analgesic drugs or modalities can regulate pain receptors and conduction pathways at different sites, thereby acting on different targets to interfere with neuronal sensitisation.20–23 thus reducing nociceptive sensation and producing additive and synergistic analgesic effects. This is conducive to promoting functional exercise in the early postoperative period as well as in reducing the dosage of opioids used, nausea and vomiting, respiratory depression and other adverse effects.24–28 However, few studies have investigated the use of oxycodone combined with paravertebral nerve block for postoperative analgesia in lung cancer surgery, and objective data on the effects and doses of oxycodone in multimodal analgesic regimens for postoperative lung cancer are lacking. It is possible that this multimodal analgesic mode can compensate for the shortcomings of single-drug treatments.
Objective
The objective of this study is to investigate the optimal effective dose of oxycodone for PCIA combined with paravertebral nerve block, for multimodal analgesia management in patients with thoracoscopic lung cancer lobectomy.
Methods and analysis
Study design
This is a prospective, single-centre, double-blind, randomised controlled study that will be conducted at the First Affiliated Hospital of Shandong First Medical University, a tertiary university hospital in China. The study protocol will adhere to the standard protocol item: Intervention Trial Recommendation Statement and Uniform Standard Statement for Reporting Trials to ensure accurate reporting of trial results.
Study setting
This study will be performed at The First Affiliated Hospital of Shandong First Medical University, located in Jinan City, Shandong Province.
Patients and recruitment
From 7 April 2023 to 31 December 2024, 160 patients aged over 60, who provide written informed consent online supplemental file 1 and plan to undergo elective thoracoscopic lobectomy for lung cancer, are randomly assigned to different groups based on inclusion and exclusion criteria. The patients will be divided into four groups: the control group (SF group), test group 1 (OCA group), test group 2 (OCB group) and test group 3 (OCC group). Randomisation is achieved using a computer-generated table of random numbers (see figure 1: study flow chart).
Supplemental material
Study flow chart. PCIA, patient-controlled intravenous analgesia
Inclusion criteria
The inclusion criteria included patients 60 year of age or older undergoing thoracoscopic lobectomy, who have an American Society of Anaesthesiologists (ASA) grades I–III diagnosis, and who have signed the informed consent form for participation in this clinical study.
Exclusion criteria
Exclusion criteria included emergency surgery, scheduled to undergo bilateral thoracoscopic surgery, coagulation disorders, long-term opioid users, nerve block failure, mental illness and allergies to local anaesthetic medications.
Intervention
Following the randomisation method, patients will be randomly divided into four groups according to different interventions used for PCIA after the surgery: OCA group (oxycodone: 0.5 mg/kg), OCB group (oxycodone: 1.0 mg/kg), OCC group (oxycodone: 1.5 mg/kg) and one sufentanil group (sufentanil: 2 µg/kg). Flurbiprofen 50 mg and ondansetron 16 mg will be added to each group. All the drugs will be diluted with 0.9% saline in a 100 mL volume, with a background infusion rate of 2 mL/h, a bolus dose of 0.5 mL and a lockout interval of 15 min. The OCA, OCB and OCC groups will receive a loading dose (oxycodone: 0.1 mg/kg), as well as the SF group (sufentanil: 0.1 µg/kg).
After patients are recruited, hospital staff will use an operating room monitor to monitor patient vital signs such as ECG, oxygen saturation (SpO2) and blood pressure—with invasive blood pressure monitoring obtained by radial artery puncture. Patients will be given a thoracic paravertebral nerve block under ultrasound guidance before surgery. The procedure for a nerve block is as follows.
The patient will be positioned laterally with standard skin disinfection and a sterile membrane wrapped with a linear array probe. All nerve blocks will be administered by an anaesthesiologist with more than 10 years of experience in ultrasound-guided regional anaesthesia. The fourth thoracic paraspinal space (T4) will be identified under ultrasound guidance. Then, a 22-gauge 80 mm needle will be subsequently advanced towards the space in a plane direction. The needle’s position will be confirmed by the pleura’s descent when 2–3 mL of saline solution is injected for hydrolocalisation. Then, 20 mL of 0.25% ropivacaine will be injected, and an intermittent negative aspiration test will be conducted every 4 mL.
