CYP2D6 interaction with codeine — MRCPsych Paper A MCQ
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Correct answer: E — Inhibition of CYP2D6 reduces conversion of codeine to morphine
The correct answer is E. Codeine has relatively low affinity for mu-opioid receptors, and much of its analgesic effect depends on CYP2D6-mediated conversion to morphine. Paroxetine is a potent CYP2D6 inhibitor, so concurrent treatment can cause functional reduction of CYP2D6 activity and diminished morphine formation, producing inadequate analgesia. Paroxetine does not antagonise mu-opioid receptors. CYP1A2 induction is relevant to medicines such as clozapine and olanzapine but does not explain failure of codeine activation. Renal alkalinisation is not produced by paroxetine and is not the relevant determinant of codeine efficacy. Plasma-protein displacement would also not account for reduced formation of the active metabolite.
Reference: Electronic Medicines Compendium, Codeine phosphate 15 mg Tablets BP SmPC, sections 4.4 and 5.1, revised 2026, https://www.medicines.org.uk/emc/product/11268/smpc; and Paroxetine 20 mg film-coated tablets SmPC, section 4.5, revised 2026, https://www.medicines.org.uk/emc/product/537/smpc