A 4-year-old child given routine post-tonsillectomy codeine dies suddenly at home. Genotyping reveals duplication of the CYP2D6 gene. What is the mechanism of death?

• A Failure to metabolize codeine, causing accumulation of unmetabolized codeine in the brainstem
• B Ultra-rapid conversion of codeine to morphine producing high systemic morphine levels and respiratory depression ✓
• C Codeine-induced serotonin syndrome in combination with residual anaesthetic agents
• D Formation of a toxic quinone metabolite causing fulminant hepatic failure

Explanation

Codeine is a prodrug converted by CYP2D6 O-demethylation to morphine, which accounts for all of its analgesia. Ultra-rapid metabolizers generate supratherapeutic morphine concentrations, and in children after tonsillectomy for obstructive sleep apnoea this has caused fatal respiratory depression. Regulatory authorities now contraindicate codeine in children under 12 years and in breastfeeding mothers who are ultra-rapid metabolizers.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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