Intravenous Methadone for Sternotomy Pain Control in Cardiac Surgery: Double-blinded, Randomized Controlled Trial
Phase: PHASE3
Conditions: Pain, Postoperative
Sponsor: Chinese University of Hong Kong

Intravenous methadone for cardiac surgical patients – Ver 1.0                                            28 Nov 2024 
 
 
1
Intravenous methadone for sternotomy pain control in cardiac surgical patients: 
a randomized controlled trial 
 
*Corresponding author: Dr Henry MK Wong, Department of Anaesthesia and Intensive Care, 
Prince of Wales Hospital. 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong 
(email: wmk047@ha.org.hk) 
 
Funding: This work was funded by the Health and Medical Research Fund from the Health Bureau 
of the Government of HKSAR (Reference number: 10211156), and internally supported by the 
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong. This funding 
has no role in the design of this study and will not have any role during its execution, analyses, 
interpretation of the data, or decision to submit results. 
 
Competing interests: None declared 
Date and protocol version: 28 November 2024, Version 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Intravenous methadone for cardiac surgical patients – Ver 1.0                                            28 Nov 2024 
 
 
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BACKGROUND 
 
PAIN IN CARDIAC SURGERY 
Despite modern day improvements in pain treatment and availability of different analgesic 
modalities, suboptimal postoperative pain control remains an issue in cardiac surgical patients. Acute 
postoperative pain is common among cardiac surgical patients, particularly within the first 2 days 
after surgery, with reported at least moderate intensity.1 There could be many facets for 
postoperative pain after adult cardiac surgery. Pain can be caused by surgical incisions and 
dissections, sternal fracture or incomplete bone healing, multiple drainage cannulas and chest tubes 
and sternal wound infections.2-4 Poorly controlled acute postoperative pain is associated with adverse 
physiological outcomes that impair the recovery of cardiac surgical patients. It is associated with 
decreased patient satisfaction, delayed postoperative ambulation, and the development of chronic 
postsurgical pain (CPSP).5 The association between sternotomy pain and pulmonary complications 
has been observed, and the sympathetic activation secondary to pain can induce myocardial ischemia 
and arrhythmias.6-7 Pain control has also been pointed out as one of the major concerns to cardiac 
surgical patients in intensive care unit.8 Therefore, optimal acute pain control not only can improve 
clinical outcomes, but also improves patient satisfaction after cardiac surgery. 
 
Postoperative pain that persists beyond the normal time for tissue healing is increasingly recognized 
as an important complication after various types of surgery. According to the International 
Association for Study of Pain, CPSP is defined as the persistence of pain at surgical site or referred 
area, at least 3 months following the surgical procedure.9 CPSP is common after cardiac surgery. The 
reported incidence was 28% to 56% up to 2 years postoperatively.10-12 Several mechanisms have 
been involved in the development of chronic pain after sternotomy. These include dissection, nerve 
entrapment by sternal wires, sternal retraction, ribs fractures, and intercostal neuralgia as a 
consequence of nerve damage during dissection of the internal mammary artery during coronary 
artery bypass graft (CABG).2-3 In addition, poorly controlled pain has been a general risk factor for 
the development of CPSP. All can stimulate the release of pro-inflammatory cytokines which 
sensitize the afferent nociceptive fibres to cause chronic pain. CPSP has the potential to impact daily 
functioning and quality of life of patients, as well as increasing the healthcare costs. CARDpain 
study reported that among those with CPSP, over 50% had significant pain-related interferences with 
activities of daily living (family and home responsibilities, recreation and employment) at 3, 6 and 
12 months following cardiac surgery.13 Therefore, apart from optimal acute pain control, it is equally 

Intravenous methadone for cardiac surgical patients – Ver 1.0                                            28 Nov 2024 
 
 
3
important to prevent and manage CPSP, to ensure better satisfaction and quality of lives for our 
patients. 
 
