Objectives
The primary objective of this pilot trial is a feasibility study to evaluate the protocol and the effect of methadone on acute and chronic pain control after open cardiac surgery, compared with conventional opioid-based approach using morphine and fentanyl. In addition, the effects of methadone on opioids consumption, opioid-related side effects, patient satisfaction, postoperative extubation times, and length of stay in hospital and ICU will be determined. This trial will provide the foundation for a larger, adequately powered clinical trial, designed to evaluate the effect of methadone in pain management in cardiac surgery. The protocol of this pilot study was prepared using the SPIRIT checklist (Supplemental file 1)
Study population and design
This is a single-centre, double-blinded, pilot randomized controlled trial conducted at Prince of Wales Hospital, a university teaching hospital with 1650 beds in Hong Kong. It has been registered o ClinicalTrial.gov under a registration ID NCT05913284, date of registration 8 August 2023. Ethics approval was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Research Ethics Committee on 12 January 2023 (CREC Ref No. 2022.636-T). All elective cardiac surgical patients will be admitted to a 23-bed ICU for early postoperative care and monitoring with 1:1 nursing at all times, with an expectation of discharge from ICU to a high-dependency cardiac ward within 24 hours after surgery. Currently 350–400 adults undergo elective coronary artery bypass graft and/or valvular surgery each year.
Randomization and concealment
Patients will be randomized to receive either methadone 0.2mg/kg (maximum dose 20mg) or equipotent dose of morphine, adding to a syringe containing saline made up to 50ml in total, by drawing sequentially numbered, coded sealed, opaque envelops each containing the group assignment of either methadone or morphine group. The sealed envelopes for randomization will be prepared by a third party who takes no further part in the study. The study syringes containing the drug solution will be prepared by a nurse not involved in the study with blind labelling. The primary care team, blinded to the group allocation, will perform all surgical procedures using standardized techniques. Anaesthetists and nurses blinded to group allocation will record data intraoperatively, in ICU, and at regular intervals in the cardiac wards.
Eligibility criteria
We will include adult patients age 18 or older, undergoing elective coronary artery bypass graft (CABG), valve repair/replacement, or combined CABG/valve procedure via sternotomy, with an expected extubation within 12 hours of surgery. The exclusion criteria include emergency surgery, aortic surgery, redo surgery, preoperative renal failure requiring renal replacement therapy or creatinine clearance < 30ml/min (calculated by Cockcroft-Gault formula), liver dysfunction (liver enzymes twice upper limit normal), LVEF < 40%, requirement of mechanical hemodynamic support in perioperative period, history of chronic pain or who regularly used pain medications (except paracetamol and non-steroidal anti-inflammatory drugs), history of psychiatric illnesses or illicit drug use, intraoperative use of remifentanil and unable to provide informed consent.
Anaesthesia and interventions
All patients will receive standard monitoring for cardiac surgery. General anaesthesia will be induced with midazolam 0.01-0.05mg/kg, fentanyl 2-5mcg/kg and rocuronium 0.5-1mg/kg to facilitate intubation with single-lumen cuffed endotracheal tube. Anaesthesia will be maintained with sevoflurane and propofol infusion that target Bispectral Index 40–60. The study drug (either methadone 0.2mg/kg or morphine at equipotent dose) in blind labelling will be administered at time of induction by intravenous infusion over 30 minutes. No further morphine will be given throughout the operation. No other analgesics (paracetamol, non-steroidal anti-inflammatory agents, dexmedetomidine, ketamine), steroids or antiemetics will be given intraoperatively. Patient-controlled analgesia (PCA) morphine protocol will be prescribed to patients for 72 hours after operation for postoperative analgesia. Oral analgesics including paracetamol 1g every 6 hours and dihydrocodeine 30mg three times a day will be prescribed by parent surgical team. At the end of the operation, the patients will be kept sedated with propofol infusion to ICU. Propofol infusion will be stopped upon admission to ICU to facilitate weaning from ventilator. Adaptive Support Ventilation (ASV) is used in ICU for weaning which adjusts the ventilation parameters depending on the patient’s lung mechanics and effort. Pain will be assessed by nurses in ICU at 4h after stopping sedation, then once every 2h. Upon extubation, patient will be assessed the pain score and the level of sedation at 15min, 8h, 12h, 24h, 48h and 72h. 1mg morphine will be administered via PCA to patients if pain of more than mild severity was noted. Any nausea or vomiting, and use of rescue antiemetics will be documented.
Outcome measures
Primary outcomes
Primary outcomes include the proportion of patients that can be recruited (defined as the number of patients that fits the recruitment criteria divided by the total number of elective cardiac surgical patients over a period of time), proportion of patients excluded based on inclusion and exclusion criteria (with reasons for exclusion), appropriateness of randomization process, the attrition rate (defined as the number of drop out divided by the total number of recruited patients, with reasons for withdrawal recorded), any risks or safety issues arising from this pilot, and the perceived trial feasibility.