Fifteen minutes after performing the thoracic paravertebral nerve block, another anaesthesiologist will measure the spread of blocked dermatomes using cold sensation tests. An ice cube approximately 2 cm long will be held in the hand of a disposable rubber plastic glove for cold testing. The sensory blocked region will be examined between the midaxillary and midclavicular lines from the fourth thoracic dermatome along the cranial and caudal axes. Before each measurement, a reference cold sensation will be administered to the third cervical dermatome and compared with the sensation obtained on the blocked side. After assessing the peak levels of sensory cephalic block and caudal block, the number of blocked dermatomes will be recorded. If patients still report cold sensations, they will be considered thoracic paravertebral nerve block failure and will be excluded from the study. Appropriate analgesia will be administered as recommended by the clinician.
The depth of anaesthesia and the patient’s consciousness status will be evaluated by Bispectral Index (BIS). The general anaesthesia will be inducted with midazolam injection 0.02 mg/kg, sufentanil citrate injection 0.3–0.5 µg/kg, propofol injection 1–2 mg/kg and atracurium besylate injection 0.8–1 mg/kg. Then, the patients will be intubated with a double-lumen tracheal tube, which will be positioned using fiberoptic bronchoscopy, and they will be ventilated using ventilator-assisted breathing. Propofol and remifentanil will be administered during the procedure to maintain anaesthesia based on the patient’s physical condition. Additionally, atracurium will be intravenously injected as required to ensure an appropriate level of anaesthesia, as indicated by a BIS value between 40 and 60. The drug dose will be adjusted according to changes in vital signs. If necessary, vasoactive drugs will be used to maintain the heart rate and blood pressure within 20% of the preoperative basal values.
Twenty minutes before the end of the operation, the patient will be given a loading dose of the intervention analgesic drugs prepared in advance intravenously. At the end of the operation, the patient will be connected to a preprepared PCIA pump and transferred to the postanaesthesia care unit (PACU). The endotracheal tube will be removed when breathing is recovered satisfactorily.
After removing the endotracheal tube in PACU, if the NRS score is≥4, the nurse anaesthetist will press the demand button of the analgesic pump to administer the drug until the NRS score is less than 4. If the NRS score is still greater than four after three consecutive presses (15 min between each), the analgesic pump may be gradually adjusted upwards in a single dose on demand until the patient’s NRS score is less than 4. The analgesic pump will be adjusted back to its original parameters after the eruption of pain is over. Postoperative follow-up will last 48 hours.
Data collection and management
All patients’ demographic information as well as clinical data will be gathered. At each time point, including on admission, during anaesthetic induction, the commencement of surgery, the end of the surgery and the time of extubation, haemodynamic indices such as blood pressure, heart rate, SpO2 and mean arterial pressure will be monitored. It will be noted how long it takes for spontaneous breathing to return, how long until the double-lumen bronchial tube is removed, and whether any negative reactions, including choking and delirium, occur after the double-lumen tube is removed. Following surgery, anaesthesia nurses will check in with the patients and record their pain levels on a NRS, as well as any adverse events including nausea, vomiting or respiratory depression.
Throughout the study, data will be gathered and managed securely and privately. Data gathering will be carried out automatically via the anaesthetic information system and vital sign monitoring system. A nursing anaesthetist will also manually collect portions of the data. Unless otherwise specified, participants will be identified throughout the study by code numbers rather than names. For 5 years, all pertinent records and files will be archived. During the study, the data will only be accessible to researchers who have signed a confidential disclosure agreement, as well as institutional or government auditors. Data without patient identification will be made accessible to the general public after the study.
Outcomes measures
Primary outcome measure
The primary outcome is the NRS score at rest and dynamic at the time of 24 hours after surgery. Dynamic NRS scores are defined as NRS when coughing. The NRS scores of 0–10 will be used to evaluate the degree of pain, 0 means the absence of pain and 10 is the severest pain imaginable.
Secondary outcome measure
The secondary outcomes include the following variables: (1) NRS score at rest and dynamic at 2, 4, 12 and 48 hours postoperatively; (2) total dose of sufentanil or oxycodone consumption in patient-controlled analgesia (PCA); (3) total pressing times of PCA; (4) Ramsay Sedation Score (RSS) at 2, 4, 12, 24 and 48 hours after the surgery—the RSS is conducted to assess the sedation state (with a range from 1 to 6, with a RSS>3 signifying excessive sedation); (5) extubation time—time from withdrawal of anaesthetic to extubation; (6) incidence of postoperative nausea and vomiting (PONV)—PONV is assessed by a 3-point ordinal scale (0=none, 1=nausea and 2=vomiting); (7) incidence of itching—the severity of itching can be evaluated using a verbal rating scale (0=no itching, 1=itching without scratching, 2=itching, need to scratch, 3=itching, need to scratch and need to treat); (8) incidence of respiratory depression—when there is a decrease in the level of consciousness 2, a pulse oximetry of <92% without additional oxygen or a respiratory rate of <6 breaths/min and (9) gastrointestinal recovery (exhaust time).
