Codeine

Codeine at a Glance

Codeine is the 3-methyl ether of morphine, the second morphinan alkaloid of opium, and one of the most widely used medicines in the world. It is a weak mu-opioid agonist in its own right; nearly all of its analgesic effect comes from the fraction that the liver enzyme CYP2D6 demethylates back into morphine ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}.

Its more instructive property is a negative one. For most of the twentieth century codeine was the reference antitussive — the comparator every new cough medicine was measured against. When it was finally put through modern placebo-controlled trials, it did not beat placebo for cough caused by upper-respiratory infection or by COPD ^{1Reference 1Bolser DC · 2007ReviewCodeine and cough: an ineffective gold standard — reviewView study →}. A Cochrane review looking for randomised evidence in children with chronic cough found no eligible studies at all ^{2Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →}. A drug can occupy the gold-standard slot for decades without ever having earned it.

The same CYP2D6 step that makes codeine work also makes it dangerous in a way morphine is not. Conversion rates vary from effectively zero to several times normal depending on genotype, so the same dose delivers wildly different morphine exposure to different people — and children with duplicated functional CYP2D6 genes have died of respiratory depression after ordinary post-tonsillectomy doses ^{8,9Reference 8Kelly LE et al. · 2012Case reportMore codeine fatalities after tonsillectomy in North American children — case reportView study →Reference 9Ciszkowski C et al. · 2009Case reportCodeine, ultrarapid-metabolism genotype, and postoperative death — case reportView study →}. Regulators in the USA, Europe, Canada, Australia and New Zealand now restrict codeine in children ^{2Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →}.

The Gold Standard That Fails Against Placebo

Codeine’s reputation as a cough suppressant is older than the trial methods that could test it, and it did not survive them.

In adults. Placebo-controlled studies published in the 2000s found codeine no more effective than placebo at suppressing cough in either upper-respiratory disorders or chronic obstructive pulmonary disease ^{1Reference 1Bolser DC · 2007ReviewCodeine and cough: an ineffective gold standard — reviewView study →}. This is not a clean reversal of an empty literature — several older placebo-controlled studies had found codeine effective, and the discrepancy between the old and new results is unresolved. The proposed explanation is mechanistic: cough is regulated by a layered control system, and codeine appears to act at a level of that hierarchy which is not the one driving cough in these particular conditions ^{1Reference 1Bolser DC · 2007ReviewCodeine and cough: an ineffective gold standard — reviewView study →}. Whatever the reason, the drug that every new antitussive was benchmarked against cannot reliably be shown to work.

In children. A Cochrane review searched for randomised, placebo-controlled trials of codeine or its derivatives in children with cough lasting four weeks or more. It screened 556 records, retrieved 70 in full — and included none. Not a weak evidence base: an empty one ^{2Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →}. The review notes that reviews of acute cough reach the same place, and that the lack of evidence has been repeatedly reaffirmed by chronic-cough guidelines and by medicines regulators in the USA, Europe, Canada, New Zealand and Australia ^{2Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →}. The broader Cochrane review of over-the-counter cough medicines finds the same for antitussives generally in children: no more effective than placebo ^{3Reference 3Smith SM et al. · 2014Meta-analysisOver-the-counter (OTC) medications for acute cough in children and adults in community settings — meta-analysisView study →}.

Why this matters more than a positive result would. Codeine was not a fringe remedy. It was the comparator — the thing a new drug had to beat, which meant that any new antitussive matching codeine looked successful. An unvalidated reference standard does not just fail its own patients; it quietly certifies everything tested against it.

And the risk side of the ledger never depended on the efficacy side. Children remain the group in whom variable CYP2D6 conversion produces the least predictable morphine exposure, which is why an absent benefit and a real hazard together produced the restrictions rather than either alone ^{2,8,9Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →Reference 8Kelly LE et al. · 2012Case reportMore codeine fatalities after tonsillectomy in North American children — case reportView study →Reference 9Ciszkowski C et al. · 2009Case reportCodeine, ultrarapid-metabolism genotype, and postoperative death — case reportView study →}.

Codeine Is a Prodrug for Morphine

Codeine binds the mu-opioid receptor only weakly. Most of what it does, it does as morphine.

