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Codeine is an established, familiar and widely used analgesic. It is considered a weak opioid, with a potency around one tenth that of morphine (i.e. 60mg of codeine is equivalent to around 6mg of morphine)​[1]​. Codeine is administered in doses of 15–60mg up to four times per day (maximum of 240mg in 24 hours) and confers beneficial analgesic, antitussive and antidiarrhoeal effects​[2,3]​.

Despite its utility and ubiquity, codeine actually has little or no analgesic activity until it is metabolised into morphine​[4,5]​. Consequently, codeine can be regarded as a prodrug (a compound that is pharmacologically inactive until it is metabolised into an active form by the human body)​[6]​.

The extent of this metabolism varies however: individuals with differing CYP2D6 enzyme activity may derive differing effects (and associated adverse effects) from the same dose of codeine. Additional limitations include the potential for drug–drug interactions, and a so-called ‘ceiling effect’ that adversely tips the risk–benefit scale at supratherapeutic doses​[2,3,6]​. To appreciate the wide-ranging clinical significance of these factors fully, the metabolism of codeine must first be understood.


Codeine is primarily metabolised by two different pathways (see Figure)​[2]​. In most people, around 80% of codeine is conjugated to form codeine-6-glucuronide, which may have weak analgesic activity​[2,7]​. However, typically less than 10% of codeine undergoes CYP2D6-mediated O-demethylation to the potent analgesic, morphine

The CYP2D6 enzyme belongs to the CYP450 super-family of enzymes, which are responsible for the metabolism of many drugs and endogenous compounds​[9]​.

These enzymes exist throughout the body, but are most prevalent in the liver. The expression and function of these enzymes can be altered by genetic variation, with large inter-ethnic differences being observed​[10]​. For example, clinically significant alterations in CYP2D6 functionality are known to affect Caucasians (5–10%) and Africans (0–34%) more than Asians (≤1%)​[10–12]​.

Such variations can significantly affect how an individual responds to a drug​[11]​. This can be said to be true of codeine​[9,10]​. The extent of that conversion can vary from none to potentially too much, meaning that, for some people, codeine may not be the right choice of analgesic​[8,13–15]​.

Although pharmacogenetic testing can determine a patient’s genotype and CYP2D6 functionality, in practice, such testing has not been shown to be cost effective and is therefore not routinely employed prior to initiating drugs such as codeine​[10–12]​. Nevertheless, as differing CYP2D6 metaboliser statuses can have clinically observable consequences for patients, it remains important to understand how the metabolism of codeine can be affected by these genetic differences. CYP2D6 statuses are classified as poor, intermediate, extensive or ultra-rapid 

Box: CYP2D6 statuses and the associated analgesic benefit versus potential adverse effects

  • Poor metabolisers (5–10% of individuals) lack functional enzymes and will thus derive little to no analgesic benefit from codeine, owing to an inability to convert it into its active form, morphine​[10,13]​. Poor metabolisers still experience similar rates of adverse effects (such as sedation, dizziness, euphoria, blurred vision and dry mouth) from codeine when compared with the general population​[14,15]​. This subset of individuals may experience undesirable effects, without any clinical analgesic benefit.
  • Intermediate metabolisers (2–11% of individuals) may express enzymes with decreased function or have a combination of functioning and non-functioning enzymes​[10,13]​. Consequently, drug metabolism may be reduced, and such individuals may also derive little benefit from codeine​[10,13]​.
  • Most individuals (77–92%) are extensive metabolisers. They have normal enzyme activity, and will metabolise around 10% of codeine to morphine, deriving analgesic benefit​[13]​.
  • A rarer, but not-to-be-overlooked subset (1–2% of individuals) are considered ultra-rapid metabolisers. Ultra-rapid metabolisers have increased enzymatic activity, which leads to them metabolising a greater proportion of codeine into morphine than the general population​[10,13]​. This is potentially very hazardous: Gasche et al. described a case of life-threatening opioid toxicity in a man aged 62 years who had received a low dose of codeine (75mg per day) for management of cough[8]. The patient was later identified as being a CYP2D6 ultra-rapid metaboliser. Unfortunately, similar cases have been reported in children, some of which have resulted in fatalities​[16]​. Consequently, codeine for management of pain, cough and diarrhoea is contraindicated in patients aged under 12 years​[17,18]​.

Hence, up to nearly a quarter of individuals may show a response to codeine that ranges from inefficacy — but still with adverse effects — to potentially life-threatening toxicity​[11]​.

In practice, the CYP2D6 metabolism status of patients can be determined through clinical observation. Poor metabolisers may experience limited to no therapeutic response to codeine (also see drug–drug interactions below), while those displaying signs of opioid toxicity — such as respiratory depression, myoclonic twitches, confusion and hallucinations — may be ultra-rapid metabolisers​[8,13,17]​. In both cases, the most appropriate course of action may be to discontinue codeine and decide, along with the patient and prescriber, on an alternative analgesic. For example, pharmacists can liaise with prescribers and suggest starting low-dose morphine (10mg modified-release morphine sulphate twice daily) in place of codeine, if appropriate. If the patient is thought to be a poor metaboliser, a ‘wash out’ period does not need to be observed, but if toxicity to codeine is suspected, prescribers should wait for signs of toxicity to abate as the drug washes out before prescribing an alternative. In the latter scenario, specialist input is advised​[1,13,19]​.

Metabolism status aside, the co-administration of drugs that alter the function of CYP2D6 must also be considered as an important determinant of the variable efficacy of codeine.

Drug–drug interactions

Medications that inhibit CYP2D6 are predicted to diminish, or abolish, the effect of codeine by preventing its metabolism into morphine. These are outlined in the Table​[15,20]​. Therefore, regardless of CYP2D6 status, inefficacy of codeine may occur as a result of a drug–drug interaction. Patients reporting limited to no therapeutic reponse from codeine should also have their medications reviewed for the presence of CYP2D6 inhibitors (see Table). For people taking CYP2D6 inhibitors, conversion to an alternate opioid which does not rely on CYP2D6 metabolism (e.g. morphine) should be considered

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