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

BACKGROUND: Guidelines 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. METHODS: We 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. RESULTS: Of 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). CONCLUSION: Occurrence 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.