The bulk of a codeine dose is glucuronidated to codeine-6-glucuronide and cleared. Two minor routes matter more: N-demethylation to norcodeine, and O-demethylation to morphine by CYP2D6 ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}. That last pathway carries the analgesia. The evidence is direct — people who are CYP2D6 poor metabolisers, and people whose CYP2D6 is blocked pharmacologically with quinidine, get no analgesic effect from codeine on experimental pain, because neither group can perform the conversion ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}.

CYP2D6 is one of the most variable enzymes in the human genome, and its variation is graded rather than binary. Around 7% of people of European ancestry are poor metabolisers with essentially no functional enzyme; at the other end, people carrying gene duplications convert faster and reach higher morphine exposure from the same dose. Frequencies of both differ substantially between ancestral populations ^{6,7Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →Reference 7Crews KR et al. · 2021Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid TherapyView study →}. The Clinical Pharmacogenetics Implementation Consortium publishes prescribing recommendations keyed to genotype for exactly this reason, and codeine is the drug that guideline was originally written for ^{7Reference 7Crews KR et al. · 2021Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid TherapyView study →}.

The consequences run in both directions and neither is benign:

• Poor metabolisers get little or no analgesia, and are liable to be treated as drug-seeking or non-compliant rather than as pharmacogenetically unable to respond ^{6,7Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →Reference 7Crews KR et al. · 2021Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid TherapyView study →}.
• Ultrarapid metabolisers produce more morphine, faster, than the prescriber intended. Functional gene duplications caused excess morphine production in two fatal paediatric cases after adenotonsillectomy, alongside a third life-threatening case of respiratory depression ^{8Reference 8Kelly LE et al. · 2012Case reportMore codeine fatalities after tonsillectomy in North American children — case reportView study →}; the index case was a toddler who died after a routine post-operative course ^{9Reference 9Ciszkowski C et al. · 2009Case reportCodeine, ultrarapid-metabolism genotype, and postoperative death — case reportView study →}. A case-control study of breastfed neonates with opioid toxicity after maternal codeine found the same pharmacogenetic pattern ^{10Reference 10Madadi P et al. · 2009ObservationalPharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control studyView study →}.

This is the structural difference between codeine and morphine as drugs. Morphine’s dose-response is variable but the molecule given is the molecule that acts. With codeine, an unknown fraction of the dose becomes a much stronger drug at a rate the prescriber cannot see.

What It's Used For

Codeine’s evidence divides sharply by indication: modest and real for pain, absent or negative for the indication it is most associated with.

Evidence by IndicationStrength of support · Beta

01Cancer PainShaky44%15 studies, 721 participants; better than placebo, but no poolable data and poor adverse-event reporting ^{5Reference 5Straube C et al. · 2014Systematic reviewCodeine, alone and with paracetamol (acetaminophen), for cancer pain — systematic reviewView study →}

02Acute Post-Operative PainShaky36%35 studies; NNT 12 for 60 mg, and worse than paracetamol/NSAID alternatives ^{4Reference 4Derry S et al. · 2010Meta-analysisSingle dose oral codeine, as a single agent, for acute postoperative pain in adults — meta-analysisView study →}

03Cough Suppression In AdultsShaky18%Modern placebo-controlled trials find no benefit in URI or COPD cough; older trials conflict ^{1,3Reference 1Bolser DC · 2007ReviewCodeine and cough: an ineffective gold standard — reviewView study →Reference 3Smith SM et al. · 2014Meta-analysisOver-the-counter (OTC) medications for acute cough in children and adults in community settings — meta-analysisView study →}

04Cough In ChildrenShaky0%Cochrane found no eligible randomised trials for chronic cough; antitussives no better than placebo for acute cough ^{2,3Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →Reference 3Smith SM et al. · 2014Meta-analysisOver-the-counter (OTC) medications for acute cough in children and adults in community settings — meta-analysisView study →}

Mechanisms

The first row governs all the others. Codeine’s pharmacology is mostly morphine’s pharmacology, arriving late and in an unpredictable amount.

