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Pediatric Codeine Prescriptions in Outpatient and Inpatient Settings in Korea

Dajeong Kim, MS; Inmyung Song, PhD; Dongwon Yoon, PharmD; and Ju-Young Shin, PhD
Codeine was frequently prescribed for children in Korea despite the actions taken to restrict its use in that age group in Korea and other countries.
ABSTRACT

Objectives: To examine the extent of codeine prescriptions for children younger than 12 years in Korea and to investigate characteristics associated with pediatric codeine use.

Study Design: A retrospective observational study was conducted to examine codeine prescriptions and patients’ characteristics.

Methods: We used the Korea Health Insurance Review and Assessment Service National Patient Sample database. The study participants were patients younger than 12 years who were prescribed codeine as inpatients or outpatients between 2011 and 2016. Pediatric codeine use was defined as codeine prescribed at least once for a child younger than 12 years. The frequency and proportion of pediatric codeine users were analyzed by age group (0-2, 3-6, or 7-11 years), sex, year, region, diagnosis, type of medical institution, and coprescribed medication. Logistic regression analyses were performed to identify characteristics associated with pediatric codeine use.

Results: Of all patients younger than 12 years, 518,895 (55.8%) and 16,337 (1.7%) were treated with codeine in outpatient and inpatient settings, respectively. Odds of pediatric codeine prescriptions were highest for outpatients at clinics (adjusted odds ratio [OR], 1.19; 95% CI, 1.16-1.21) and public hospitals (adjusted OR, 1.56; 95% CI, 1.28-1.91) and for inpatients at public hospitals (adjusted OR, 8.38; 95% CI, 6.64-10.58).

Conclusions: Codeine was frequently prescribed for pediatric outpatients in Korea, especially in primary care clinics. Efforts to limit codeine use in children are required to prevent the occurrence of codeine-related adverse events.

Am J Manag Care. 2019;25(8):e224-e229
Takeaway Points
  • Of patients younger than 12 years in Korea, 55.8% and 1.7% were treated with codeine in outpatient and inpatient settings, respectively.
  • Children were more likely to be treated with codeine in the outpatient setting at clinics and public hospitals.
  • Efforts to limit codeine use in children are needed to prevent the occurrence of codeine toxicity events.
Codeine, an opioid alkaloid derived from opium, was first identified in 1833.1 Codeine is a prodrug that is converted into morphine by cytochrome P-450 2D6 (CYP2D6) in the liver and binds to the μ-opioid receptor in the central nervous system, thereby producing its analgesic effect.2,3 Codeine has long been used in children as an analgesic and antitussive agent, and it was the most frequently used opioid medication among European children and adolescents in the early 2000s.4 However, codeine toxicity has been linked to pediatric deaths.5 Life-threatening or fatal toxicity of codeine was attributed to ultrarapid CYP2D6 metabolizers.6,7

Owing to safety concerns, in 2012 the World Health Organization deleted codeine from its list of recommended analgesics based on the risk associated with metabolic rate differences and the insufficient pharmacological effect due to its lower metabolism in children younger than 12 years.8 Subsequently, the European Medicines Agency, the Medicines and Healthcare Products Regulatory Agency of the United Kingdom, and Health Canada also issued safety letters and guidelines recommending against the use of codeine in children younger than 12 years based on its opioid toxicity risk and suggesting a change in the drug labeling.9-11 In 2013, the FDA added a black box warning to the label of codeine-containing products to restrict the postoperative use of codeine for children, which was elevated to a contraindication in 2017 alerting that codeine should not be used to treat pain or cough in children younger than 12 years.12 Following the initiatives of other countries, the regulatory authority in Korea also issued a safety letter to warn about the risk of codeine use in children and, in November 2014, changed the drug label so that codeine is contraindicated in children younger than 12 years.13,14

Despite repeated warnings regarding weak opioids such as codeine, the off-label use of codeine in young patients appears to persist, emphasizing the urgency of the need to address the issue of its contraindicated use.15,16 Characteristics of patients (eg, age) and healthcare providers (eg, specialty) were shown to influence opioid analgesic use and off-label prescribing to children in the United States.17,18 In the United States, codeine prescriptions in the emergency department (ED) were associated with age of the patient and geographic region of the prescriber.19 Odds of pediatric codeine use were higher in children outside of the Northeast United States, with poor physical health status, and with health insurance.20 In Australia, codeine use was higher in areas that were more remote and those with higher percentages of males.21 We reasoned that the characteristics of pediatric codeine use differ by patient setting, because inpatient use of codeine is mostly for management of postoperative pain but it is usually used as an antitussive agent in the outpatient setting.5 Therefore, this study aims to examine the patterns of prescribing codeine for children younger than 12 years and to identify characteristics associated with pediatric codeine prescriptions in outpatient and inpatient settings in Korea using population-based health insurance claims data. In addition, we sought to understand if a change in prescribing practice occurred after the label change for codeine in Korea.

METHODS

Data

The patterns of prescribing codeine were analyzed using Health Insurance Review and Assessment Service National Patient Sample (HIRA-NPS) data. The primary aim of the HIRA-NPS database is to construct sample data representative of the Korean population for researchers to access by compiling patient visit and prescription data from National Health Insurance claims data. The data are anonymized by replacing personal information with random unique identifiers. The database includes information on general characteristics of the patient (age and sex), medical services (inpatient and outpatient procedures and inpatient prescriptions), diagnoses (specialty codes, diagnosis codes, and names), outpatient prescriptions (generic code, dose, and prescribed days), and medical institution (type, number of beds, and region).

The HIRA-NPS database contains claims data on a stratified random sample of 3% of all patients covered by the National Health Insurance system; the mandatory health insurance system covers approximately 98% of all inhabitants of Korea.22 Stratified by sex and age, the patient sample was divided into a total of 32 strata (2 for sex and 16 for age) before random extraction. Different patients are selected for the sample data each year, and the patient samples are updated annually because they are developed through the accumulation of claims data over a yearlong cycle. HIRA, a government agency, has constructed and maintained the database annually since 2009. The database is publicly available to qualified researchers through HIRA’s website.

Study Participants

The study participants were patients younger than 12 years of age who received care as inpatients or outpatients in Korea between January 1, 2011, and December 31, 2016. The study drugs were drugs that contain codeine phosphate as the only analgesic and antitussive agent or codeine combination products that contain acetaminophen or ibuprofen as an active ingredient and are approved and listed as reimbursable drugs. Unlike in the United States and some European countries where low-strength codeine products are sold as over-the-counter medications, all codeine-containing products are sold as prescription-only medications in Korea. Inpatient prescriptions of codeine were analyzed separately from outpatient prescriptions owing to differences in dosage and the use of codeine for the management of postoperative pain.


 
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