Patient and public involvement
There will be no patient or public involvement in the conduct, reporting, or dissemination of this research.
Participant timeline
The postenrolment timeline starts when the patient enters the operating room and ends when the patient leaves the PACU. All relevant variables will be recorded by individuals who are unaware of the grouping. The follow-up staff will evaluate the patient’s postoperative analgesia 48 hours after the surgery to assess the relevant situation (table 1).
SPIRIT flow diagram: schedule of enrolment, interventions and assessments
Sample size calculation
The sample size is estimated on the basis of the NRS score for the main outcome indicator, using PASS V.15.0 software, and the sample size is calculated based on the comparison of the means of multiple groups. The means of our review of similar studies are 4.0, 2.5, 3.5 and 2. The SD are 2.2, 1.8, 1.9 and 1.7. Set the type I error alpha for hypothesis testing at 0.008 (Bonferroni correction). The power is set to 0.9 and the sample size for each group is set to 1:1:1:1, yielding a sample size of n=32 for each of the four groups and setting the missing data rate at 20%, resulting in a final number of 40 people in each group and 160 people in total. The purpose of using the Bonferroni correction method is to address the issue of increasing type I error probability with an increasing number of tests. This correction method involves adjusting the significance standard by dividing the prior significance level (α=0.05) by the number of comparisons (c). In our study, since we have six comparisons, the calculated significance criterion is 0.008.
Randomisation and blinding
After recruitment, the block randomisation approach with a block size of three (ASA I, ASA II and ASA III) according to ASA classification will be used to randomly assign patients to the OCA, OCB, OCC and SF group in a 1:1:1:1 ratio. An independent investigator will generate a random table using SAS software (SAS) without any contact with the participants or researchers.
The groups’ assignments will be recorded and sealed in opaque envelopes that are maintained by the nurse. Treatment allocation will be known only to the non-blinded pharmacist. The drug in each group’s postoperative analgesia pump is made to have a similar appearance, smell and volume. During the anaesthesia, both the anaesthesiologists and participants will be unaware of the groups’ assignments, which will be recorded and sealed in opaque envelopes that are maintained by the nurse. Postoperative follow-up will be conducted by a nurse anaesthetist, and the clinical data will be analysed by an analyst. Both the clinical investigator and data analyst will be blinded to randomisation. If a participant experiences an adverse reaction that cannot be attributed to any other factors and emergency unblinding is necessary for patient medical management, it will be permitted.
Statistical analysis
The measurement data will be statistically described in terms of mean±SD, such as NRS score at rest and cough at 24 hours postoperatively, age, RSS and exhaust time. The ratio of oxycodone to sufentanil is hypothesised to be 1000:1 according to the Opioid Oral Morphine Milligram Equivalent Conversion table. Statistical analysis of pain scores will be conducted using repeated measures analysis of variance with Bonferroni correction. Conversely, if some of the metrics do not conform to a normal distribution, we will use a non-parametric rank test for multigroup comparisons, and analyse the differences between each group using a two-pair post-hoc comparison. Count data are described statistically using frequency and percentage, such as the incidence of adverse reactions. The between-group differences will be performed using the χ2 test or the Fisher exact probability method. The statistical analysis will rely on SPSS V.25.0 (IBM, Armonk, NY, USA), and the statistical tests will be double-sided tests. P<0.05 will be considered to be statistically significant.
Ethics and dissemination
The Ethics Committee of the First Affiliated Hospital of Shandong First Medical University has examined and approved this protocol. All patients will be required to complete a written informed consent form before enrollment.
On completion of this trial, we intend to publish the results in an appropriate peer-reviewed, scientific journal to facilitate widespread use of the information obtained.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
YW, GW and ZL contributed equally.
Contributors PS contributed to the study's conception and design. Patients are being selected, and data are being collected by YW and XW. ZL, HF, GW and JS made significant contributions to the organisation of the protocol. The protocol has been given unanimous approval by all authors.
Funding The research has been provided funding by the Bethune Foundation (ezmr2022-003).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.