Opioid analgesics can cause side effects such as constipation, nausea, and vomiting by acting on opioid receptors widely distributed in the peripheral nervous system. This can sometimes make it difficult to achieve and maintain pain relief and continue pain treatment. Among these side effects, nausea and vomiting are specifically referred to as opioid-induced nausea and vomiting (OINV). OINV is known to occur during the initial administration or dose escalation of opioid analgesics, and it not only decreases the quality of life for patients but also reduces adherence to opioid analgesics, which can have a negative impact on pain management. Therefore, appropriate management is crucial.

While the administration of conventional antiemetic drugs is recommended for the treatment of OINV, there is a lack of high-quality studies evaluating their effectiveness, and studies comparing treatment effects with a placebo have not been reported.

The objective is to verify the effectiveness of naldemedine in preventing OINV in patients starting opioid analgesics for cancer

Inclusion Criteria:

1. Patients who can be expected to initiate regular administration of opioid analgesics (tramadol, morphine, oxycodone, hydromorphone) for cancer pain and continue for 7 days or more.
2. Patients who are 18 years of age or older at the time of obtaining consent
3. Patients who can take oral medications, food, and beverages
4. Patients who are considered capable of self-recording in the patient's diary (proxy recording in the patient's diary is acceptable if the patients are capable of self-assessment).
5. Patients who are not expected to have a rapid change in their condition during the study period.
6. Patients who can obtain written consent to participate in the study of their own will

Exclusion Criteria:

1. Patients who have used opioid analgesics within 28 days prior to the date of consent

2. Patients who have taken or are currently taking naldemedine

3. Patients who have nausea and vomiting of CTCAE grade 2 or higher at the time of obtaining consent

4. Patients who have taken the following antiemetic drugs within 7 days prior to the date of consent Metoclopramide, domperidone, H1 histamine receptor antagonists, phenothiazine antipsychotics (chlorpromazine, levomepromazine, prochlorperazine), haloperidol, atypical antipsychotics (perospirone, risperidone, olanzapine), serotonin 5HT3 receptor antagonists (ondansetron, granisetron, ramosetron, palonosetron), corticosteroids (dexamethasone), scopolamine hydrobromide, NK1 receptor antagonists (aprepitant, fosaprepitant, fosnetupitant)

5. Patients who have received cancer chemotherapy that is certain to affect nausea and vomiting within 14 days prior to the date of consent or who are scheduled to receive such therapy within the study period. Cancer chemotherapy that is certain to affect nausea and vomiting will be defined as follows:

   ① Initial administration of a therapeutic regimen containing irinotecan (CPT-11)

   ② Other cancer chemotherapy that is considered certain to affect nausea and vomiting.

   However, the following cases may be considered as not affecting defecation

   • Chemotherapy with the same regimen as the previous course or chemotherapy with the same drug and dose, and there was no moderate or greater nausea and vomiting (CTCAE v5.0 Grade 2 or higher) during the previous course or previous chemotherapy.
   • Patients who have received oral anticancer agents (e.g. TS-1) daily and have not had moderate or severe nausea and vomiting (CTCAE v5.0 Grade 2 or higher) for at least 1 week from the start of oral chemotherapy to the date of consent.

6. Pregnant or lactating patients

7. Patients with suspected hypersensitivity to opioid receptor antagonists such as naldemedine, naltrexone, methylnaltrexone, and naloxone

8. Patients with contraindications listed in the package inserts for naldemedine and opioid analgesics (tramadol, morphine, oxycodone, hydromorphone)

9. Patients participating or scheduled to participate in clinical trials or other interventional studies

10. Patients with gastrointestinal obstruction or suspected gastrointestinal obstruction, or patients with a history of gastrointestinal obstruction and a high risk of recurrence

11. Patients who have undergone surgery or treatment (e.g., nerve block) that affects gastrointestinal function, or radiation therapy to the head, intestinal tract, or pelvis within 14 days prior to the date of consent acquisition, or patients who are scheduled to undergo such treatment during the observation period

12. Patients with medically significant cardiovascular, respiratory, hepatic, or renal dysfunction based on history, clinical laboratory values, electrocardiogram, or physical examination, who are judged inappropriate to participate in the study

13. Patients with symptomatic intracranial conditions (such as brain metastases or leptomeningeal disease)

14. Patients with suspected dysfunction or impairment of the blood-brain barrier

15. Patients for whom it is difficult to explain the contents of the study or obtain consent due to cognitive impairment or psychiatric illness

16. Patients who are judged by the principal investigator or sub-investigator to be inappropriate to participate in this study based on other concomitant therapies or medical findings

De-identified individual participant data (IPD) underlying the results reported in this study will be shared.

These data will include those related to the primary outcome (complete response within 120 hours [CR5]) as well as secondary outcomes, including complete response rates at different time points (CR1, CR3, and CR7), nausea Numerical Rating Scale (NRS) scores, vomiting events, and use of rescue medications.

Data will be available beginning 6 months following publication of the primary results, with no end date.

Access to the IPD and supporting information will be granted to researchers who provide a scientifically and methodologically sound research proposal.

The data to be accessed will include de-identified individual participant data underlying the primary and secondary outcomes of the study, including complete response rates (CR5, CR1, CR3, and CR7), nausea Numerical Rating Scale (NRS) scores, vomiting events, duration of nausea, and use of rescue antiemetic medications. The study protocol will also be available.

Data will be made available upon submission of a research proposal to the corresponding investigator. Access will be granted following review and approval by the study team. Data will be shared after execution of a data sharing agreement, in accordance with institutional and ethical guidelines.