CHALLENGES IN PAIN MANAGEMENT 
Intravenous opioids such as fentanyl and morphine have been the mainstay of perioperative analgesia 
for cardiac surgery, either by intermittent boluses or through a patient-controlled device. The primary 
problem with this mechanism of delivery is that significant fluctuations in serum opioid 
concentrations can occur, resulting in effects which range from inadequate analgesia to overdose and 
respiratory depression. These peaks and troughs of analgesia that occur with intermittent opioids 
administration may explain the suboptimal pain control during the initial postoperative period. In 
contrast to intermittent administration of short-acting opioids such as morphine and fentanyl, a single 
dose administration of methadone can be considered. Methadone was conventionally used in cancer 
and chronic pain management. It can be administered via oral, intravenous, and other parenteral 
routes. Despite being an often-used alternative to morphine, it remains relatively invisible in 
perioperative settings. Methadone is a unique opioid that may provide several important potential 
benefits for surgical patients in the perioperative period. It is a potent mu receptor agonist with a 
rapid onset and longest half-life (24-36 hours) of the clinically used opioids. According to a 
pharmacokinetic study,14 central nervous system effect site methadone concentration rapidly 
equilibrates with plasma concentrations, evidenced by a short lag time between plasma 
concentrations and effects (t1/2ke0 4min). This is comparable to the rapid onset and effect 
compartment equilibration of fentanyl and sulfentanil (5-6min), and in contrast the slow onset time 
of morphine, where t1/2ke0 has been reported to exceed 4 hours.15 In addition, as reviewed in an 
editorial, when methadone is administered at a dose of 20mg or higher, the duration of analgesia 
approximates the half-life of 24-36 hours. Therefore, a single intravenous dose 20mg administered to 
an adult at induction of anaesthesia should provide a rapid onset and significant pain relief up to 1-2 
days postoperatively, which is the period reported to have the highest pain score after cardiac 
surgery. Methadone is also a N-methyl-D-aspartate (NMDA) receptor antagonist. It has been 
reported to possess anti-hyperanalgesic and anti-allodynic properties, that is important in preventing 
pain sensitization and the development of CPSP,16-17 which is of high risk in cardiac surgical 
patients. 
 
SIDE EFFECTS OF METHADONE 
Methadone shares the same opioid-related side effects as with many other opioids such as nausea and 
vomiting, drowsiness and respiratory depression. According to a meta-analysis in 2020 which 

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included seven randomized controlled trials on intraoperative use of intravenous methadone18, four 
studies reported no adverse events. One study reported that the patients who received intraoperative 
methadone experienced more sedation compared to control group at 24 hours after surgery. One 
study reported that the intraoperative morphine group had more sedation compared to methadone 
group during the postoperative period. Methadone was not shown to have a higher incidence of 
postoperative nausea and vomiting compared to the morphine group. Methadone has been reported 
to be associated with cardiac conduction abnormalities such as QT prolongation, QT interval 
dispersion and cardiotoxicity (Torsade de pointes).19 However, most of the cardiac-related side 
effects were seen in patients on prolonged or maintenance treatment with methadone. Significant 
dose-dependent QTc prolongation usually occurs at a high dose of methadone. A single injection of 
intravenous methadone at low dose is unlikely to result in significant cardiotoxicity. No cardiac 
disturbances were reported from the meta-analysis.18  
 
GAPS IN THE LITERATURES 
Only a few trials have studied intravenous methadone as an analgesic in surgical patients, in 
particular, there have not been many studies in the field of cardiac anaesthesia. A randomized 
controlled trial done by Murphy et al showed intraoperative methadone to be superior to fentanyl for 
patients undergoing cardiac surgery.20 Methadone was demonstrated to reduce morphine 
consumption in the first 24 postoperative hours and improved pain scores at 12h after extubation 
compared to patients receiving fentanyl. There was 40% reduction in morphine requirement during 
the first 24h after extubation, and the severity of postoperative pain was decreased by 30-40% during 
the first three days after cardiac surgery. There was only one study comparing the analgesic efficacy 
between methadone and morphine give at the time of induction in cardiac surgical patients.21 
Methadone was shown to reduce opioid requirement at 24h postoperatively and significantly reduce 
the incidence of postoperative nausea and vomiting. So far there has not been any studies on using 
methadone for cardiac surgery in Chinese populations, and none on the role of methadone for 
prevention of chronic post-surgical pain in cardiac surgical patients. Substantial literatures have 
demonstrated the ethnic differences in pain perception and endogenous pain modulation is postulated 
to be a mechanism for ethnic differences. Studies comparing Caucasians and Asians, such as Chinese 
and Indians, generally demonstrated lower pain tolerance in Asian populations.22-23 The primary aim 
of this study is to evaluate the use of methadone on acute and chronic pain control after open cardiac 
surgery, compared with conventional opioid-based approach using morphine and fentanyl.  
 

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METHODS/DESIGN 
 
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. 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 

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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 
The most intense pain typically occurs in the first 2-3 days after open heart surgery, leading to 
greater need for analgesia during this period. The primary outcome will be set at 72-hour time frame 
based on the postoperative morphine consumption.  
 
