Which of the following opioids is a prodrug that requires hepatic metabolism to its active metabolite morphine?

Explanation

## Codeine as a Prodrug **Key Point:** Codeine is a naturally occurring opioid alkaloid that undergoes O-demethylation by hepatic cytochrome P450 enzyme CYP2D6 to form morphine, which is responsible for most of its analgesic effect. ### Metabolism Details - Codeine itself has weak μ-receptor affinity - Approximately 5–10% of codeine is converted to morphine in the liver - The remaining codeine is conjugated with glucuronic acid and excreted - Patients with CYP2D6 deficiency (poor metabolizers) show reduced analgesia from codeine - Patients with CYP2D6 gene duplication (ultra-rapid metabolizers) may experience toxicity ### Clinical Implications - Codeine efficacy varies significantly based on genetic polymorphisms of CYP2D6 - This explains the wide interindividual variability in analgesic response - Codeine is often combined with paracetamol or aspirin to enhance effect **High-Yield:** Codeine is the classic example of a prodrug in opioid pharmacology — its therapeutic action depends entirely on hepatic conversion to morphine. **Mnemonic:** **CODEINE = Converted by Oxidative Demethylation to morphinE** — remember the enzyme (CYP2D6) and the product (morphine).