Secondary outcomes
The secondary outcomes are the time successfully weaned to spontaneous breathing according to ASV; morphine consumption within 24 and 72 hours after surgery, pain score at rest and on coughing, and patient satisfaction score to pain within 72h after the operation; time to first morphine rescue; side effects of opioids including the number of episodes of postoperative nausea and vomiting; time to first bowel movement; the recovery from surgery in terms of length of ICU and hospital stay; and psychological distress of pain at 3 and 6 months after surgery. The psychological distress will be assessed using the Neuropathic Pain Scale and the Pain Catastrophizing Scale.
Data collection
Patients will be screened the day before operation for eligibility. Eligible patients will be given the patients’ information sheets regarding the main aspects of the trial. Research nurses will then discuss with the patients in light of the information provided in the information sheets. Written informed consent will be obtained from patients willing to participate in the trial. All data is collected by research team members blinded to group assignment. Patient demographics and body mass index will be recorded. The time weaned to spontaneous breathing on ASV will be recorded. At 15min after tracheal extubation and at 8h, 12h, 24h, 48h and 72h post-extubation, pain score at rest and on coughing will be quantified using Numerical Rating Scale (NRS) from 0 to 10. Zero represents no pain at all while 10 points represents the worst pain ever. The time to first morphine rescue (in minutes after surgery) will be measured. The level of sedation will be measured using the Ramsay Sedation Scale (1 = anxious, agitated or restless, or both; 2 = co-operative, oriented and tranquil; 3 = respond to command only; 4 = exhibit brisk response to light glabellar tap or loud auditory stimulus; 5 = exhibit sluggish response to light glabellar tap or loud auditory stimulus; 6 = exhibits no response), episodes of nausea and vomiting, and whether antiemetics are prescribed will also be recorded at the above time points. At the same time, patients will be asked to rate the overall satisfaction with pain management on a verbal analogue scale (0 = worst possible, 100 = best possible).
The Chinese version of the Neuropathic Pain Questionnaire (NPQ)28 will be used to evaluate the presence of neuropathic pain and the extent of pain interfering with various components of functioning, including physical functioning, emotional functioning and sleep within the last 24 hours at 3 and 6 months after surgery. Pain Catastrophizing Scale (HK-PCS)22 will be used to assess patients’ negative cognitive-affective response to pain within the last 24 hours at 3 and 6 months after surgery.
The following medical and surgical data during the hospital stays will be extracted from patient charts:
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Patient demographics (age, gender, EuroScore)
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Type of surgery
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Duration of surgery and duration of cardiopulmonary bypass
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ASV time to spontaneous breathing
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Total morphine consumption at 24 and 72 hours after surgery
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Episodes of nausea and vomiting, and use of rescue antiemetics
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Length of ICU and hospital stay
Figure 1 Assessments overview. NRS, numerical rating scale; ASV, adaptive support ventilation; NPQ, Neuropathic Pain Questionnaire; HK-PCS, Pain Catastrophizing Scale Hong Kong version.
Blood sampling for methadone level
Venous blood samples (5ml) will be obtained at 0, 30 and 60 minutes after drug administration, and at 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72 and 96 hours after dosing. Plasma concentration of methadone will be determined by LC-MS/MS (ESI pos). The internal standard (7-dimethylamino-5,5-diphenyl-4-octanone, 2.5ng) will be added to plasma (0.5ml), which will be acidified and then processed by SPE (Waters Oasis MCX cartridges).
Sample size calculation and statistical methods
Based on the recommendations from Whitehead et al24, a sample size of 60 patients (30 per arm) would provide an adequate estimate of the treatment effect to minimize the sample needed for a future RCT, assuming 90% power, a small-medium effect size of 0.3, and to account for 10% lost to follow-up.
There are approximately 350 cardiac surgical patients per year at the study hospital. The authors anticipate that half of the patients will fit our recruitment criteria. Given that intravenous methadone is a novel drug for acute pain management in Hong Kong, it is estimated that half of the patients will agree to participate. With an expected drop-out rate of less than 25%, it should be able to achieve the target sample size of 60 patients.
The primary analyses will be performed on a modified intention-to-treat basis. Patients will be analysed according to their randomized allocated groups but will be excluded from the analysis if they do not adhere to the protocol after randomisation. Categorical data are reported as numbers and percentages. Continuous variables are reported as mean (standard deviation) or median (interquartile range) as appropriate after checking for normality using the Shapiro-Wilk’s test. Comparison of continuous data is performed by Student’s t test and by Mann-Whitney U test for non-normally distributed data. Chi-square test is used to compare groups with categorical variables. Level of significance is set at P < 0.05. SPSS 27.0 software (IBM Corp, Armonk, NY) will be used for data analysis.