• Nausea and vomiting

To the Editor

Opioid-induced nausea and vomiting (OINV) is an important side effect of opioids, causing interruption of opioid therapy and inadequate pain control.1 There is currently no standard of care for OINV; the first randomised controlled trial for the prevention of OINV found no significant preventive effect of prochlorperazine on OINV.2

OINV has similar mechanisms to chemotherapy-induced nausea and vomiting (CINV),3 and dexamethasone is shown to be effective for preventing CINV. Dexamethasone is also effective for preventing postoperative nausea and vomiting, which is also known to have similar aetiologies to OINV.4 Considering overall usefulness of dexamethasone, we conducted a prospective study to investigate the feasibility of a randomised controlled trial of a single dose of dexamethasone for OINV.

This study is a multicentre, prospective clinical trial. The registration number for this study is UMIN000031741.

Adult cancer patients who were scheduled to start oral opioids at a dose of at least 15 mg/day of oral morphine equivalent, and had adequate major organ function, were enrolled. Patients who had received any opioids or highly/moderately emetogenic anti-cancer drugs within 3 weeks, mildly emetogenic anti-cancer drugs within 1 week, patients with nausea or vomiting within 1 week, patients with diabetes requiring regular insulin administration and history of delirium within 1 year were excluded.

Enrolled patients received a single oral dose of 8 mg dexamethasone 0–12 hours before the first opioid dose. The patients recorded their symptoms and medication use during observation period (120 hours) in the patient diary. Symptoms during the observation period were assessed retrospectively by the attending physician, checking against the patient diary at the visit.

The primary endpoint of the study was the percentage of complete response (CR), defined as the absence of emesis and use of antiemetic drugs during the observation period. The expected CR rate for this study was 85%, and the threshold CR rate was set to 60%, considering the results of a randomised controlled trial in a similar population.2 Since this study is a feasibility study, the α was 10% one-sided, the power was 80% and the expected number of enrolled patients was set at 15. The t-test was used for group comparisons of continuous variables, and the χ² test was used for group comparisons of categorical variables.

Between May 2018 and April 2019, 15 cancer patients were enrolled. The mean age was 71 years (range: 55–83 years), 73% were male and 73% were lung cancer patients. The breakdown of opioids was 73% oxycodone, 20% hydromorphone and 7% morphine.

No patient experienced vomiting during the observation period. Nausea occurred in 3 patients (20%) within 24 hours and in 4 patients (27%) within 96 hours. The severity of nausea was Grade 1 in 1 patient and Grade 2 in 3 patients. Although antiemetic medication was recommended for Grade 3 or higher nausea, 3 patients actually took antiemetics. Therefore, the percentage of CR was 80% (80% CI: 60.7%–92.4%) at both 72 hours and 120 hours. The lower limit of the 80% CI of CR rate was above 60%, indicating that the study met its primary endpoint.

A comparison of the endpoints observed in this study with the historical control2 is shown in table 1. During the 120-hour observation period, the percentage of patients who experienced vomiting and nausea was 0% and 26.7% in this study, and 26.7% and 51.7% in the historical control, respectively. The percentage of patients who used antiemetic agents was 20% in the study and 26.7% in the historical control. In other words, 75% of patients with nausea used antiemetic agents in the study, compared with only 52% in the historical control.

Adverse events of dexamethasone observed in this study were Grade 1 constipation in 2 patients (13%). None of the patients with constipation developed nausea, and constipation resolved during management of opioid-induced constipation. No other adverse events for which information was routinely collected in this study (confusion, insomnia, gastric bleeding, duodenal bleeding, anorexia, facial oedema, trunk oedema, limb oedema, fatigue and hiccups) occurred, and no other adverse events were reported.

This prospective clinical trial of a single oral dose of 8 mg dexamethasone for OINV met the primary endpoint. Compared with data from a previous study in which placebo was given to a similar patient population with similar background, which was set as a historical control in advance, the incidence of vomiting (0% vs 26.7%) and nausea (26.7% vs 51.7%) tended to be lower.

This study suggests that the single dose of dexamethasone has a prophylactic effect against OINV and was well tolerated. Since many of the side effects of corticosteroids occur in association with long-term administration of corticosteroids, a single dose is more favourable from the standpoint of safety. It should be noted, however, that this study did not evaluate the safety of the drug in patients with high risk, as it excluded patients with diabetes requiring regular insulin and patients who developed delirium within 1 year.

The endpoints of the randomised controlled trial need to be improved based on the findings of this study. The rate of antiemetic medication in patients with mild nausea was higher in this study than in the historical control, and the CR rate did not accurately reflect the degree of nausea and vomiting. Establishing a standard of care in a randomised controlled trial requires endpoints that are robust and accurately reflect the patient’s quality of life. Given that nausea is a subjective patient symptom, patient-reported outcomes are likely to be appropriate endpoints for randomised controlled trials.

In conclusion, a single dose of dexamethasone is a promising prophylactic intervention for OINV and needs to be validated by randomised controlled trials. Considering that nausea and vomiting are subjective symptoms of patients, it is desirable to adopt patient-reported outcomes for more robust endpoints in future studies.