MDElliottMD: Pharmacogenomics prototype: codeine sandbox. Demonstrates the full schema, custom-namespace entity links (Enzyme:CYP2D6, Phenotype:CYP2D6 poor metabolizer, Phenotype:CYP2D6 ultrarapid metabolizer), CPIC 2021 phenotype-by-phenotype recommendations, interactionsummary MedTemplate field, 14 cited refs across 6 named refs (Crews 2021 CPIC, Caraco 1996/1997/1999 PK trilogy, Koren 2006 Lancet, Zipursky 2020 CPT critique). Live Codeine page untouched. Sandbox for design review before Phase 2 schema...

2026-05-19T04:39:25Z

Pharmacogenomics prototype: codeine sandbox. Demonstrates the full schema, custom-namespace entity links (Enzyme:CYP2D6, Phenotype:CYP2D6 poor metabolizer, Phenotype:CYP2D6 ultrarapid metabolizer), CPIC 2021 phenotype-by-phenotype recommendations, interactionsummary MedTemplate field, 14 cited refs across 6 named refs (Crews 2021 CPIC, Caraco 1996/1997/1999 PK trilogy, Koren 2006 Lancet, Zipursky 2020 CPT critique). Live Codeine page untouched. Sandbox for design review before Phase 2 schema...

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{{MedTemplate
| generic = Codeine
| brand = (multiple, generic dominant)
| structure = Codeine.svg
| classes = Opioid, Analgesic, Prodrug
| mechanism = Prodrug; converted to [[Morphine|morphine]] by [[Enzyme:CYP2D6|CYP2D6]] for analgesic action.
| uses = Mild to moderate pain; cough suppression (low-dose).
| starting_dose = Adult: 15–60 mg every 4 hours as needed.
| preparations = Tablet (15, 30, 60 mg); oral solution; combination products (with [[Acetaminophen|acetaminophen]] or ibuprofen).
| fda_max = 360 mg/day
| routes = PO (only formulation marketed in the US).
| onset = 30–60 min (PO)
| duration = 4–6 hours
| halflife = 2.5–3 hours
| bioavailability = ~50% (variable, CYP2D6-dependent for analgesic effect).
| pregnancy = Avoid; risk of neonatal opioid withdrawal with chronic use; UM-mother breastfeeding contraindicated.
| legal = US Schedule II (single-entity); Schedule III–V (combination products by content).
| interactionsummary = Major [[Enzyme:CYP2D6|CYP2D6]] substrate; analgesia requires CYP2D6 activation to [[Morphine|morphine]]. '''Avoid in [[Phenotype:CYP2D6 poor metabolizer|poor metabolizers]]''' (no analgesia) and in '''[[Phenotype:CYP2D6 ultrarapid metabolizer|ultrarapid metabolizers]]''' (risk of fatal morphine toxicity, including in nursing infants). Strong CYP2D6 inhibitors (e.g. [[Fluoxetine|fluoxetine]], [[Paroxetine|paroxetine]], [[Bupropion|bupropion]]) phenocopy poor metabolism and reduce efficacy.<ref name="cpic-opioid-2021">Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. ''Clin Pharmacol Ther''. 2021 Oct;110(4):888-896. PMID: 33387367.</ref>
| intro = Codeine (3-methylmorphine) is a naturally occurring opioid alkaloid of the opium poppy (''Papaver somniferum''), and historically the first opioid to be isolated in pure form, by Pierre Robiquet in 1832. It is a '''prodrug''': its analgesic effect depends on conversion to [[Morphine|morphine]] in the liver, principally by the [[Enzyme:CYP2D6|cytochrome P450 2D6]] enzyme. The proportion of any given dose converted varies markedly between individuals because of genetic polymorphism in CYP2D6, which is the most clinically consequential pharmacogenomic relationship in routine analgesic practice.<ref name="cpic-opioid-2021" />
| pharmacokinetics = Codeine is well absorbed after oral administration with a mean bioavailability around 50%, peak plasma concentrations at 30 to 60 minutes, and a terminal half-life of approximately 2.5 to 3 hours. The pharmacologically important transformation is hepatic '''O-demethylation by [[Enzyme:CYP2D6|CYP2D6]] to morphine''', which accounts for the analgesia: native codeine binds the μ-opioid receptor about 200-fold less avidly than morphine.<ref name="caraco1996">Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. ''J Pharmacol Exp Ther''. 1996 Sep;278(3):1165-74. PMID: 8819499.</ref> The fraction converted to morphine varies from essentially zero (in [[Phenotype:CYP2D6 poor metabolizer|CYP2D6 poor metabolizers]]) to greatly enhanced (in [[Phenotype:CYP2D6 ultrarapid metabolizer|ultrarapid metabolizers]] who carry functional gene duplications); in normal metabolizers the figure is typically 5–15% of the administered dose.<ref name="cpic-opioid-2021" /><ref name="caraco1999">Caraco Y, Sheller J, Wood AJ. Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects. ''J Pharmacol Exp Ther''. 1999 Jul;290(1):413-22. PMID: 10381807.</ref>

