A randomised controlled trial conducted by The Chinese University of Hong Kong (CUHK)’s Faculty of Medicine (CU Medicine) has revealed that intravenous methadone administered at anaesthetic induction during cardiac surgery provides significantly better postoperative pain control than morphine, with 60% less acute pain within the first 72 hours post-operation and nearly 70% lower postoperative morphine consumption, reducing physical and psychological distress in patients. This breakthrough offers a novel approach to postoperative pain management in cardiac surgery, speeding up recovery and reshaping pain control strategies for major surgical procedures in Hong Kong. The findings have been published in the international medical journalAnaesthesia.

Featured are research team members from CU Medicine including (from left) Dr Siu Kwan Wo from School of Pharmacy, Dr Liu Xiaodong, Assistant Professor (Non-clinical) from the Department of Anaesthesia and Intensive Care; Professor Ho Kwok-ming, Chairman of the Department of Anaesthesia and Intensive Care; Dr Henry Wong Man-kin, Assistant Professor (Clinical) and Head of the Cardiac Anaesthesia Team from the Department of Anesthesia and Intensive Care; Professor Randolph Wong Hung-leung, Chief of the Division of Cardiothoracic Surgery in the Department of Surgery; Professor Joan Zuo Zhong from School of Pharmacy; and Sandra Chiu Lok-ching, research assistant from the Department of Anesthesia and Intensive Care.

Major trauma from cardiac surgery makes first 72 hours key for pain relief

Due to the major trauma caused by cardiac surgery, patients frequently experience acute pain[1] within 48 to 72 hours post-operation, which often requires opioid analgesics for relief. Poor pain control not only hinders recovery and daily functioning but may also lead to chronic pain and cardiopulmonary complications. Hence, the management of postoperative acute pain remains a major clinical challenge.

Morphine is a commonly used opioid for the management of acute pain post-operation but its use is associated with fluctuating plasma concentrations, respiratory depression and opioid-induced hyperalgesia. Methadone, although also an opioid, has different pharmacological properties. It affects the sense of pain by modulating NMDA receptors and neurotransmitter pathways in the brain, offering prolonged analgesic effects but with a lower risk of dependence. Nevertheless, methadone’s application in cardiac surgery has remained underexplored and its efficacy requires further validation.

Researchers conducted a single-centre, double-blind, randomised controlled trial involving 80 patients (about 60 years old) undergoing cardiopulmonary bypass-assisted cardiac surgery. Participants received either 0.2 mg/kg of intravenous methadone or morphine at anaesthetic induction (the “methadone group” and the “morphine group”, respectively). Researchers assessed the participants’ pain scores, morphine consumption, opioid-related adverse effects and patient satisfaction at multiple points up to 72 hours after the operations, and analysed their plasma methadone concentrations and pain up to 96 hours post-surgery through blood samples.

CU Medicine administered methadone to 40 patients undergoing cardiopulmonary bypass cardiac surgery, and morphine at an equivalent dose to another 40 patients during anaesthetic induction. Upon comparison, it is found that methadone still had a certain analgesic effect at 80 hours post-operation without increasing opioid-related side effects, providing patients with better recovery outcomes compared with morphine.

More than 80 hours of effective pain relief improves post-operation recovery 

According to the findings, the methadone group reported significantly lower pain scores at rest and during coughing compared to those in the morphine group. At 15 minutes after operation, the average pain score in the methadone group was nearly 65% lower than that of the morphine group, and remained approximately 60% lower at 72 hours post-operation. This suggests that methadone provides more sustained and effective pain relief than morphine. The methadone group required nearly 70% less morphine over the first 24 hours postoperatively and throughout the entire trial. There were no significant differences between the two groups in terms of opioid-related side effects such as nausea and vomiting, indicating that methadone’s prolonged analgesic effect does not lead to additional side effects.

The first author of the study, Dr Henry Wong Man-kin, Assistant Professor (Clinical) and Head of the Cardiac Anaesthesia Team from the Department of Anesthesia and Intensive Care at CU Medicine, said: “Although plasma concentrations of methadone declined during cardiopulmonary bypass, they remained above the minimum effective analgesic threshold for at least 24 hours post-operation. Even at 80 hours post-operation, methadone continued to exert a certain analgesic effect, demonstrating its long-lasting pharmacological action. This suggests that methadone may be further applied in chronic pain management in the future. Crucially, despite methadone’s long duration of action, our data suggested better pain control compared to morphine without increased opioid-related side effects, including sedation and respiratory depression. Due to its rapid onset, prolonged effect and action at both opioid and NMDA receptors, methadone can be a good candidate for analgesia in cardiac surgery.”

Professor Randolph Wong Hung-leung, Chief of the Division of Cardiothoracic Surgery in the Department of Surgery at CU Medicine, said: “Over the past two decades, our cardiothoracic surgery team has performed heart and major vascular surgery on more than 6,800 patients. These procedures are classified as very high risk and critically complex, often requiring median sternotomy and prolonged cardiopulmonary bypass support. While we have significantly reduced mortality rates over the years, the post-operative pain caused by surgical wounds – both acute and chronic – remains a challenge to be addressed. Studies have shown that most of these patients experience moderate to severe wound pain post-sternotomy, with a pain score reaching six out of 10. Such pain can lead to shortness of breath and pulmonary complications. This study, led by Dr Henry Wong Man-kin, specifically addresses postoperative pain management in this patient population, and I believe it will enhance the overall quality of care and patient satisfaction.”

Professor Ho Kwok-ming, Chairman of the Department of Anaesthesia and Intensive Care at CU Medicine, remarked: “This study marks our initial step in exploring a comprehensive strategy to speed up the recovery of patients who have undergone major cardiac surgery. We are confident that the integration of these findings into clinical practice will significantly improve their speed and quality of recovery after surgery.”