Methadone-Associated Delirium in Oncology and Palliative Care: A Clinical Perspective

Methadone is widely used in cancer pain management, particularly when other opioids provide poor analgesia or unacceptable adverse effects. Although it is often considered less likely to cause classic opioid-induced neurotoxicity because it lacks active metabolites, available evidence suggests that methadone can still contribute to delirium and hallucinations in selected patients. The published literature does not support a single toxic dose threshold. Reported neuropsychiatric toxicity appears to depend more on clinical context than on dose alone, especially during opioid rotation, dose escalation, or addition to existing opioid therapy. Previous opioid exposure, drug interactions, accumulation, frailty, dehydration, infection, metabolic disturbance, and central nervous system disease all complicate attribution. At the same time, methadone is also used to improve opioid-related toxicity when patients are switched from other opioids. This creates an important clinical tension: methadone may either relieve or contribute to neuropsychiatric symptoms depending on the setting. A limited review of the literature suggests that methadone should be regarded as a plausible but not exclusive cause of delirium or hallucinations in patients with cancer. Careful monitoring is particularly important during initiation and conversion, when early neuropsychiatric symptoms may signal toxicity in a vulnerable patient.