A patient is a CYP2D6 ultrarapid metabolizer (URM) prescribed codeine for pain. What pharmacogenomic risk does this create?

• A Codeine is metabolized to morphine by CYP2D6; URM patients convert excessive codeine to morphine causing life-threatening opioid toxicity including respiratory depression ✓
• B URM patients rapidly metabolize codeine to inactive norcodeine, providing inadequate analgesia
• C URM patients develop rapid tolerance due to excessive morphine receptor downregulation
• D CYP2D6 URM patients are at risk for codeine-induced serotonin syndrome

Explanation

Codeine is a prodrug requiring O-demethylation by CYP2D6 to its active metabolite morphine. In CYP2D6 ultrarapid metabolizers (gene duplication, more common in North African and Middle Eastern populations: up to 28%), conversion to morphine is 2-6 fold higher than extensive metabolizers. Fatal cases of neonatal opioid toxicity (mothers who were URM nursing codeine-treated infants) and pediatric respiratory depression after tonsillectomy led to FDA black box warnings and restriction of codeine in children. Poor metabolizers (CYP2D6*4, *5) have inadequate analgesia because morphine is not produced. This is a landmark pharmacogenomics example prompting CPIC guidelines recommending codeine avoidance in URM patients.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.