Minor metabolic routes contribute little to analgesic effect. Codeine is N-demethylated to norcodeine by [[Enzyme:CYP3A4|CYP3A4]] (no relevant μ-opioid activity), and glucuronidated to codeine-6-glucuronide by UGT2B7 (some authors argue for a contribution to analgesia from this metabolite, but quantitatively small in most patients). Renal excretion accounts for most of the eliminated dose, principally as codeine and its glucuronide.

Inducers of [[Enzyme:CYP3A4|CYP3A4]] (notably rifampin) accelerate codeine N-demethylation and reduce both codeine and morphine plasma exposures, but the dominant clinical determinant of effect remains CYP2D6 activity.<ref name="caraco1997">Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine's respiratory, psychomotor and miotic effects. ''J Pharmacol Exp Ther''. 1997 Apr;281(1):330-6. PMID: 9103514.</ref>

=== Pharmacogenomic phenotype guidance (CPIC 2021) ===

The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides the following recommendations for codeine by CYP2D6 phenotype:<ref name="cpic-opioid-2021" />

* '''Ultrarapid metabolizer''' (UM, activity score >2.25): '''avoid codeine.''' Rapid and extensive conversion to morphine produces supratherapeutic morphine concentrations with risk of severe respiratory depression and death. Documented in infants breastfed by UM mothers prescribed codeine, and in children given codeine after tonsillectomy. Use a non-codeine analgesic (e.g. [[Morphine|morphine]] or a non-opioid). CPIC strength: '''Strong'''.<ref name="koren2006">Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. ''Lancet''. 2006 Aug 19;368(9536):704. PMID: 16920476.</ref>
* '''Normal metabolizer''' (NM, activity score >1.25 to ≤2.25): use label-recommended dosing. CPIC strength: '''Strong'''.
* '''Intermediate metabolizer''' (IM, activity score >0 to ≤1.25): use label-recommended dosing; if analgesia is inadequate and tramadol is also unsuitable, consider a non-CYP2D6-dependent opioid such as [[Morphine|morphine]], oxymorphone, or hydromorphone. CPIC strength: '''Moderate'''. (The 2021 guideline relaxed the prior IM recommendation, which had steered IMs more firmly toward alternatives.)
* '''Poor metabolizer''' (PM, activity score 0): '''avoid codeine.''' Inadequate analgesia owing to absent CYP2D6 activity. Use a non-codeine analgesic. Do not substitute [[Tramadol|tramadol]], which depends on CYP2D6 for the same activation step. CPIC strength: '''Strong'''.<ref name="cpic-opioid-2021" />

