Codeine
Checked
Opioid, Analgesic
Codeine
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Interactions
Pharmacogenomic + mechanism interactions
FDA Boxed WarningHighest-evidence regulatory action
Avoid codeine. Rapid morphine conversion risks severe toxicity (respiratory depression, death documented in nursing infants of UM mothers and UM children post-tonsillectomy). FDA Boxed Warning; CPIC Strong. Crews KR et al, Clin Pharmacol Ther 2021;110(4):888-96 (PMID 33387367). FDA labeling (boxed: Boxed Warning, Warnings and Precautions, Use in Specific Populations, Patient Co)
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Avoid codeine. Inadequate analgesia (cannot generate morphine). Do not default to tramadol (also CYP2D6-dependent). Crews KR et al, Clin Pharmacol Ther 2021;110(4):888-96 (PMID 33387367). CPIC pair-level A (CYP2D6, OPRM1, COMT, and Opioids) [PMID 22205192, 24458010, 33387367] FDA labeling (boxed: Boxed Warning, Warnings and Precautions, Use in Specific Populations, Patient Co)
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Pharmacogenomic guideline recommendationsCPIC and Dutch Pharmacogenetics Working Group clinical guidelines
CPIC rec 8093869 [Strong]: Use codeine label recommended age- or weight-specific dosing. CPIC pair-level A (CYP2D6, OPRM1, COMT, and Opioids) [PMID 22205192, 24458010, 33387367]
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CPIC rec 8093865 [Moderate]: Use codeine label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-tramadol opioid. CPIC pair-level A (CYP2D6, OPRM1, COMT, and Opioids) [PMID 22205192, 24458010, 33387367]
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Use label-recommended dosing. Crews KR et al, Clin Pharmacol Ther 2021;110(4):888-96 (PMID 33387367). CPIC pair-level A (CYP2D6, OPRM1, COMT, and Opioids) [PMID 22205192, 24458010, 33387367]
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Pharmacokinetic mechanismSubstrate / metabolism relationships from primary literature
O-demethylation to morphine, the active analgesic (5-15% of an oral codeine dose). Defines analgesic response.
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Glucuronidation to codeine-6-glucuronide; small analgesic contribution.
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N-demethylation to norcodeine; inactive pathway.
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Inferred from pharmacokinetic dataMaterialised by the inference engine; provenance shown per row
Quinidine inhibits CYP2D6 (inhibitor_strong, intensity 95); Codeine is a prodrug_activated_by of CYP2D6 (intensity 100). Derived: Codeine exposure lowered.
⏱ reversible competitive, effect resolves over ~5 inhibitor half-livesInferred via Enzyme:CYP2D6 (exposure lowered)
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Confidence in this inference: is the inferred magnitude sound?overstatedsound
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Fluoxetine inhibits CYP2D6 (inhibitor_strong, intensity 90); Codeine is a prodrug_activated_by of CYP2D6 (intensity 100). Derived: Codeine exposure lowered.
⏱ mechanism-based, interaction persists ~4-6 weeks after stopping the inhibitorInferred via Enzyme:CYP2D6 (exposure lowered)
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Paroxetine inhibits CYP2D6 (inhibitor_strong, intensity 90); Codeine is a prodrug_activated_by of CYP2D6 (intensity 100). Derived: Codeine exposure lowered.
⏱ mechanism-based, interaction persists ~4-6 weeks after stopping the inhibitorInferred via Enzyme:CYP2D6 (exposure lowered)
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Bupropion inhibits CYP2D6 (inhibitor_strong, intensity 85); Codeine is a prodrug_activated_by of CYP2D6 (intensity 100). Derived: Codeine exposure lowered.
⏱ reversible competitive, effect resolves over ~5 inhibitor half-livesInferred via Enzyme:CYP2D6 (exposure lowered)
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Mirabegron inhibits CYP2D6 (inhibitor_moderate, intensity 55); Codeine is a prodrug_activated_by of CYP2D6 (intensity 100). Derived: Codeine exposure lowered.
Inferred via Enzyme:CYP2D6 (exposure lowered)
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Summary
Classes
Opioid, Analgesic
Common uses
Pharmacy
Pharmacology
Purported mechanism
Mu-opioid receptor agonist; prodrug (metabolized to morphine)