A woman takes codeine for dental pain and reports complete lack of relief, while her sister gets good analgesia from the same dose. Genotyping reveals she carries two nonfunctional CYP2D6 alleles. What explains her poor response?

• A Codeine is a prodrug requiring CYP2D6-mediated conversion to morphine for analgesia ✓
• B Codeine acts mainly through kappa receptors, which are downregulated in poor metabolizers
• C Nonfunctional CYP2D6 alleles accelerate renal excretion of unchanged codeine
• D Codeine analgesia depends entirely on its 6-glucuronide metabolite formed by UGT2B7

Explanation

Codeine itself has very low affinity for the mu receptor; approximately 10 percent of an administered dose undergoes CYP2D6 O-demethylation to morphine, and this metabolite accounts for essentially all of the analgesia. Poor metabolizers therefore derive little benefit, while ultra-rapid metabolizers are at risk of morphine toxicity. The glucuronide pathway handles morphine elimination, not codeine activation, which removes option D.

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

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