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Written by

Assistant Professor Wojciech Leppert

Assistant Professor Wojciech Leppert is professor at the department of palliative medicine, Poznań University of Medical Sciences, Poland.

CYP2D6 and the metabolism of codeine

Published 10 July 2016

Dr Wojciech Leppert describes how individual differences in codeine metabolism are related to the expression of CYP2D6 enzymes

Key learning points

  • Codeine is metabolised through CYP2D6, an important enzyme for approximately 25% of drugs administered in clinical practice.
  • CYP2D6 is subject to a high degree of genetic variation with more than 80 distinct variants known.
  • Codeine is partially metabolised to morphine and its metabolites, and to codeine metabolites, which also contribute to analgesia.

The cytochrome P450 (CYP) haem-containing monooxygenase isoenzymes are involved in endogenous metabolism of steroids, hormones, prostaglandins and lipids, and detoxification of exogenous compounds. CYP3A4 and CYP2D6 are the most important enzymes and although CYP2D6 accounts for only 2–5% of the total hepatic P450 isoenzymes, it accounts for 25% of drugs metabolised, including codeine.1

The enzyme is highly prone to variation; more than 80 distinct allelic variants of the CYP2D6 gene are known, leading to a wide spectrum of metabolic capacity and phenotype diversity within populations.2 Individuals carrying two wild-type alleles display normal enzyme activity and are known as extensive metabolisers (EM).2

Poor metabolisers

Poor metabolisers (PMs) display two inactive alleles and are characterised by deficient metabolism of several classes of drugs such as beta-blockers, antiarrhythmics, antidepressants, neuroleptics and some opioid analgesics.2 In approximately 8–10% of the Caucasian population, an autosomal recessive trait of non-functional alleles is present.2 In PM subjects, there is an increased risk of excessive pharmacodynamic and adverse effects due to relative drug overdose where the parent compound is responsible for the therapeutic effects of the drug. When therapeutic effects depend on a prodrug being metabolised to active metabolite(s), such as codeine, therapeutic failure may be observed.2

Ultrarapid metabolisers

The duplication or multiduplication of the CYP2D6 gene (mainly CYP2D6*1 and CYP2D6*2 alleles in Caucasians) is associated with ultrarapid metabolism of compounds.3 These ultrarapid metabolisers (UMs) may experience either a lack of efficacy in cases where the parent compound is responsible for the therapeutic effect of a given drug, or very intense therapeutic or adverse effects associated with the production of excessive amount of active metabolite(s).3 The incidence of UM is low in northern (1–2%), middle European (4%), North American (4–5%) and in Asian populations (0.5–2.5%), but significantly higher in Mediterranean (7–12%), Saudi Arabian (21%) and Ethiopian (29%) populations.4


Codeine is widely used for the treatment of pain of moderate intensity, often in combination with paracetamol.5 Codeine displays approximately 30–40% bioavailability after oral administration and is metabolised in the liver.3 Codeine is partially metabolised to morphine and its metabolites, and to codeine metabolites, norcodeine (NORC) and codeine-6-glucuronide (C-6-G) (Figure 1).6

Figure 1. Codeine metabolism

The main compounds responsible for codeine analgesia are shown in blue boxes

*The figures in percentages refer to the proportion of codeine dose converted to morphine and its metabolites found in the urine in EMs and PMs after administration of a single oral dose of codeine.9 EMs = extensive metabolisers, PM = poor metabolisers.

Overdose owing to codeine UM

One case report depicted a patient who was taking oral codeine at a daily dosage of 75mg (25mg three times a day) who, after four days of treatment, experienced symptoms of drug overdose (lack of consciousness and respiratory depression). The patient recovered after intravenous administration of naloxone (0.4mg). The cause of the symptoms was CYP2D6 UM phenotype.7

Pharmacokinetics and sedation

A trial investigating the effect of single dose 30mg oral codeine on 12 UMs, 11 EMs and three PMs showed that 10 of 11 UMs experienced sedation compared with six (50%) of 12 EMs (p=0.03). Plasma concentrations of morphine and its glucuronides were approximately 50% higher in UMs compared with EMs.8

Analgesic effects

Another randomised, placebo-controlled, double-blind study of the analgesic effect of single dose oral codeine 170mg compared with single dose oral morphine 20mg and placebo in nine EM and nine PM participants was conducted, using the cold pressor test. Compared with placebo, 20mg of morphine showed a significant increase in pain tolerance in both phenotypes, EMs and PMs. Following administration of codeine, analgesia was only observed in EMs but not in PMs.9 Morphine plasma concentrations were similar in PMs and EMs after morphine administration; however, following administration of codeine, the percentage of the codeine dose converted to morphine and its metabolites was 3.9% in EM and 0.17% in PM.9

Other metabolites

The polymorphism of CYP2D6, responsible for the metabolism of codeine and the formation of its metabolites, may affect codeine analgesia. However, other codeine metabolites, predominantly C-6-G, also display significant analgesic activity and contribute to codeine analgesia.10

A trial investigated the contribution of codeine and its metabolites to opioid central nervous effects in healthy volunteers (pupil size was used as a measure of CNS effects), independent of the CYP2D6-dependent metabolism of codeine to morphine. The formation of morphine did not explain exclusively the central nervous effects of codeine and C-6-G was suggested as the most likely additional active moiety with possible contribution of NORC and the parent compound.11 Therefore, codeine may to some extent have analgesic effects unrelated to CYP2D6-mediated metabolism.11


Codeine is still widely used for the treatment of pain of moderate intensity. Codeine analgesia is affected by CYP2D6 polymorphism, but it should be noted that as well as morphine and its metabolites, the parent compound and codeine metabolites such as C-6-G and NORC also contribute to codeine analgesia.

  • Dr Wojciech Leppert is chair, Department of Palliative Medicine, Poznań University of Medical Sciences, Poznań, Poland

Read more on genetics and pain

Date of preparation: June 2016; MINT/PAEU-16010