Main findings
First, this study revealed that the proportion of end-stage patients with severe-to-intolerable cancer-related pain exceeds 30% in Japan (Fig. 1) and the median cumulative opioid prescription dose for terminally ill patients over the 90 days before death was only 311.0 mg oral morphine equivalents (Fig. 2). We found that cancer-related pain may not appropriately controlled by low-dose opioid prescriptions in patients with advanced cancer in Japan.
The ACM indicates the oral morphine-equivalent dosage of opioid analgesics required for pain relief in terminally ill patients with cancer in milligrams per capita based on the assumption that 80% of such patients require an oral morphine-equivalent dose of 75 mg/day over the 90 days before death [12] In other words, based on the ACM recommended by WHO, a total opioid dose of 5400 mg per person is required over the last 90 days before death. The prescription doses of opioids for patients with end-stage cancer did not reach the ACM recommendation in this study. In addition, a recent study using another Japanese claim database reported that the daily opioid dose was less than 60 mg oral morphine equivalents in 30–40% of patients with end-stage cancer in the last 30 days before death [13]. It is possible that the opioid prescription dose is insufficient in this patient population, resulting in severe-to-intolerable cancer-related pain in Japan.
Aiming to take particular actions to decrease the incidence of severe-to-intolerable cancer-related pain and improving the ACM, we investigated a health insurance claim database using multiple analyses and interpreted the present findings toward the objectives. We found that the proportion of patients who did not receive opioid analgesics was negatively associated with proportion of patients with severe-to-intolerable cancer-related pain (Table 2). It appears that the initiation of opioids in patients with cancer-related pain is well distributed. However, in prefectures with low rates of opioid prescription, opioid prescriptions should be provided after a pain assessment. The cumulative opioid consumption in morphine-equivalent doses within 90 days before death was negatively associated with the proportion of patients with severe-to-intolerable cancer-related pain (Table 2), indicating that a higher median cumulative dose of opioids resulted in fewer patients with severe-to-intolerable cancer-related pain. Considering the high proportion of patients with severe-to-intolerable cancer-related pain and the low doses of opioid prescriptions in Japan, a higher opioid dose should be appropriately given to these patients in terms of appropriate pain management.
Other findings of our multiple analyses might provide clues to overcoming challenges regarding both the high proportion of patients with severe-to-intolerable cancer-related pain and the extremely low opioid doses. Interestingly, as a cause of low-dose opioid prescription, the total number of basic palliative care practice visits per patient unrelated to opioid prescriptions in the 90 days before patient death, which can be claimed by physicians and nurses regardless of experience in palliative training, was negatively associated with the opioid prescription dose in this period (Table 3). These findings might indicate that basic palliative care support is provided to patients with cancer nationwide by mainly nurses certified in palliative care. These nurses usually screen for severe-to-intolerable cancer-related pain and refer patients to physicians because they are not eligible to prescribe opioids in Japan, but physicians do not prescribe opioid analgesics or treat cancer-related pain with sufficient doses of opioids. This clinical situation implies that the screening of patients with severe-to-intolerable pain by certified nurses might not lead to appropriate opioid prescription.
Because the proportion of patients receiving opioid analgesic prescriptions in the outpatient setting from specialized palliative physicians was positively associated with the opioid prescription dose in the 90 days before cancer-related death (Table 3), possible barriers to adequate opioid availability could prevent nurses from consulting physicians with specialized experience in palliative care. In addition, the proportion of patients who did not receive opioid analgesics was negatively associated with the opioid prescription dose over the 90-day period before cancer-related death. To prescribe an appropriate opioid dose to patients with cancer-related pain, education to reduce the number of patients who do not receive opioid analgesics is required for medical staff across the country.
The opioid prescription dose depends on certified palliative care in the outpatient setting. No correlation was noted with the proportion of patients treated in inpatient settings, which was eliminated in the initial screening of candidate explanatory variables.
