Methadone exerts analgesic effects through μ-opioid receptor affinity and N-methyl-D-aspartate receptor antagonism, which may benefit refractory cancer pain with neuropathic components. Methadone can be introduced by the ‘stop-and-go’ (SAG) method or the ‘add-on’ (AO) method, in which low-dose methadone is added to existing opioids. Observational studies suggest AO may improve pain control but no double-blind randomised controlled trial (RCT) has evaluated this approach. Therefore, the primary aim of this study is to assess the feasibility of conducting a double-blind RCT comparing methadone AO therapy with opioid dose escalation according to standard practice for refractory cancer pain while also exploring safety and preliminary efficacy signals.

A two-centre, randomised, double-blind, two-arm feasibility trial will enrol 22 patients with advanced or recurrent cancer and inadequately controlled pain (oral morphine equivalent daily dose 60–300 mg). Participants will be allocated 1:1 to the methadone AO or opioid-escalation group using a web-based randomisation system with the minimisation method. The primary endpoint is the completion rate of the 2-week study treatment. Secondary outcomes include pain intensity (Brief Pain Inventory), time to adequate pain control, achievement of a personalised pain goal, adverse events (Common Terminology Criteria for Adverse Events (CTCAE)/Patient-Reported Outcomes version of the CTCAE) and quality of life (European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire Core 15-PAL). Feasibility will be determined based on achieving a treatment completion rate of 70% or higher.

The protocol was approved by the Certified Review Board of the National Cancer Centre Hospital (CRB3180008). Written informed consent will be obtained from all participants. The trial is registered in the Japan Registry of Clinical Trials. Results will be published in peer-reviewed journals and presented at international conferences.

jRCTs031240220.

Opioid-induced nausea and vomiting (OINV) in patients with cancer imposes a substantial clinical burden and may compromise adherence to opioid therapy. Naldemedine, a peripheral μ-opioid receptor antagonist, is currently approved for the treatment of opioid-induced constipation. Recent evidence suggests similar benefits for the treatment of OINV. This study aims to evaluate the preventive effect of naldemedine on OINV in patients with cancer pain initiating opioid analgesics.

This multicentre, double-blind, randomised, placebo-controlled, parallel-group comparison trial will be conducted across 20 hospitals and clinics in Japan. An estimated 120 patients with cancer scheduled to initiate opioid analgesic therapy will be recruited and randomly assigned (1:1) to receive either naldemedine or placebo on day 1 (visit 1). From days 1 to 7, patients will receive blinded study medication concurrently with opioid analgesics and will be followed for 8 days. The primary endpoint will be the proportion of patients achieving a complete response (CR) on day 5, defined as no vomiting and no use of rescue antiemetics for up to 120 hours after initiation of opioid analgesics. Key secondary endpoints will include the proportion of patients achieving CR on days 1, 2, 3 and 7; changes in Numerical Rating Scale scores from baseline; duration of nausea; proportion of patients who experience vomiting; proportion of patients using rescue antiemetics and frequency of rescue antiemetic use. Additionally, the incidence of adverse events and serious adverse events will be recorded throughout the observation period.

This study has been reviewed and approved by the Hattori Clinic Certified Review Board (approval number: CRB3180027). Written informed consent will be obtained from all participating patients before study commencement. The results of the study will be presented at academic conferences in Japan or overseas and submitted for publication in a peer-reviewed journal.

NCT07038551 and jRCTs031250128.