The clinical impact of OPRM1 (μ-opioid receptor) and COMT (catechol-O-methyltransferase) variants on codeine response has been studied but the data are inconsistent; CPIC does not currently make codeine-dosing recommendations for either gene.<ref name="cpic-opioid-2021" />

| pharmacodynamics = The analgesic effect of codeine is mediated almost entirely by its [[Enzyme:CYP2D6|CYP2D6]]-derived morphine, acting as a full agonist at the μ-opioid receptor. The intrinsic μ-receptor affinity of codeine itself is approximately 200-fold lower than morphine's, which is why CYP2D6 activity dominates the dose-response relationship. Minor activity at δ- and κ-opioid receptors contributes little to clinical effect. Codeine also has a centrally mediated antitussive action that is preserved across CYP2D6 phenotypes (i.e. cough suppression does not require activation to morphine), which is why CYP2D6 poor metabolizers still derive antitussive benefit even when they derive no analgesia.<ref name="caraco1996" />

| indications = * Mild to moderate acute pain (adults)
* Cough suppression (low-dose, generally over-the-counter where available)
* '''Contraindicated''' in children <12 years for any indication (FDA boxed warning since 2017)
* '''Contraindicated''' in adolescents 12 to 18 after tonsillectomy or adenoidectomy
* '''Contraindicated''' in breastfeeding, owing to risk of morphine toxicity in nursing infants of CYP2D6 ultrarapid-metabolizer mothers

| dosing = '''Adult acute pain:''' 15 to 60 mg PO every 4 hours as needed; maximum 360 mg per 24 hours. Begin at the lower end for opioid-naive patients.

'''Renal impairment:''' Reduce dose and extend interval; active morphine metabolites accumulate.

'''Hepatic impairment:''' Use with caution; reduced first-pass metabolism may increase parent codeine exposure but may also reduce conversion to active morphine.

'''Pharmacogenomic guidance:''' See the pharmacokinetics section above. Pre-prescription CYP2D6 genotyping is not routine, but a known CYP2D6 PM or UM phenotype should prompt avoidance of codeine and selection of an alternative opioid or non-opioid analgesic.<ref name="cpic-opioid-2021" />

| effects = Common: nausea, vomiting, constipation, somnolence, dizziness, pruritus. Less common: confusion, urinary retention, miosis, sweating. Serious (especially in UMs or with strong CYP2D6 inhibitor co-prescription producing phenotype reversal): respiratory depression, sedation, hypotension; in opioid-tolerant or opioid-naive overdose, fatal respiratory depression. Tolerance develops to most effects on chronic use; physical dependence develops in days to weeks.

| interactions = <pharmaInteractions/>

| pregnancy_details = Crosses placenta. Chronic maternal use late in pregnancy is associated with neonatal opioid withdrawal syndrome. Codeine is contraindicated in breastfeeding because of the risk of morphine toxicity in nursing infants when the mother is a CYP2D6 ultrarapid metabolizer; the magnitude of this risk has been debated in the literature.<ref name="koren2006" /><ref name="zipursky2020">Zipursky J, Juurlink DN. The Implausibility of Neonatal Opioid Toxicity from Breastfeeding Codeine-Treated Mothers. ''Clin Pharmacol Ther''. 2020 Nov;108(5):964-970. PMID: 32378749.</ref>

| monitoring = Pain relief, sedation level, respiratory rate. With chronic dosing: bowel function, signs of physical dependence. Genotype-testing is not routine but is reasonable in pre-emptive pharmacogenomic programs or when atypical response prompts the question.

| counseling = This medicine relies on a liver enzyme (CYP2D6) to produce its painkilling effect, and people vary widely in how active that enzyme is for genetic reasons. A small percentage of people get no pain relief from codeine at all, while a different small percentage convert it too rapidly and are at risk of serious side effects. Tell your prescriber if codeine has not worked for you in the past, or has produced unusually strong or alarming effects. Avoid combining with alcohol or other sedating medicines. Constipation is the most common bothersome effect; preventive measures (fluids, fibre, sometimes a stool softener) help.

| anecdotes =

| seealso = [[Morphine]], [[Tramadol]], [[Oxycodone]], [[Hydrocodone]], [[Enzyme:CYP2D6|CYP2D6]], [[Phenotype:CYP2D6 poor metabolizer|CYP2D6 PM]], [[Phenotype:CYP2D6 ultrarapid metabolizer|CYP2D6 UM]], [[:Category:Opioids|opioids]]

| references = <references/>
}}

[[Category:Opioids]]
[[Category:Natural opioids]]
[[Category:Analgesics]]
[[Category:Mu-Opioid Receptor Agonists]]

Pharmacopedia:Pharmacogenomics sandbox/Codeine - Revision history