Intravenous Methadone in Perioperative Acute and Chronic Management in Chinese Adult Cardiac Surgical Patients: a Pilot Randomized Controlled Trial
Phase: PHASE3
Conditions: Pain, Postoperative, Pain, Acute, Pain, Chronic, Anesthesia
Sponsor: Chinese University of Hong Kong

Intravenous methadone in cardiac surgery (Ver 2.0) 
 
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Intravenous methadone in perioperative acute and chronic pain 
management in Chinese adult cardiac surgical patients: a pilot feasibility 
trial  
1. BACKGROUND 
 
Significance of acute and chronic pain management 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 intensity1. 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 infections2-4. 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 arrhythmias6-7. Pain control has also been pointed out as one of the major 
concerns to cardiac surgical patients in intensive care unit8. 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 procedure9. CPSP is common after cardiac surgery. The 
reported incidence was 28% to 56% up to 2 years postoperatively10-12. 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)13-14. 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 surgery15. Therefore, apart from optimal acute pain control, it is equally 
important to prevent and manage CPSP, to ensure better satisfaction and quality of lives for our 
patients. 
 

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Challenges in pain management in cardiac surgical patients 
Intravenous opioids such as fentanyl and morphine have been the mainstay of perioperative 
analgesia for cardiac surgery, either by intermittent boluses by healthcare staff or through a patient-
controlled device (PCA). 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 study16, 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 hours17. 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 CPSP19-20, which is of high risk in cardiac surgical patients. 
 
Potential adverse effects of methadone 
Intravenous methadone hydrochloride 10mg/ml will be procured from pharmaceutical company in 
United States via the Hospital Pharmacy at Prince of Wales Hospital. The clinical trial pharmacy will 
be involved in dispensing to ensure drug safety during blind labelling. According to the Pain 
Management Best Practices Inter-Agency Task Force Report29 in 2019, methadone is one of the 
common prescription opioid medications that can be considered for management of acute and 
chronic pain.  
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-analysis29 in 2020 which 
included 7 randomized controlled trials on intraoperative use of intravenous methadone, 4 studies 
reported no adverse events (respiratory suppression and excessive sedation). 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 
experienced more sedation compared to methadone group during the postoperative period. 

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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)30. However, most of the 
cardiac-related side effects were 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 would be unlikely to result in 
significant cardiotoxicity. No cardiac disturbances were reported from the included studies in the 
meta-analysis29. 
All patients will be under full cardiac monitoring (ECG, non-invasive and invasive blood pressure 
monitoring and transoesophageal echocardiography) throughout the operation. Patient will also be 
transferred and monitored in intensive care unit for 12 hours after operation and in cardiac high-
dependency unit for at least 24 hours after discharge from intensive care. 
 
Gaps in the literatures 
There have been few randomized controlled trials comparing between intravenous methadone and 
other opioids for perioperative pain control in cardiac surgery requiring sternotomy, and none in the 
Asian populations. In addition, the effect of methadone on chronic postsurgical pain in cardiac 
surgical patients has not been widely reported in literature. Therefore, the primary aim of this pilot 
randomized controlled 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 approach 
of opioid-based analgesia 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. We hypothesized that intravenous 
methadone is associated with a reduction in opioids requirement intraoperatively and in the first 24 
hours after surgery, and improvement in acute pain score at 12h after extubation. Our secondary 
hypothesis is that patients administered with methadone would experience less CPSP compared with 
standard treatment group. 
 
Work done by us 
To date, we have worked on individual components in fast-track cardiac anaesthesia to optimize pain 
management. A pilot study we did has shown that 61% of our cardiac surgical patients suffered from 
chronic post-surgical pain at 3 months after the operation. The focus of cardiac surgery in Hong Kong 
has been on the immediate postoperative period and surgical outcomes, rather than on the quality 
of recovery particularly the pain management as a long-term patient reported outcome measure. A 
few projects from our research team is going on, targeting at anaesthesia techniques and strategies 
in optimizing acute and chronic management (eg. regional anaesthesia). Intravenous methadone is a 
novel approach in Hong Kong. 
 
