Prevalence of opioid-induced adverse events across opioids commonly used for analgesic treatment in Japan: a multicenter prospective longitudinal study

This study was a preplanned secondary analysis of a multicenter prospective longitudinal study conducted in Japan from 1 November 2020 to 30 June 2021. Five specialized palliative care consultation teams and four palliative care units in tertiary care hospitals in Japan participated in the study. The original study assessed the time to achieve cancer pain management by specialized palliative care provided by certified palliative care physicians, advanced practice nurses, and multidisciplinary palliative care staff (psycho-oncology physicians, pharmacists, medical social workers, rehabilitation specialists, and dentists, among others). We defined cancer pain in this study as pain associated with cancer invasion and metastasis; the definition of cancer pain excluded pain related to anticancer treatments such as surgery, chemotherapy, and radiotherapy. In patients with multiple cancer pain, we focused on the cancer pain that was most severe and interfered with daily life. We enrolled consecutive eligible inpatients who received specialized palliative care. All observations were performed within the range of routine clinical practice. The inclusion criteria for the patients in the original study were 1) receipt of specialized palliative care, 2) cancer pain, and 3) requirement for further cancer pain management. In this study, we added the inclusion criteria: the patients who were used opioids for cancer pain management. We excluded patients 1) whose most severe pain was not cancer pain, 2) who were admitted for surgery, and 3) who could not evaluate their symptoms and therapeutic interventions because of a severe symptom burden, serious psychological distress, or cognitive disorders preventing us from evaluating their symptoms or treatment. All patients were followed up until they indicated that there was no need for further cancer pain management because the management was sufficient, they developed other types of cancer pain that required more intervention, or they were discharged without adequate pain management. Although the patients had been previously registered, they were re-registered each time if they required further cancer pain management because of worsening or new pain.

Palliative care physicians prospectively recorded the data collection sheets every day to determine whether the enrolled patients considered their cancer pain management successful and whether they needed further management. We collected the following patient data at enrollment (baseline): age, sex, primary cancer site, organ dysfunction (liver dysfunction: total bilirubin of > 1.5 mg/dL and renal dysfunction: estimated glomerular filtration rate of < 45 mL/min/1.73 m²), concomitant drugs (nonsteroidal anti-inflammatory drugs, acetaminophen, and analgesic aids), opioids, and daily morphine milligram equivalents. AEs were assessed every day until termination of follow-up.

We performed a daily assessment of the severity of constipation, delirium, drowsiness, nausea, and other AEs due to analgesics and analgesic adjuvants until termination of follow-up. We rated AEs from grade 1 to 5 based on the Common Terminology Criteria for Adverse Events version 5.0 [13]. A patient was considered to have an AE if the causal relationship between opioids and AEs was “possible,” “probable,” or “definite” and the grade was ≥ 1. When the same AEs occurred more than two times during the observation period, we only recorded the higher-grade events.

We calculated the dose of opioid at enrollment as daily morphine milligram equivalents based on previous studies [14, 15]: oral morphine 60 mg = intravenous (IV)/subcutaneous (SC) morphine 30 mg = oral oxycodone 40 mg = IV/SC oxycodone 30 mg = fentanyl patch 25 μg/h = IV/SC fentanyl 0.6 mg = oral tapentadol 200 mg = oral hydromorphone 12 mg = IV/SC hydromorphone 2.4 mg = oral tramadol 300 mg.

First, we extracted opioid-using patients from all enrolled patients. We excluded patients who received analgesic treatment by only non-opioids, such as nonsteroidal anti-inflammatory drugs.

Second, descriptive analyses were performed to summarize the analyzed baseline patient characteristics.

Third, multivariate logistic analysis was performed to compute the adjusted odds ratio (OR) for each AE with the following variables: opioid (reference group = oxycodone), age (per 10 years), sex (reference group = male), renal dysfunction (reference group = absent), and primary cancer site (digestive tract, lung, and others; reference group = others). As for opioid, we selected oxycodone because of the most frequency prescription in the analyzed patients. Opioids prescribed to less than 30 patients were excluded from the analysis because they would destabilize the logistic model. Potential confounding variables were identified based on previous studies [9‐11].

All analyses were performed using JMP version 16 for Windows (SAS Institute, Cary, NC). A p value between 0.01 and 0.05 was considered to be a weak indication of the finding, and a p value of < 0.01 was considered to be a clear indication of a finding.

The present study was conducted in accordance with the ethical standards of the Declaration of Helsinki and the ethical guidelines for medical and health research involving human subjects presented by the Ministry of Health, Labour and Welfare, Japan. This study was approved by the institutional review board of each participating institution and by the Independent Ethics Committee of Tohoku University School of Medicine (approval no. 2020–1-1085). Japanese law does not require individual informed consent from participants in a noninvasive observational trial such as the present study. Therefore, we used an opt-out method rather than obtaining written or verbal informed consent. All patients could receive information on the study through the instructions posted on the ward or institutional website and had the opportunity to decline participation.

In total, 522 patients were enrolled during the study period. Fifty-seven patients were excluded because of no opioid use. Thus, we analyzed 465 patients, including 265 (57.7%) men and 194 (42.2%) women (mean ± standard deviation age, 62.6 ± 13.8 years). Among the opioids, oxycodone (n = 189, 40.9%) was the most commonly used, followed by hydromorphone (n = 89, 19.3%), fentanyl (n = 80, 17.3%), tramadol (n = 52, 11.3%), tapentadol (n = 29, 6.3%), and morphine (n = 20, 4.3%). The median observation duration was 3.0 days (range, 1.0–7.0 days). The patients’ characteristics are shown in Table 1.

The OR for each AE is shown in Table 2. Based on the descriptive analysis for opioid prescription, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs for all opioids, delirium (n = 27, 5.8%) was the most frequent, followed by drowsiness (n = 23, 4.9%), nausea and vomiting (n = 22, 4.7%), and constipation (n = 20, 4.3%). With respect to the prevalence of AEs for the four analyzed opioids, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). After controlling for age (per 10 years), sex, renal dysfunction, and primary cancer site (digestive tract, lung, and others), no single opioid was identified as a statistically significant independent predictor of any AE. However, the following trends were shown: the risk of constipation was decreased with fentanyl (adjusted OR, 0.15; 95% confidence interval [CI], 0.02–1.23; p = 0.08) compared with oxycodone, and the risk of nausea and vomiting was increased with tramadol (adjusted OR, 3.03; 95% CI, 0.87–10.57; p = 0.08) compared with oxycodone. Additionally, the risk of constipation was clearly increased in patients with renal dysfunction (adjusted OR, 5.42; 95% CI, 1.61–18.22; p < 0.01).