The International Association for the Study of Pain defines pain as an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage [1]. Pain, also known as the fifth vital sign, has a significant impact on patients’ prognoses and quality of life [2]. According to a systematic review in 2016 [3], approximately 30-50% of cancer patients experienced moderate to severe pain, and the proportion of patients with pain increased in those with more advanced disease. Another study found that the prevalence of moderate to severe pain among all cancer patients was more than 80%, and approximately 60% of patients felt that their pain was adequately managed [4]. The prevalence of chronic non-cancer pain varies by country, with the United States reporting 30% and European countries 19% [5,6].

According to the 3-step analgesic ladder to relieve cancer pain proposed by the World Health Organization (WHO), opioids are very important drugs for the treatment of moderate to severe pain [7]. Recent pain management guidelines recommend that doctors prescribe analgesics such as opioids depending on patients’ symptom severity [8]. The utilization of opioids has markedly increased in many Asian countries, including Taiwan, Malaysia, and Singapore, in addition to Western countries such as the United States, Canada, and European countries [9-12]. However, there is a lack of studies demonstrating trends in prescriptions of strong opioids in Korea.

Therefore, the purpose of this descriptive study was to provide data on recent trends in opioid prescriptions in terms of cases (prescription numbers) and amounts (morphine milligram equivalent; MME) in Korea over 14 years (from 2002 to 2015) using data from the Korean National Health Insurance Service (NHIS)-National Sample Cohort (NSC).

The number and amount of annual opioid prescriptions in Korea increased over the 14-year study period. The highest AAPCs were observed in the elderly population, patients in general hospitals, and patients receiving potent opioids such as fentanyl and hydromorphone.

The use of morphine is indicated for cancer pain treatment according to the WHO [16,17]. Morphine consumption has not increased in several countries since 2000, while increased use of other opioids, such as fentanyl and oxycodone, has been reported in many countries [18-22]. Although the quantity of morphine prescriptions has not increased greatly, the number of morphine prescriptions gradually increased in this study. Another Korean study also reported that chronic opioid use had increased since 2002 [23]. That study demonstrated that chronic use of strong opioids was positively associated with 5-year mortality, while weak opioid use was inversely related to mortality in Korea [23]. Although opioids are appropriately indicated for pain control for cancer patients, they should be used with caution.

Several factors appear to contribute to the increasing trends in overall prescriptions of opioids. First, the number of elderly patients increased. Age is closely associated with increased opioid use [24]. Studies from European countries between 2000 and 2010 reported that the utilization of strong opioids was highest among patients aged 66-80 years [21,25]. A study from Malaysia showed that opioid prescriptions increased with patient age (11% in the 40s, 19% in the 50s, and 47.28% in the 60-80s) [25]. Elderly people consume more opioids due to pain from multiple comorbidities. Second, the prevalence of diseases that cause pain, such as cancer and musculoskeletal diseases, increased [26]. Opioids are the most frequently used drugs to control cancer pain [2,27]. In 2017, there was a total of 232,255 new cancer cases in Korea [28]. Furthermore, the number of cancer survivors has been increasing due to the high incidence rate of cancers and the improved survival rates [28]. In addition, the Korean Ministry of Health and Welfare has supported more hospice and palliative care services since 2009 [29]. Because cancer is recorded with a special code, patients with cancer pay 5% of their total hospital costs, and the remaining hospital costs are paid by the NHIS. Thus, low out-ofpocket payments of cancer patients might result in more active pain management and increased prescriptions of pain medications such as opioids. In addition to the increased number of cancer patients as a factor influencing the upward trend in opioid prescriptions in Korea, opioid prescriptions have been gradually rising in patients with non-cancer diseases, including diseases that cause musculoskeletal pain [27]. Third, some new opioids were launched after 2000. Oxycodone was launched in the Korean market in 2001 and has taken, together with fentanyl, part of the market share of morphine. Hydromorphone was introduced to Korea in 2006, and since 2009, Korean national insurance has covered its use in treatment for cancer pain, which might have contributed to the dramatically increased prescriptions of hydromorphone. A sharp increase in use of fentanyl, oxycodone, and hydromorphone was identified. Higher growth rates for fentanyl, oxycodone, and hydromorphone use have been observed in other countries [18,20,21]. Fourth, awareness of active pain management has improved. The Korean Ministry of Health and Welfare launched pilot research for hospice and palliative care in 2005 and piloted a new payment system in 2009 [29]. The introduction and stabilization of hospice and palliative care have improved awareness and policies (e.g., insurance coverage) supporting more active pain management.

This study has several limitations. First, the data contained no clinical information on compliance with opioid medication prescriptions. Second, only strong opioids (morphine, fentanyl, oxycodone, and hydromorphone) were included in the analyses. Weak opioids, such as codeine and tramadol, are more commonly used but are not closely controlled by the Korean health authorities. Thus, it is difficult to estimate how many prescriptions of weak opioids were issued. On the contrary, because the Korean health authorities tightly regulate prescriptions of strong opioids, we can estimate usage trends relatively accurately. Third, the cohort from the Korean NHIS-NSC database was operated as a partially closed system. Only newborn infants were newly enrolled during the study period after the baseline. Thus, the accumulation of double-counted people each year might have contributed to the increasing pattern of opioid prescriptions. To minimize these errors, we calculated the total MME per year per 10,000 registrants after age-standardization. In addition, the number of patients who were newly prescribed opioids increased from 3 individuals in 2002 to 941 individuals in 2015. Fourth, since the clinical outcomes were not evaluated (e.g., whether patient symptoms such as pain were improved after administration of opioids), it was not possible to determine whether prescriptions of opioids directly led to an improvement in pain control. Fifth, we could not compare the increasing trends of opioid prescriptions with other pain killers such as acetaminophen or non-steroidal anti-inflammatory drugs as a control. Because these drugs are available without prescriptions in Korea, the exact amount of usage is infeasible to assess. If a comparison between opioids and other painkillers was possible, it would have been possible to identify trends in opioid usage more accurately. As an alternative method, we investigated age-standardized trends in opioid use, since changes in the age structure of the study population have a major impact on epidemiological studies.

There are several strengths of the present study. First, trends in both the number and amount of prescribed opioids over a period of 14 years were investigated using a nationally representative cohort. Second, trends in both the number and amount of annual opioid prescriptions per 10,000 registrants were estimated. Few previous reports have used a national patient sample, although an earlier study analyzed patterns of opioid prescriptions in Health Insurance Review and Assessment Service claims data in Korea [30]. Third, both short-term and long-term trends were examined. After the AAPCs for the entire study period were estimated, we calculated segmental short-term trends. This approach allowed us to infer factors influencing the increasing trends.

Opioid use disorder and overdose deaths currently pose a great threat to public health in the United States [31], while Europe does not appear to be facing an opioid crisis [32]. On the contrary, underuse has been more of a problem in Korea, as Korean culture disfavors opioid use and the Korean government strictly regulates strong opioids. However, this study reported that opioid prescriptions, calculated as the total prescription cases (numbers) and amount (MME), markedly increased over 14 years from 2002 to 2015 in Korea. These increasing patterns were prominent in the elderly population, patients treated at general hospitals, and patients prescribed potent opioids (fentanyl and hydromorphone). The finding that the legal use of opioids has increased suggests improved awareness of the importance of pain control over time. These increasing trends in opioid prescriptions and use in Korea will be very helpful in relieving and managing pain for patients with severe pain. However, policy-making to prevent misuse, dependence, addiction, and death from overuse is required.