Because interdisciplinary palliative care support has been consolidated under the inpatient setting in Japan, oncologists or primary care physicians, opposed to specialized palliative medicine, are usually in charge of palliative care in the outpatient setting. Encouraging such physicians to play an important role in pain control in the outpatient setting might contribute to overcoming the two aforementioned challenges. Anecdotal evidence was obtained in our previous study, in which the outpatient medical expenditure per day for hypertension and diabetes, which are representative of primary care practice, were associated with prefectural differences in the adequacy of opioid availability in Japan [7].
Since WHO proposed morphine and other strong opioids as essential drugs for cancer-related pain control in the 1980s, numerous educational activities aiming to improve knowledge and negative attitudes toward opioids were rapidly expanded globally. Most countries successfully increased opioid availability for cancer-related pain in the 1990s to early 2000s [14, 15]. Focusing on the situation in Japan, the national educational program for palliative care started in 2008, and approximately 150,000 physicians completed this training in 2021. The Japanese program consists of all-around contents regarding palliative care (e.g., pharmacotherapy for various symptoms, advanced care planning, communication skills, regional cooperation). Because the lack of training and awareness of health professionals on opioid management for cancer-related pain is the most important barrier15, the context of the educational program should be reformed to specialize in the practical use of opioid analgesics for cancer-related pain relief.
Our goal is to decrease the number of patients with severe-to-intolerable pain in Japan. For appropriate pain assessment and opioid prescription, the lack of training and awareness of healthcare professionals has been identified as the primary barrier for adequate opioid availability [7]. Education to balance the advantages of improving adequate opioid availability with preventing opioid addiction is essential for realizing the benefits of opioid analgesics and minimizing their drawbacks to improve QOL among terminally ill patients with cancer. Opioid availability is extremely low in East Asian countries including Japan as well as Eastern Europe compared with that in other advanced countries in Western Europe, the US, and Canada11. There might be ingrained factors affecting pain control practices in different global regions. Berterame et al. identified impediments to opioid use, including the absence of training and awareness among healthcare professionals, cultural attitudes, fear of dependence, fear of diversion, and onerous regulation [16]. Our study suggests that trained palliative physicians, preferably palliative care team members, are required for appropriate opioid prescription to control severe-to-intolerable cancer-related pain at the level of the global standard in patients with end-stage cancer.
Study limitations
No symptoms were obtained from the health insurance claims database. Instead, objective indicators were obtained using a questionnaire targeting medical staff closest to patients at the end stage of cancer, and we combined and analyzed the questionnaire survey data with the health insurance claims data. There are several limitations in combining the results of two experiments. First, the direct correlation between the proportion of patients with severe-to-intolerable pain and opioid consumption could not be investigated in the same population, although the numbers of comprehensive support care centers in each prefecture to which the questionnaire was sent was determined according to the population. However, the number of responses from caregivers was smaller than required in several prefectures. Therefore, the imbalance of the data collection might influence the correlations with the health insurance claims data among the 47 prefectures. Second, the participants in the health insurance claims database used in this study included patients with cancer employed by companies or their relatives. In addition, people aged 65 years or older were not included in the database. Therefore, the possibility of bias in the social background attributes of patients with end-stage cancer cannot be excluded. Third, a medical fee for basic palliative care practices prescribing opioid analgesics has been claimed by physicians regardless of their training in basic palliative care before 2016. The differences in pain intensity and opioid prescription doses between trained and “untrained” physicians could not be clarified in this study. However, a recent study using another Japanese claim database revealed that the proportion of patients with end-stage cancer who received opioid prescriptions increased from 2016 to 2017, and this increase was especially notable among patients staying in palliative wards compared with general hospitals13. This suggests that opioid prescriptions provided by trained palliative physicians are important for opioid dose adjustment. Changes in medical claims and a mandate for palliative care claims training might be effective for treating cancer-related pain and improving the circumstances regarding opioid prescriptions.