Codeine

Codeine is an opioid analgesic commonly marketed under brand names such as Tylenol 3. It is used to relieve mild to moderate pain and in some formulations for cough suppression.

As a prodrug, codeine requires metabolic activation in the liver to morphine, its primary active form. This conversion is catalyzed mainly by the cytochrome P450 enzyme CYP2D6.

Morphine exerts its effects by binding to mu-opioid receptors in the central nervous system, producing analgesia and sedation.

The primary gene influencing codeine response is CYP2D6, which encodes the cytochrome P450 2D6 enzyme responsible for converting codeine into morphine. Inherited variations in CYP2D6 activity define metabolizer status: ultrarapid, normal, intermediate, or poor.

Individuals with high-activity CYP2D6 variants convert codeine to morphine more quickly and may face higher drug levels and toxicity risk. Conversely, low-activity variants produce less morphine, reducing pain relief. These genetic differences arise from polymorphisms—natural DNA variations that affect how well the enzyme works.

Genetic differences in CYP2D6 metabolic capacity significantly affect circulating morphine levels and clinical response to codeine. Ultrarapid metabolizers can have excessive morphine exposure and toxicity risk, normal metabolizers experience expected effects, intermediate metabolizers may have reduced pain relief, and poor metabolizers often obtain minimal benefit. For individuals with indeterminate or unavailable genotypes, standard dosing with clinical monitoring is recommended.

Ultrarapid Metabolizer

• Effect on drug levels: Increased conversion to morphine leading to high active metabolite levels.
• Clinical consequence: Elevated risk of opioid toxicity, including respiratory depression.
• Side effects: Potentially severe and life-threatening respiratory depression; rare but serious.

Normal Metabolizer

• Effect on drug levels: Normal formation of morphine and expected drug levels.
• Clinical consequence: Standard analgesic effect as per usual dosing.
• Side effects: Typical opioid-related side effects (e.g., nausea, constipation); generally mild to moderate.

Intermediate Metabolizer

• Effect on drug levels: Reduced morphine formation resulting in lower active metabolite levels.
• Clinical consequence: May experience decreased pain relief.
• Side effects: Fewer opioid side effects; generally mild and less frequent.

Poor Metabolizer

• Effect on drug levels: Greatly reduced conversion to morphine leading to minimal active metabolite levels.
• Clinical consequence: Likely insufficient analgesia.
• Side effects: Minimal opioid-related side effects due to low morphine levels; rare.

Indeterminate/Not Available

• Effect on drug levels: Unknown impact.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Unknown.

CYP2D6 Dosing Guideline

Examples of alternative treatment options include non-tramadol opioids such as morphine, hydromorphone, or oxycodone. These examples are provided for illustrative purposes based on guideline recommendations and are not direct medical advice.

• CPIC – Guideline for Codeine and CYP2D6
• FDA – Table of Pharmacogenetic Associations