Delirium Prolonged for Three Days after Addition of One Dose of 5 mg Methadone to Ongoing Opioid

Dear Editor:

It was recently reported that favorable pain relief could be achieved by adding low-dose methadone (AdOn), precluding the need to switch to another opioid. Not only is it easy, but also an excellent analgesic effect is reported.^1,2 However, we herein report a case of severe adverse effects associated with AdOn.

A 65-year-old man had been diagnosed with mediastinal thyroid papillary carcinoma 3 years ago. After surgery, anticancer drug treatment had been continued. One month ago, he began to suffer chest pain due to the fifth thoracic vertebrae and sternal metastasis. Although oral oxycodone was started, it was ineffective. The patient was referred to the palliative care team. After the first visit, titration by oxycodone injection was started.

When the dose exceeded 120 mg/day, methadone 5 mg was added. After the first dose in the evening, he became restless, aggressive, and wandering. Disorientation disorder continued for up to three days while antipsychotics were administered. Oxycodone injection was changed to oral oxycodone again, and other drugs were administered similarly except methadone. One week later, he underwent radiotherapy as pain control was difficult. With the radiotherapy, we were able to manage his pain for six months until he died.

Since methadone is not only a μ receptor agonist but also an N-methyl-d-aspartate (NMDA) antagonist, an analgesic effect is highly expected. We expected similar benefits in this case, but the result was unexpected, with delirium continuing for three days, whereas pain was not controlled. The key mechanism involved here seems to be NMDA antagonism rather than increased action on μ receptors.

NMDA antagonism is thought to be related to opioid tolerance.

We suspect that adding methadone diminished the opioid tolerance and abruptly intensified the effects of oxycodone, which had previously not worked well. Unfortunately, in this case only adverse effect became obvious, whereas pain was not alleviated. Pain in this patient was difficult to control with opioid therapy.

This prolonged effect might be explained by long half-life time of methadone. It would be better to explain one dose of methadone has changed tolerant status rather than methadone itself worked.

AdOn may thus suddenly lead to an overdose of oxycodone and cause adverse events, as seen in this case. Adding a small amount of methadone is not always safe.