Pharmacokinetics

Codeine is well absorbed orally and is mainly glucuronidated; the minor pathways are N-demethylation to norcodeine and O-demethylation to morphine via CYP2D6 ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}. Only a small fraction of the dose takes that last route, yet it carries the analgesia — the reason the analgesic effect is disproportionate to the low plasma morphine levels reached after standard doses may be local O-demethylation within the central nervous system, also CYP2D6-catalysed ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}. Because codeine has a low affinity for CYP2D6, even weak inhibitors of the enzyme can reduce its effect: quinidine, several SSRIs, some antipsychotics and probably the tricyclic antidepressants ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}. The onward pharmacokinetics of the morphine formed are morphine’s — glucuronidation to the active M6G and renal clearance — so renal impairment compounds the variability rather than offsetting it.

Clinical Trials

The interesting entry here is the one with nothing in it. Cochrane’s search for randomised evidence on codeine for chronic cough in children returned zero includable studies, and its acute-pain and cancer-pain reviews describe a literature that is old, small and poorly reported for a drug this widely used ^{2,4,5Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →Reference 4Derry S et al. · 2010Meta-analysisSingle dose oral codeine, as a single agent, for acute postoperative pain in adults — meta-analysisView study →Reference 5Straube C et al. · 2014Systematic reviewCodeine, alone and with paracetamol (acetaminophen), for cancer pain — systematic reviewView study →}.

Last checked: September 2026.

Isolate vs. Plant Studies

Every trial cited here used pharmaceutical codeine phosphate or sulfate at a stated dose. There is no clinical literature for poppy preparations as a source of codeine, and the measurement literature explains why there could not be a useful one: codeine recovered from commercially sold poppy seed by home-brewing methods ranged from under 1 to 247.6 mg/kg, alongside morphine at up to 2,788 mg/kg from the same material ^{12Reference 12Powers et al. · 2018Quantification of Morphine, Codeine, and Thebaine in Home-Brewed Poppy Seed Tea by LC-MS/MSView study →}.

There is a second reason the plant cannot substitute here, specific to this molecule. A poppy preparation never delivers codeine alone — it delivers codeine on top of a much larger and more variable quantity of morphine ^{12,14Reference 12Powers et al. · 2018Quantification of Morphine, Codeine, and Thebaine in Home-Brewed Poppy Seed Tea by LC-MS/MSView study →Reference 14Frick S et al. · 2005Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivarsView study →}. Any effect would be morphine’s, at an unknown dose, with codeine as a minor passenger. The isolate is not merely better studied; it is the only way the molecule exists as a distinct drug.

Prevalence in Nature

Codeine occurs with morphine in the latex of the opium poppy (Papaver somniferum) and is the second morphinan by quantity. In the Tasmanian pharmaceutical cultivar C048-6-14-64, morphine, codeine and thebaine together account for 91.2% of latex alkaloids; in the condiment cultivar “Marianne”, morphinans fall to 18.8% and the latex is dominated instead by narcotoline and noscapine ^{14Reference 14Frick S et al. · 2005Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivarsView study →}. The distribution within the plant is not uniform, and codeine’s gradient runs opposite to morphine’s: in the stems of the narcotic cultivar, morphine concentration decreases toward the roots while codeine increases toward the lower stem ^{14Reference 14Frick S et al. · 2005Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivarsView study →}.

Culinary poppy seed contains no latex but is contaminated with capsule alkaloid at harvest, which is why seed carries measurable codeine — under 1 to 247.6 mg/kg in the material tested for home-brewing studies — and why thermal processing changes the load ^{12,13Reference 12Powers et al. · 2018Quantification of Morphine, Codeine, and Thebaine in Home-Brewed Poppy Seed Tea by LC-MS/MSView study →Reference 13Carlin et al. · 2020Opium Alkaloids in Harvested and Thermally Processed Poppy SeedsView study →}.

In the plant, codeine sits near the end of the morphinan branch of benzylisoquinoline alkaloid metabolism: L-tyrosine to (S)-reticuline, then through salutaridine to thebaine, and on to codeine and morphine ^{15,16Reference 15Vadhel A et al. · 2023ReviewOpium alkaloids, biosynthesis, pharmacology and association with cancer occurrence — reviewView study →Reference 16Beaudoin GA · 2014ReviewBenzylisoquinoline alkaloid biosynthesis in opium poppy — reviewView study →}. Codeine is a biosynthetic precursor of morphine in the poppy, which is the reverse of its role in human pharmacology, where morphine is the product of codeine.

