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Opiates: Codeine

Codeine is a prodrug. This means that it doesn’t exert its analgesic effect until after it is metabolized to morphine.
  • Codeine has four primary metabolites.
  • Morphine is the most important. Codeine is converted to morphine by CYP2D6 by conversion of a methyl group (-CH3) to a hydroxyl group (-OH). It is an active metabolite and accounts for 5-13% of the total dose. The remaining metabolic pathway for morphine will be discussed separately.
  • Norcodeine is an inactive metabolite and accounts for 10-20% of the dose. It undergoes phase II metabolism to norcodeine glucuronide.
  • Codeine itself also undergoes phase II metabolism. It is conjugated to codeine glucuronide which accounts for 32-46% of the dose.
  • Hydrocodone is a minor metabolite. Hydrocodone is metabolized from codeine by dehydrogenation (R-C-OH → R-C=O) catalyzed by CYP2D6. Hydrocodone undergoes further metabolism which will be discussed separately.
Codeine has a half-life of 1 to 4 hours and can be detected in urine for 2 to 3 days after ingestion.
  • Both codeine and morphine will be detected in the urine of patients prescribed codeine.
  • The ratio of codeine to morphine is generally around 6:1.
  • If the ratio is below 2:1, the source of morphine could be due to ingestion of morphine or heroin in addition to codeine.
  • If it has been more than thirty hours after a single dose of codeine, morphine alone may be detected at low concentrations.
  • If codeine is present at very low levels compared to a much higher concentration of morphine, the presence of codeine could be due to an impurity produced in the manufacturing process of pharmaceutical morphine. Some opiate tablets can have codeine impurities present at low concentrations (0.04% has been reported). Clinicians and laboratory staff should be made aware of this possibility.
  • In patients taking codeine, hydrocodone can be expected at about 10% of the codeine concentration.
  • If hydrocodone is detected at a concentration greater than 40% of codeine, its presence is probably due to separate use of hydrocodone.
  • If a very high dose of codeine is consumed, it is also possible to see hydromorphone present at a low concentration as a minor metabolite of morphine.
Of course, in drug tests of patients who are poor or rapid metabolizers or are taking medications that interact with codeine by inhibiting or inducing CYP2D6, these ratios can be significantly affected making interpretation extremely challenging.