Work done by others 

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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 surgery23. Methadone was demonstrated to reduce morphine 
consumption in the first 24 postoperative hours and improved pain scores 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 3 days after cardiac surgery. 
There was only one study the comparing the analgesic efficacy between methadone and morphine 
given at the time of induction in cardiac surgical patients24. 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 have compared Caucasians with Asians such as Chinese and Indians. Asians generally 
demonstrated lower pain tolerance than Caucasians26-27. 
 
2. Aims and hypothesis 
 
We hypothesized that intravenous methadone is feasible and applicable in cardiac anaesthesia, and 
is associated with opioid-sparing intraoperatively and within 24h after surgery, as well as better acute 
and chronic pain control when compared to conventional opioid-based approach with morphine and 
fentanyl in adult cardiac surgical patients. The aims of the study are as follows: 
1 
To determine the feasibility of using intravenous methadone in adult cardiac surgical patients  
2 
To evaluate the effect of methadone in acute and chronic pain management in adult cardiac 
surgical patients requiring sternotomy 
 
3. Methods 
 
Study design 
This is a single-centre, prospective, randomized-controlled, and double-blinded pilot study. The study 
was conducted at the Prince of Wales Hospital, a university teaching hospital with 1650 beds in Hong 
Kong. All elective cardiac surgical patients are admitted to our 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, 300-350 adults undergo elective 
coronary artery bypass graft and/or valvular surgery each year. 
This is a pilot feasibility study to determine the effect size of methadone compared with morphine in 
acute and chronic pain management in cardiac surgery requiring sternotomy. By using a sample size 
calculator, with an estimated effect size of 0.75 and a significant level of 0.05 using a 2-sided two-

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sample equal-variance t-test, and to account for a 10% lost to follow-up, a total sample size of 86 (43 
per arm) will achieve 90% power to reject the null hypothesis. 
 
Inclusion and exclusion 
We include adult patients age 18 or older, undergoing elective primary isolated coronary artery 
bypass grafting, aortic valve repair/replacement, mitral valve repair/replacement or combined 
coronary artery bypass/valve procedure via sternotomy for the first time, with expected extubation 
within 12 hours of surgery, in Prince of Wales Hospital, Hong Kong. 
The exclusion criteria include: emergency surgery, aortic 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, unable to provide informed 
consent, and history of known or suspected allergy to methadone or other opioid-related drugs. 
 
Randomization and concealment 
The patients are randomized to receive either methadone 0.2mg/kg (maximum dose of 20mg) or 
equipotent dose of morphine, added to a syringe containing saline made up to 50ml in total. 
Randomization will be carried out by an independent investigator, on the day before operation, from 
pre-prepared envelops each containing the group assignment of either methadone or morphine 
group. The group assignment will be done by sequence generation with computer models. The study 
syringes containing the drug solution will be of identical appearance and with blind labelling so that 
the primary care team and the patient will be blinded to the treatments. An independent assessor 
blinded to the study will be responsible for the data analysis. 
 
Anaesthesia and interventions 
Intravenous access will be established and all patients will be monitored with standard monitors 
(non-invasive blood pressure, oxygen saturation, 5-lead ECG, distal radial arterial catheter and 
Bispectral index). Anaesthesia will be induced with midazolam 0.01-0.05mg/kg, fentanyl 2-5mcg/kg 
and TCI Propofol 0-1ng/ml Marsh model. Rocuronium 0.5-1mg/kg will be administered to facilitate 
intubation with single-lumen cuffed endotracheal tube. Anaesthesia is maintained and titrated 
according to Bispectral index 40-60 with sevoflurane and TCI Propofol infusion. Muscle relaxants are 
administered to maintain at train-of-four counts less than two. 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, 
but administration of intraoperative fentanyl will be left to the discretion of the attending 
anaesthesiologists. 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 given to patients for 72 hours after operation 

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for postoperative analgesia. Other oral medications for postoperative analgesia will be prescribed by 
the parent surgical team. 
At the end of the operation, the patients will be kept sedated with Propofol infusion to ICU. Propofol 
infusion is 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 is assessed by nurses in ICU after stopping Propofol 
infusion hourly for 4h, then once every 4h. 1mg morphine will be administered to patients if pain of 
more than mild severity was noted. 
 
