What Did My Patient Actually Take? Codeine Results Interpretation
Codeine is an all-natural opioid that is found in opium and is used pharmaceutically to treat mild to moderately severe pain. The interpretation of codeine and other drugs in drug testing can be complicated due to the many variables that can affect the presence of metabolites. Codeine can be metabolized to norcodeine, morphine, hydrocodone, norhydrocodone, hydromorphone, and dihydrocodeine. Furthermore, the metabolites morphine, hydrocodone, and hydromorphone are also drugs that can be prescribed (Figure 1).1 Please note that the interpretation of results differs when using presumptive vs. definitive testing methods and may also differ among laboratories. The information provided here is intended to assist providers with deciphering positive codeine results reported by Aegis, which have undergone definitive testing by liquid chromatography/tandem mass spectrometry.
Norcodeine, the normetabolite of codeine, is a unique biomarker that results from the CYP 3A4 metabolism of codeine after ingestion.2 Although norcodeine possesses weak opioid activity, it is not likely to contribute to the overall analgesic effect.3-5 CYP3A4 metabolism is subject to induction and inhibition by many drug-drug and drug-food interactions, potentially altering opioid normetabolite concentrations.6-10 Drugs that inhibit or induce the CYP3A4 route of metabolism can modify the effect of opioids by increasing or decreasing analgesic effects or causing adverse drug effects such as sedation, respiratory depression, and/or death.
Morphine, hydrocodone, and hydromorphone are pharmacologically active metabolites of codeine and are products of CYP2D6 metabolism.8-11 Although CYP2D6 cannot be induced, it is subject to inhibition by a host of medications and may also become saturated. CYP2D6 also exhibits a tremendous amount of genetic variability.8,12 The clinical significance of CYP2D6 inhibition is variable and can bring about either an increase in active parent drug causing adverse drug effects such as sedation, respiratory depression, and/or death or it can lead to a decrease in active metabolite, resulting in decreased analgesic effects.
Figure 1. Opioid Metabolism
The period of detection for codeine is based on pharmacokinetic data and drug concentrations found in controlled administration studies, when available. Codeine, and most opioids, typically have a period of detection up to about 5 days in urine and up to about 48 hours in oral fluid. Typically, in oral fluid, parent drug concentrations exceed metabolite concentrations (Figure 2), whereas the reverse is true for urine. However, this is not always the case (Figure 3). Therefore, metabolite ratios should not be used to establish codeine compliance. Concentrations yielded in urine are typically ten times higher than in oral fluid.13
There is no validated algorithm that substantiates a correlation between the amount of drug ingested and the amount found in a urine drug screen. Due to the number of factors that can influence the amount of drug eliminated, there can be significant fluctuations in concentrations from test to test in the same patient, and from patient to patient on similar dosages of the same drug. This includes, but is not limited to, concentration of the urine specimen, timing of last dose in relation to collection, frequency of dosing, amount ingested, chronicity of ingestion, extent of drug absorption, liver/kidney function, drug-drug interactions, genetic differences, etc.14,15
Codeine Minor Metabolism
Metabolites may be present in the absence of parent drug. For example, a patient who ingests codeine could have only detectable morphine in the urine.2 Though it would be helpful for interpretation, parent to metabolite ratios do not allow for the identification of the initial opioid ingested. There is, however, one notable exception for codeine: the metabolism of codeine to hydrocodone, which will typically have a concentration of less than 5% of the codeine concentration16 and should not exceed parent drug concentrations.2 The enzymes responsible for these metabolic pathways have not been identified, and metabolism may not occur in all patients. The laboratory report example in Figure 4 demonstrates a hydrocodone metabolite concentration of 1.5% of the total codeine concentration in urine.
Codeine No Metabolites Detected
It is possible to observe parent codeine in urine in the absence of metabolites. The likelihood of such a finding may be increased in patients with impaired metabolism due to genetics or drug-drug/drug-food interactions. Finding parent-only codeine may suggest recent oral drug ingestion, though concentrations in these cases should typically be low (Figure 5). Additionally, when concentrations are very low, it is difficult to assess if the metabolites may have fallen just below the threshold and, as a result, are reported as negative. On the other hand, when parent-only results are significantly higher (Figure 6), further patient assessment to rule out bingeing or abuse is warranted. Addition of a drug to the sample post-collection, in an effort to appear adherent with prescribed therapy or after sample substitution, may often result in high parent drug urine concentrations with no metabolites present. The clinician should take the laboratory report into consideration with a patient’s medication use history and clinical presentation.17
Patient under-reporting and denial of nonprescribed or illicit drug use are common. However, there are instances when an unexpected positive result has a rational explanation that does not involve extracurricular drug use. It is important to explore all potential sources before enforcing disciplinary action (Table 1). Codeine is present in pharmaceutical products including Tylenol #3; Tylenol #4; Fioricet with Codeine; Pergoric; Tincture of Opium; and Belladona & Opium and will subsequently be present on prescription drug monitoring programs since codeine is a controlled substance. In some states, over-the-counter medications can contain codeine mixed with cough suppressants like dextromethorphan and/or promethazine.18
Both codeine and morphine may be present in poppy seeds which can be found in many food products such as breads, muffins, cakes, bagels, salad dressings, and poppy seed enriched curry, as well as commercial or homemade teas.19,20 Historically, we assume to expect only morphine in urine following poppy seed ingestion as it has been the subject of numerous small studies. Codeine, however, may also be detected, though it tends to appear at significantly lower levels and typically would not be present in the absence of morphine. Small amounts of morphine and/or codeine may be present in oral fluid for two to four hours21-23 and in urine for up to 48 hours13 following poppy seed consumption. One notable exception exists in the literature with the case of a subject who consumed bread containing a poppy seed variety with an unusually high codeine-content. The resultant urine specimens contained several times more codeine than morphine, suggesting ingestion of codeine alone.24 The best advice for patients undergoing drug testing is to completely avoid poppy seed-containing products. Lastly, although the most prevalent metabolite for heroin is morphine, codeine can also result in concentrations above the threshold after heroin use.25
Table 1. Possible Sources of Drugs (After Definitive Testing)
NOTICE: The information above is intended as a resource for health care providers. Providers should use their independent medical judgment based on the clinical needs of the patient when making determinations of who to test, what medications to test, testing frequency, and the type of testing to conduct.
