Relationship Between Severe Respiratory Depression and Codeine-Containing Antitussives in Children: A Nested Case-Control Study.

Sachiko Ono,Hideo Yasunaga,Yosuke Ono,Daisuke Koide

doi:10.2188/jea.je20180224

Abstract

BackgroundGuidelines recommend against all codeine use in children for its common indications of analgesia and cough suppression because of uncertain benefits and potential risk of death. However, because of its rarity, the occurrence of severe respiratory depression associated with codeine-containing antitussives has been poorly investigated. The objective of this study was to investigate the association between codeine-containing antitussives and severe respiratory depression in children.MethodsWe retrospectively identified Japanese children who were prescribed antitussives for respiratory diseases from a large Japanese administrative claims database (JMDC, Tokyo, Japan). We collected data on baseline characteristics including age, sex, and comorbidity. Each case was matched with four controls with the same sex and age in the same year from the same type of medical institution. We then examined the association between codeine-containing antitussives and subsequent severe respiratory depression using multivariable conditional logistic regression analysis.ResultsOf 164,047 children, 18,210 (11.1%) were prescribed codeine-containing antitussives. Of the children who took codeine-containing drugs, seven experienced severe respiratory depression. After adjusting for confounding factors, there was no significant difference in the proportion of severe respiratory depression between children with and without codeine-containing antitussives (odds ratio 1.15; 95% confidence interval, 0.48–2.78).ConclusionOccurrence of respiratory depression was very rare, and the association of codeine with respiratory depression was insignificant, even in a large sample of children in Japan.

Highlights

Codeine is an opioid drug that has been used as a pain reliever and an antitussive
There have been several reports of fatalities associated with standard doses of codeine among ultra-rapid metabolizers,[4,5,6] these fatal case reports have been limited to children who underwent tonsillectomy and=or adenoidectomy.[5]
National and international guidelines recommend against all use of codeine for the common indications of analgesia and cough suppression because of the uncertain benefits of codeine[7] and its potential risk of death.[8,9,10,11]

Summary

Introduction

Codeine is an opioid drug that has been used as a pain reliever and an antitussive. Children who are ultra-rapid metabolizers convert 5 to 30 times more codeine to morphine than do normal metabolizers,[1,2,3] which can lead to fatal toxicity.[4,5,6] There have been several reports of fatalities associated with standard doses of codeine among ultra-rapid metabolizers,[4,5,6] these fatal case reports have been limited to children who underwent tonsillectomy and=or adenoidectomy.[5]For children, national and international guidelines recommend against all use of codeine for the common indications of analgesia and cough suppression because of the uncertain benefits of codeine[7] and its potential risk of death.[8,9,10,11] people in both the United States and Japan can obtain over-the-counter drugs for children that contain codeine—mostly antitussive preparations—partly because the estimated population of ultrarapid metabolizers is quite small.[5]Epidemiological evidence of the risks associated with codeinecontaining antitussives is scarce. National and international guidelines recommend against all use of codeine for the common indications of analgesia and cough suppression because of the uncertain benefits of codeine[7] and its potential risk of death.[8,9,10,11] people in both the United States and Japan can obtain over-the-counter drugs for children that contain codeine—mostly antitussive preparations—partly because the estimated population of ultrarapid metabolizers is quite small.[5]. One case report of codeinecontaining antitussive intoxication in twins has been published.[12] In Japan, following an international movement of guideline changes, the Ministry of Health, Labour and Welfare investigated the risk of codeine use in children under 18 years of age and reported that the incidence of severe respiratory depression was less than 1%.13. The objective of this study was to investigate the association between codeine-containing antitussives and severe respiratory depression in children

Objectives

Methods

Results

Conclusion