How is codeine metabolism primarily processed in the body?

Codeine Metabolism

Codeine is metabolized primarily by hepatic glucuronidation to inactive metabolites, with a critical minor pathway involving CYP2D6-mediated O-demethylation to morphine, which is responsible for its analgesic effect. 1

Primary Metabolic Pathways

Codeine undergoes three main metabolic routes:

• Glucuronidation (major pathway): Converts codeine to codeine-6-glucuronide, accounting for the majority of metabolism 1, 2
• O-demethylation via CYP2D6 (minor but critical): Converts codeine to morphine, the active analgesic metabolite—this pathway represents only a small fraction of total metabolism but is essential for pain relief 1
• N-demethylation: Produces norcodeine as a minor metabolite 1, 2

The CYP2D6 Genetic Polymorphism Problem

Codeine is a prodrug with minimal intrinsic analgesic activity—it depends entirely on conversion to morphine via CYP2D6 for pain relief. 1, 3 This creates three clinically significant metabolizer phenotypes:

Poor Metabolizers (PM)

• Prevalence: 5-10% of European Caucasians, lower in Asian populations 1
• Clinical consequence: Experience reduced or no analgesic effect from codeine because they cannot convert it to morphine 1, 3
• Critical pitfall: These patients still experience full adverse effects (nausea, constipation, sedation) despite receiving no pain relief 3

Extensive Metabolizers (EM)

• Standard metabolism: Achieve typical morphine plasma concentrations and expected analgesic response 4
• Morphine AUC after 30mg codeine: Median 11 μg·h/L 4

Ultrarapid Metabolizers (UM)

• Prevalence: Up to 28% in Middle Eastern/North African populations, up to 10% in Caucasians, up to 1% in Asians 1
• Clinical consequence: Produce approximately 50% higher morphine plasma concentrations (median AUC 16 μg·h/L vs 11 μg·h/L in EM) 4
• Toxicity risk: Experience excessive sedation (91% vs 50% in EM), and in extreme cases can develop severe opioid toxicity including respiratory depression and death 1, 4
• Breastfeeding danger: UM mothers produce dangerously high morphine concentrations in breast milk, which has caused neonatal deaths 1

Secondary Metabolism of Morphine

Once codeine is converted to morphine, the morphine undergoes further metabolism:

• Morphine-3-glucuronide: Inactive metabolite 1
• Morphine-6-glucuronide: Active metabolite that contributes to analgesia and accumulates in renal insufficiency, potentially causing neurotoxicity 1

Clinical Implications for Practice

Avoid codeine entirely in favor of alternatives that don't require CYP2D6 activation. 3 The unpredictability of genetic polymorphism makes codeine an unreliable analgesic:

• For mild pain: Use dihydrocodeine (analgesic effect from parent compound, not dependent on CYP2D6), NSAIDs, or acetaminophen 1, 3
• For moderate-to-severe pain: Skip directly to morphine, hydromorphone, oxycodone, or fentanyl—these provide predictable analgesia without CYP2D6 activation 3
• Absolute contraindication: Breastfeeding women should not receive codeine due to inability to predict UM status and risk of neonatal death 1

Drug Interactions Affecting Metabolism

CYP2D6 inhibitors will convert EM patients into functional PM, eliminating codeine's analgesic effect: 2

• Potent inhibitors: Quinidine, selective serotonin reuptake inhibitors (SSRIs), some neuroleptics 2
• Moderate inhibitors: Tricyclic antidepressants (will reduce but not eliminate morphine formation) 2

Special Populations

Hepatic impairment: Codeine metabolism to morphine may be compromised in chronic liver disease, reducing analgesic efficacy 5

Renal impairment: Morphine-6-glucuronide accumulates, increasing risk of neurotoxicity (myoclonus, seizures, respiratory depression)—avoid codeine in renal failure 1