1. Smith HS. The metabolism of opioid agents and the clinical impact of their active metabolites. Clin J Pain. 2011;27(9):824-38.
2. Cone EJ, Caplan YH. Urine toxicology testing in chronic pain management. Postgrad Med. 2009;121(4):91-102.
3. Hutchinson MR, Menelaou A, Foster DJ, et al. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol. 2004;57:287-97.
4. Lalovic B, Phillips B, Risler LL, et al. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004;32:447-54.
5. Weinstein SH, Gaylord JC. Determination of oxycodone in plasma and identification of a major metabolite. J Pharm Sci. 1979;68:527–8.
6. Leow KP, Smith MT. The antinociceptive potencies of oxycodone, noroxycodone, and morphine after intracerebroventricular administration to rats. Life Sci. 1994;54:1229-36.
7. Thompson CM, Wojno H, Greiner E, et al. Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther. 2004;308:547-54.
8. Coller JK, Christrup LL, Somogyi AA. Role of active metabolites in the use of opioids. Eur J Clin Pharmacol. 2009;65:121-39.
9. Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part II. Psychosomatics. 2003;44:515-20.
10. 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;281:330-6.
11. Zhou SF, Xue CC, Yu XQ, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007;29:687-710.
12. Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613-24.
13. Heltsley R, Zichterman A, Black DL, et al. Urine drug testing of chronic pain patients II. Prevalence patterns of prescription opiates and metabolites. J Anal Toxicol. 2010;34:32-8.
14. Nafziger AN, Bertino JS. Utility and application of urine drug testing in chronic pain management with opioids. Clin J Pain. 2009;29(1):73-9.
15. Frederick D. Toxicology testing in alternative specimen matrices. Clin Lab Med. 2012;32(3):467-92.
16. Totah RA, Sheffels P, Roberts T, et al. Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology. 2008;108:363-74.
17. Galloway JH, Marsh ID. Detection of drug misuse – an addictive challenge. J Clin Pathol. 1999;52(10):713-8.
18. Drugs@FDA: FDA-Approved Drugs
19. Lachenmeier DW, Sproll C, Musshoff F. Poppy seed foods and opiate drug testing--where are we today? Ther Drug Monit. 2010;32(1):11-18.
20. Sproll C, Perz RC, Lachenmeier DW. Optimized LC/MS/MS analysis of morphine and codeine in poppy seed and evaluation of their fate during food processing as a basis for risk analysis. J Agric Food Chem. 2006;54(15):5292-5298.
21. Samano KL, Clouette RE, Rowland BJ, Sample RH. Concentrations of morphine and codeine in paired oral fluid and urine specimens following ingestion of a poppy seed roll and raw poppy seeds. J Anal Toxicol. 2015;39(8):655-661.
22. Rohrig TP, Moore C. The determination of morphine in urine and oral fluid following ingestion of poppy seeds. J Anal Toxicol. 2003;27(7):449-452.
23. Gan CY, Zainuddin Z, Muhamad Noh H, Rahmat R, Mohd Akir F, Mahad NH, Mohd Fazil NF, Nasir R, Isahak M, Samad HA. Profiling of morphine and codeine in urine after the ingestion of curry containing poppy seed as an evidence for opiates defence in Malaysia. Forensic Sci Int. 2019 Sep;302:109865. doi: 10.1016/j.forsciint.2019.06.023. Epub 2019 Jun 24. PMID: 31279278.
24. Chang J, Wang M, Appleton C. Headache bread--a case of high codeine containing variety of poppy seed. J Anal Toxicol. 2012;36(4):288
25. Konstantinova SV, Normann PT, Arnestad M, Karinen R, Christophersen AS, Mørland J. Morphine to codeine concentration ratio in blood and urine as a marker of illicit heroin use in forensic autopsy samples. Forensic Sci Int. 2012;217(1-3):216-221.