Discovery & Synthesis

Codeine was isolated from opium by the French chemist Pierre Jean Robiquet in 1832, a quarter-century after Sertürner’s morphine and from the same starting material. The discovery reached the medical press quickly: the Lancet was publishing experiments on the mode of action of “the new substance discovered in opium by M. Robiquet” the following year ^{17Reference 17[author not listed] · 1833Experiments on the mode of action of codeine, the new substance discovered in opium by MView study →}. The name comes from the Greek kodeia, poppy head.

Manufacture is chiefly semi-synthetic. Codeine is present in opium at only a few per cent, far too little to meet demand, so most pharmaceutical codeine is made by methylating morphine — running the last step of the plant’s own biosynthetic pathway backwards relative to the way the poppy built it. That leaves codeine’s supply tied to the same licensed poppy cultivation as morphine’s, since the morphine it is made from is still farmed rather than synthesised.

Patents: not yet researched.

Toxicity & Safety

Codeine’s risk profile is not a milder version of morphine’s. It is morphine’s risk profile, delivered through an unpredictable conversion step — which is why the group at greatest risk is the one that gets the smallest doses.

Safety at a Glance

☠️ PoisonousOverdose riskDependence riskControlled substanceSedative interactions

• Adult analgesic use at ordinary doses has a long safety record, with the usual opioid adverse effects: constipation, nausea, drowsiness.
• Not for children. Regulators in the USA, Europe, Canada, New Zealand and Australia advise against codeine for cough in children, and against its use after tonsillectomy or adenoidectomy, following fatal respiratory depression in ultrarapid metabolisers.
• CYP2D6 genotype changes the dose delivered. Poor metabolisers get no analgesia; ultrarapid metabolisers get far more morphine than intended from the same tablet.
• Breastfeeding. Maternal codeine has produced opioid toxicity in breastfed neonates, with the same pharmacogenetic pattern.
• CYP2D6 inhibitors blunt it. Quinidine, several SSRIs and some antipsychotics reduce or abolish codeine’s analgesic effect.
• Dependence is real at over-the-counter strengths, and codeine-containing pharmacy medicines are among the most commonly misused.

Full Safety & Interactions Detail

Paediatric respiratory depression. The defining safety signal. Following the 2009 report of a toddler who died after codeine given for post-adenotonsillectomy analgesia, three further North American cases were reported: two fatalities in children carrying functional CYP2D6 gene duplications, which produced significantly greater conversion of codeine to morphine, plus one severe respiratory depression in an ordinary extensive metaboliser ^{8,9Reference 8Kelly LE et al. · 2012Case reportMore codeine fatalities after tonsillectomy in North American children — case reportView study →Reference 9Ciszkowski C et al. · 2009Case reportCodeine, ultrarapid-metabolism genotype, and postoperative death — case reportView study →}. The authors’ conclusion was that codeine, and other opioids using the CYP2D6 pathway, may not be safe after adenotonsillectomy in young children with obstructive sleep apnoea — the population in which the operation is most often performed ^{8Reference 8Kelly LE et al. · 2012Case reportMore codeine fatalities after tonsillectomy in North American children — case reportView study →}. Combined with the complete absence of randomised efficacy evidence for cough in children, this drove regulatory restriction across the USA, Europe, Canada, New Zealand and Australia ^{2Reference 2Gardiner SJ et al. · 2016Systematic reviewCodeine versus placebo for chronic cough in children — systematic reviewView study →}.

Neonatal exposure through breast milk. A case-control study of neonates with opioid toxicity following maternal codeine use during breastfeeding identified the same pharmacogenetic mechanism, with maternal and infant genotype contributing to the morphine exposure reaching the infant ^{10Reference 10Madadi P et al. · 2009ObservationalPharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control studyView study →}.