4. 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 at which the patient is successfully weaned to spontaneous 
breathing according to ASV; the total morphine consumption within 24h after the operation; 
intraoperative fentanyl consumption; the total morphine consumption, pain score at rest and upon 
exertion, 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; 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, Brief Pain Inventory Interference Scale and the Pain Catastrophizing Scale. 
 
5. Data collection 
 
All consenting participants will be interviewed on the day before operation. 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 12h, 24h, 48h and 72h postoperatively, patients will be asked to quantify 
the intensity of postoperative pain at rest and upon maximal coughs with numerical rating scale (0 = 
no pain, 10 = worst pain imaginable). The time to first morphine rescue (in minutes after the 
operation) 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 

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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 and Brief Pain Inventory (BPI) 
interference scale21 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: 
1. 
Patient demographics (age, gender, EuroScore) 
2. 
Type of surgery 
3. 
Duration of surgery and duration of cardiopulmonary bypass 
4. 
Intraoperative fentanyl (mcg) consumption 
5. 
Daily and total morphine consumption within 72 hours postoperatively 
6. 
ASV time to spontaneous breathing 
7. 
Length of ICU stay 
8. 
Length of hospital stay 
 
 
 
Assessment 
Baseline 
(day 0) 
15min 
extubation 
12h 
postop 
24h 
postop 
48h 
postop 
72h 
postop 
3-
month 
postop 
6-
month 
Enrolment 
Eligibility screen 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demography data 
X 
 
 
 
 
 
 
 
Comorbidity data 
X 
 
 
 
 
 
 
 
EuroScore 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Outcomes 
NRS score 
 
X 
X 
X 
X 
X 
 
 
ASV time to 
spontaneous 
breathing 
 
X 
 
 
 
 
 
 
NPQ 
 
 
 
 
 
 
X 
X 

Intravenous methadone in cardiac surgery (Ver 2.0) 
 
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BPI 
 
 
 
 
 
 
X 
X 
Pain 
Catastrophizing 
Scale 
 
 
 
 
 
 
X 
X 
Intraoperative 
fentanyl 
consumption 
 
X 
 
 
 
 
 
 
Time to first 
morphine rescue 
 
 
X 
 
 
 
 
 
Postop morphine 
consumption 
 
 
X 
X 
X 
X 
 
 
Nausea / vomiting 
 
X 
X 
X 
X 
X 
 
 
Pain satisfaction 
 
 
X 
X 
X 
X 
 
 
Extubation time 
 
X 
 
 
 
 
 
 
ICU stay 
 
 
 
X 
 
 
 
 
Hospital stay 
 
 
 
 
 
 
X 
 
 
6. Ethics and statistical analysis 
 
Patients will be screened for recruitment on the day before operation and explained the risks and 
benefits of the study. Written informed consent will be obtained from the patient. Data will be kept 
confidential in securely locked offices of the Department of Anaesthesia and Intensive Care, Prince 
of Wales Hospital and on secure password-protected computers for 3 years. Access to data will be 
restricted to study investigators. Identifiable patient data will remain confidential. Ethics approval 
will be obtained from the Joint CUHK-NTEC Research Ethics Committee. The study will adhere to 
local laws, Declaration of Helsinki, international Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use Good Clinical Practice and institutional policies. 
 
Descriptive and summary statistics will mainly be used for outcome measures. Continuous variables 
will be expressed as mean ± standard deviation (SD) for normally distributed data or median ± 
interquartile range (IQR) if not normally distributed. Categorical data will be shown as numbers and 
percentage. Comparison of continuous data will be performed with Student’s t test with normal 
distribution and by Mann-Whitney U test for non-normally distributed data. Chi-square test will be 
used to compare groups with categorical variables. P value less than 0.05 is considered significant. 
Multivariate analysis will be used to find the association between CPSP and methadone use. SPSS 
26.0 software (SPSS, Inc, Chicago, IL, USA) is used for data analysis. 
 
7. References 

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