Evaluating the efficacy of combination of low dose Methadone with Morphine vs Morphine for pain management in Gastrointestinal cancers- a Randomised Control Trial

According to GLOBOCAN 2022, approximately a quarter (24.6%) of all cancer cases worldwide are GI tract cancers, yet they account for more than one-third (34.2%) of all cancer-related deaths. Notably, the burden of GI tract cancers is disproportionately higher in Asia, where an estimated 63% of cases and 65% of deaths occur. Pain is a prevalent and distressing symptom experienced by many patients with Gastrointestinal cancer. It encompasses not only physical sensations but also emotional and psychological components, significantly impacting patient’s quality of life. Chronic cancer pain associated with GI cancers, often presents as a prolonged and fluctuating condition with ill-defined onset. The management of cancer related pain usually involves the combination of multiple drugs, with opioids as the key component of most therapeutic strategies. In some cases, pain is not relieved due to lack of efficacy of opioids or due to intolerable adverse reactions leading to refractory pain. Due to these reasons, Opioid rotation is frequently employed to improve pain relief while simultaneously avoiding opioid side effects. Methadone is usually used in opioid rotation due to its distinctive properties, including a rapid onset of action, prolonged action, high oral bioavailability, and incomplete cross-tolerance with other opioids. These characteristics make it an optimal choice for opioid rotation.

Morphine related side effects are one of the main reasons for starting opioid combination, as it can be a way to improve analgesic effect with less side effects. Methadone is a potent opioid that has usually been used in combination with other opioids. In a retrospective observational study, the authors concluded that “low doses of methadone could be associated with other opioids and could be part of first line treatment for palliative pain treatment”. In another retrospective case series study, the combination of methadone with other opioids provided better control of cancer-related pain. Another retrospective study conducted on patients who received methadone as a co analgesic opioid showed a reduction in pain intensity of >30% in about half of patients with cancer pain under palliative care. A national Swedish survey in specialized Palliative care upon conducting a survey came to a conclusion that the addition of low-dose methadone as a co analgesic to other ongoing opioid therapy appears to be a safe way to benefit from the unique pharmacodynamics of methadone, especially in patients with complex cancer-related pain at the end of life.

Another multicentre prospective study supports the validity of using methadone as an adjunct to opioid-based treatment for cancer pain, especially for patients already on high doses of opioids without adequate pain control. A RCT was done in Brazil to check the efficacy and feasibility of combination of morphine and low dose methadone for cancer pain management, which gave us a result that a combination of low dose methadone with morphine provided significantly less pain after 2 weeks of treatment and provides a good alternative for patients with cancer related pain that is difficult to control. Although this study was not planned to show differences in adverse effects no differences were noticed. Based on these previous literatures, and low usage and fear around using methadone as an analgesic, I wanted to design a study and plan a Randomized control trials to compare the efficacy of combination of low dose methadone with Morphine vs Morphine for cancer pain management in Gastrointestinal cancers.