Pharmacogenetic variability in both directions. Poor metabolisers — around 7% of people of European ancestry, with frequencies differing markedly between populations — obtain no analgesic effect from codeine, a finding demonstrated experimentally both in genotypic poor metabolisers and in extensive metabolisers given the CYP2D6 blocker quinidine ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}. CPIC’s opioid guideline provides genotype-keyed prescribing recommendations for codeine on this basis ^{7Reference 7Crews KR et al. · 2021Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid TherapyView study →}.

Drug interactions. Because codeine has low affinity for CYP2D6, inhibition of the enzyme is clinically consequential at modest potency. Strong inhibitors include quinidine; several SSRIs and antipsychotics are potent enough to matter, and tricyclic antidepressants probably reduce the effect as well ^{6Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →}. In the opposite direction, additive central nervous system depression with alcohol, benzodiazepines, gabapentinoids and other opioids is a pharmacodynamic interaction that applies to codeine exactly as to morphine ^{11Reference 11Paul AK et al. · 2021ReviewOpioid Analgesia and Opioid-Induced Adverse Effects: A Review — reviewView study →}.

Common effects, tolerance and dependence. Constipation, nausea, vomiting and drowsiness are frequent, and were common in the multiple-dose cancer-pain studies ^{5Reference 5Straube C et al. · 2014Systematic reviewCodeine, alone and with paracetamol (acetaminophen), for cancer pain — systematic reviewView study →}. All clinically used opioids are mu-agonists, and analgesic tolerance, dependence and behavioural adverse effects follow from that receptor action rather than from anything peculiar to codeine ^{11Reference 11Paul AK et al. · 2021ReviewOpioid Analgesia and Opioid-Induced Adverse Effects: A Review — reviewView study →}. Codeine’s over-the-counter and pharmacy availability in many countries makes it one of the medicines most frequently identified in reviews of non-prescription medicine misuse and dependence ^{18Reference 18Algarni M et al. · 2021Systematic reviewA mixed-methods systematic review of the prevalence, reasons, associated harms and risk-reduction interventions of over-the-counter (OTC) medicines misuse, abuse and dependence in adults — reviewView study →}.

Poppy material. Codeine content of poppy seed spans more than two orders of magnitude, and any preparation delivering codeine delivers considerably more morphine alongside it ^{12,13,14Reference 12Powers et al. · 2018Quantification of Morphine, Codeine, and Thebaine in Home-Brewed Poppy Seed Tea by LC-MS/MSView study →Reference 13Carlin et al. · 2020Opium Alkaloids in Harvested and Thermally Processed Poppy SeedsView study →Reference 14Frick S et al. · 2005Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivarsView study →}. There is no preparation, dose or method that makes this a usable route.

Reproductive note. Opioid alkaloids cross the placenta and enter breast milk, and neonatal toxicity from maternal codeine is documented ^{10Reference 10Madadi P et al. · 2009ObservationalPharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control studyView study →}. Decisions about use in pregnancy and lactation belong to the prescribing context, where the preparation and dose are known.

Dosage

Codeine is a prescription or pharmacy medicine, and the figures below are the doses used in the randomised trials rather than a recommendation.

Two qualifications change how those numbers should be read. First, the acute-pain figure is for codeine alone, and the review’s own conclusion is that it compares poorly with paracetamol, NSAIDs and their combinations with codeine — the combination products are where the analgesia is ^{4Reference 4Derry S et al. · 2010Meta-analysisSingle dose oral codeine, as a single agent, for acute postoperative pain in adults — meta-analysisView study →}. Second, none of these doses means the same thing in two different people: what reaches the mu receptor is morphine, in an amount set by CYP2D6 genotype rather than by the tablet ^{6,7Reference 6Sindrup SH · 1995ReviewThe pharmacogenetics of codeine hypoalgesia — reviewView study →Reference 7Crews KR et al. · 2021Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid TherapyView study →}.

Poppy preparations have no dose. Codeine recovered from commercially sold poppy seed by home-brewing methods ranged from under 1 to 247.6 mg/kg, always alongside a much larger quantity of morphine ^{12Reference 12Powers et al. · 2018Quantification of Morphine, Codeine, and Thebaine in Home-Brewed Poppy Seed Tea by LC-MS/MSView study →}.

