The global disease burden of cancer is increasingly prevalent, and cancer is the second leading cause of death worldwide. About 75-90% of patients with advanced cancer experience pain at moderate to high severity levels, that require multiple interventions, including medications, to maintain a desired quality of life. Opioids continue to be the foundation of medication therapy, and buprenorphine has continued to emerge as an effective alternative opioid to treat pain. On the contrary, methadone has existed for over half a century as an effective analgesic for pain management in the palliative care setting. Both buprenorphine and methadone are well-recognized as Food and Drug Administration-approved opioid medications for opioid use disorder however, both have distinctive pharmacodynamic and pharmacokinetic characteristics that lend themselves as an effective medication in refractory pain syndromes, including advanced cancer-related pain. In this presentation, we will review the pharmacology of methadone and buprenorphine and their advantageous role in managing cancer-related pain, in the palliative care setting.