Secondary outcomes 
Key secondary outcomes include the postoperative pain scores measured by numerical rating scale 
(NRS) represented as AUC at rest and movement; the time successfully weaned to spontaneous 
breathing according to ASV; 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 chronic postsurgical pain at 3 and 6 months assessed using the Douleur 
Neuropathique en 4 questionnaire (DN4). It is a ten items questionnaire and the Mandarin Chinese 

Intravenous methadone for cardiac surgical patients – Ver 1.0                                            28 Nov 2024 
 
 
7
version has been validated in previous study. 26 Each item of DN4 is assigned a score of 0 when the 
participant answered ‘no’ and a score of 1 when the participant answered ‘yes’. The total DN4 score 
ranges from 0 to 10, and a score ≥ 4 indicates a diagnosis of neuropathic pain. 27-28  
 
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 Douleur Neuropathique en 4 questionnaire (DN4)26 will be used to evaluate the presence of 
neuropathic pain at 3 and 6 months after surgery. 
 
The following medical and surgical data during the hospital stays will be extracted from patient charts: 
1. 
Patient demographics (age, gender, EuroScore) 
2. 
Type of surgery 
3. 
Duration of surgery and duration of cardiopulmonary bypass 
4. 
ASV time to spontaneous breathing 
5. 
Total morphine consumption at 24 and 72 hours after surgery 
6. 
Episodes of nausea and vomiting, and use of rescue antiemetics 
7. 
Length of ICU and hospital stay 
 

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STUDY PERIOD 
 
Enrolment 
Post-allocation 
TIMEPOINTS 
Baseline 
OT 
4h stop 
sedation 
15min 
extubate 
12h 
extubate 
24h 
extubate 
48h 
extubate 
72h 
extubate 
3-
month 
postop 
6-
month 
postop 
ENROLMENT: 
 
 
 
 
 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
 
 
 
 
 
Informed 
consent  
X 
 
 
 
 
 
 
 
 
 
Demographic 
data 
X 
 
 
 
 
 
 
 
 
 
Comorbidity 
data 
X 
 
 
 
 
 
 
 
 
 
EuroScore 
X 
 
 
 
 
 
 
 
 
 
Allocation 
X 
 
 
 
 
 
 
 
 
 
INTERVENTIONS 
 
 
 
 
 
 
 
 
 
 
Intraoperative 
methadone 
 
X 
 
 
 
 
 
 
 
 
Intraoperative 
morphine 
 
X 
 
 
 
 
 
 
 
 
OUTCOMES: 
 
 
 
 
 
 
 
 
 
 
Ramsay 
sedation scale 
 
 
X 
X 
X 
X 
X 
X 
 
 
NRS score 
 
 
X 
X 
X 
X 
X 
X 
 
 
ASV time to 
spontaneous 
breathing 
 
 
 
X 
 
 
 
 
 
 
DN4 
 
 
 
 
 
 
 
 
X 
X 
Time to first 
morphine rescue 
 
 
 
 
X 
X 
X 
X 
 
 
Postoperative 
morphine 
consumption 
 
 
 
 
X 
X 
X 
X 
 
 
Patient 
satisfaction 
 
 
 
 
X 
X 
X 
X 
 
 
Use of rescue 
antiemetics 
 
 
 
 
X 
X 
X 
X 
 
 
Nausea/vomiting 
 
 
 
 
X 
X 
X 
X 
 
 
Time to first 
bowel movement 
 
 
 
 
X 
X 
X 
X 
 
 
ICU and hospital 
stay 
 
 
 
 
 
 
 
X 
 
 

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9
 
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, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 hours after 
administration of methadone. 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 
The sample size is calculated using G*Power software version 3.1.9.3 (Kiel University, Kiel, 
Germany), and based on postoperative morphine consumption at 24 hours, which is the primary 
outcome variable. Because there was no randomized controlled trial on use of methadone in cardiac 
surgery in Asian population, a pilot study (50 patients) was conducted from cardiac surgical patients 
in Prince of Wales Hospital, Hong Kong. The mean (SD) postoperative morphine consumption at 24 
hours was 21.5 (8.2) mg in patients receiving methadone, whereas that for morphine group was 30.3 
(14.0) mg. With an alpha probability of 0.05 and a power of 90%, a sample size of 34 patients in each 
group will be needed. Assuming 15% drop-out rate, the sample size is increased to 86 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. 
 
DECLARATIONS 
Consent to participate 
All participants will provide written informed consent. All research will be conducted in accordance 
with the Declaration of Helsinki and all other relevant guidelines and regulations. 
 

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Consent for publication 
Not applicable 
 
Competing interests 
The authors declare that they have no competing interests. 
 
Funding 
This work was funded by the Health and Medical Research Fund from the Health Bureau of the 
Government of HKSAR (Reference number: 10211156), and internally supported by the Department 
of Anaesthesia and Intensive Care, The Chinese University of Hong Kong. This funding has no role 
in the design of this study and will not have any role during its execution, analyses, interpretation of 
the data, or decision to submit results. 
 
 
 
 
 
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