These are doses recorded in research, not a personal recommendation.

References

1. Bolser DC, Davenport PW (2007). Codeine and cough: an ineffective gold standard — review. Curr Opin Allergy Clin Immunol. https://pubmed.ncbi.nlm.nih.gov/17218808/
2. Gardiner SJ, Chang AB, Marchant JM, et al. (2016). Codeine versus placebo for chronic cough in children — systematic review. Cochrane Database Syst Rev. https://pubmed.ncbi.nlm.nih.gov/27405706/
3. Smith SM, Schroeder K, Fahey T (2014). Over-the-counter (OTC) medications for acute cough in children and adults in community settings — meta-analysis. Cochrane Database Syst Rev. https://pubmed.ncbi.nlm.nih.gov/25420096/
4. Derry S, Moore RA, McQuay HJ (2010). Single dose oral codeine, as a single agent, for acute postoperative pain in adults — meta-analysis. Cochrane Database Syst Rev. https://pubmed.ncbi.nlm.nih.gov/20393966/
5. Straube C, Derry S, Jackson KC, et al. (2014). Codeine, alone and with paracetamol (acetaminophen), for cancer pain — systematic review. Cochrane Database Syst Rev. https://pubmed.ncbi.nlm.nih.gov/25234029/
6. Sindrup SH, Brøsen K (1995). The pharmacogenetics of codeine hypoalgesia — review. Pharmacogenetics. https://pubmed.ncbi.nlm.nih.gov/8845855/
7. Crews KR, Monte AA, Huddart R, et al. (2021). Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther. https://pubmed.ncbi.nlm.nih.gov/33387367/
8. Kelly LE, Rieder M, van den Anker J, et al. (2012). More codeine fatalities after tonsillectomy in North American children — case report. Pediatrics. https://pubmed.ncbi.nlm.nih.gov/22492761/
9. Ciszkowski C, Madadi P, Phillips MS, et al. (2009). Codeine, ultrarapid-metabolism genotype, and postoperative death — case report. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/19692698/
10. Madadi P, Ross CJ, Hayden MR, et al. (2009). Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther. https://pubmed.ncbi.nlm.nih.gov/18719619/
11. Paul AK, Smith CM, Rahmatullah M, et al. (2021). Opioid Analgesia and Opioid-Induced Adverse Effects: A Review — review. Pharmaceuticals (Basel). https://pubmed.ncbi.nlm.nih.gov/34832873/
12. Powers, Erickson, Swortwood (2018). Quantification of Morphine, Codeine, and Thebaine in Home-Brewed Poppy Seed Tea by LC-MS/MS. Journal of Forensic Sciences. https://doi.org/10.1111/1556-4029.13664
13. Carlin, Dean, Ames (2020). Opium Alkaloids in Harvested and Thermally Processed Poppy Seeds. Frontiers in Chemistry. https://doi.org/10.3389/fchem.2020.00737
14. Frick S, Kramell R, Schmidt J, et al. (2005). Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivars. J Nat Prod. https://pubmed.ncbi.nlm.nih.gov/15921406/
15. Vadhel A, Bashir S, Mir AH, et al. (2023). Opium alkaloids, biosynthesis, pharmacology and association with cancer occurrence — review. Open Biol. https://pubmed.ncbi.nlm.nih.gov/37132222/
16. Beaudoin GA, Facchini PJ (2014). Benzylisoquinoline alkaloid biosynthesis in opium poppy — review. Planta. https://pubmed.ncbi.nlm.nih.gov/24671624/
17. [author not listed] (1833). Experiments on the mode of action of codeine, the new substance discovered in opium by M. Robiquet. The Lancet. https://doi.org/10.1016/s0140-6736(02)94149-8
18. Algarni M, Hadi MA, Yahyouche A, et al. (2021). A mixed-methods systematic review of the prevalence, reasons, associated harms and risk-reduction interventions of over-the-counter (OTC) medicines misuse, abuse and dependence in adults — review. J Pharm Policy Pract. https://pubmed.ncbi.nlm.nih.gov/34517925/

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