Codeine is an opioid analgesic indicated for the relief of mild to moderately severe pain. The analgesic properties of codeine stem from its conversion to morphine and morphine-6-glucuronide because codeine’s affinity for μ-opioid receptors is 200-fold weaker than that of morphine.9
Both codeine and morphine also have antitussive effects.
-Demethylation of codeine into morphine by CYP2D6 represents a minor pathway in extensive metabolizers, accounting for only 5–10% of codeine clearance in such individuals; however, this pathway is essential for its opioid activity (). The percentage of codeine converted into morphine can be affected by drug interactions and can be much higher in ultrarapid metabolizers.11
Morphine is further glucuronidated to morphine-3-glucuronide and morphine-6-glucuronide. Morphine-6-glucuronide is known to have analgesic activity in humans, whereas morphine-3-glucuronide is generally not considered to possess analgesic properties. Approximately 80% of an administered dose of codeine is converted to inactive metabolites by glucuronidation to codeine-6-glucuronide via UDPglucuronosyltransferase (UGT) 2B7, and by N
-demethylation to norcodeine via CYP3A4. The analgesic activity of codeine-6-glucuronide in humans is unknown, whereas norcodeine is thought to have no analgesic properties.
Codeine analgesia is closely related to CYP2D6
pharmacogenetics. The association between CYP2D6 metabolizer phenotype and the formation of morphine from codeine is well defined. Pharmacokinetic and pharmacodynamic studies show a decrease in morphine levels and a decrease in analgesia in poor metabolizers receiving codeine as compared with extensive metabolizers.12
Mikus et al
. reported a decreased incidence of gastrointestinal side effects (i.e., constipation) in poor metabolizers as compared with extensive metabolizers;14
a later study by the same group of investigators found that central side effects (e.g., sedation, nausea, and dry mouth) did not differ between poor metabolizers and extensive metabolizers.12
Further studies are needed to fully investigate the impact of the CYP2D6 poor metabolizer phenotype on the adverse-effect profile of codeine.
On the other hand, increased conversion to morphine in CYP2D6 ultrarapid metabolizers can result in toxic systemic concentrations of morphine11
even at low codeine doses. The most common adverse reactions to codeine include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. Serious adverse reactions include respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. Pharmacokinetic studies show increased conversion of codeine to morphine in ultrarapid metabolizers as compared with extensive metabolizers. 15
Case reports detail the occurrence of severe or lifethreatening side effects following standard doses of codeine in ultrarapid metabolizers.11
Despite these data, codeine continues to be widely used, and most patients receive codeine without prior CYP2D6 genotyping. This guideline recommends using alternative analgesics in patients who are CYP2D6 poor metabolizers or ultrarapid metabolizers. It is important to recognize that, in addition to codeine, several other opioids are metabolized, at least in part, by CYP2D6. The opioids tramadol, hydrocodone, and oxycodone are O-demethylated by CYP2D6 to O-desmethyltramadol, hydromorphone, and oxymorphone, respectively.
Tramadol in its available racemic form is extensively metabolized via several pathways, including CYP2D6-mediated oxidation to O
-desmethyltramadol, which has a 200-fold greater affinity for μ-opioid receptors than the parent drug does.10
-desmethyltramadol is principally responsible for opioid receptor-mediated analgesia, whereas (+)- and (−)-tramadol contribute to analgesia by inhibiting reuptake of the neurotransmitters serotonin and noradrenaline. As compared with CYP2D6 extensive metabolizers, poor metabolizers have been shown to have much lower median values of area under the concentration–time curves for the active metabolite after a dose of tramadol.19
In addition, several prospective clinical trials have shown that, as compared with CYP2D6 extensive metabolizers, poor metabolizers more often fail to exhibit analgesia in response to tramadol.18
Judging from this evidence, it is likely that tramadol has reduced clinical efficacy in CYP2D6 poor metabolizers.
Pharmacokinetic studies showed higher peak plasma concentrations of (+)-O
-desmethyltramadol after a dose of tramadol, and also greater analgesia, stronger miosis, and higher incidence of nausea in ultrarapid metabolizers as compared with extensive metabolizers.22
There is one case report of respiratory depression in a CYP2D6 ultrarapid metabolizer with renal impairment after postsurgical tramadol treatment.23
On the basis of these data, the use of analgesics other than tramadol may be preferable in CYP2D6 poor metabolizers and also in ultrarapid metabolizers.
Hydrocodone is biotransformed by CYP2D6 into hydromorphone, which has a 10- to 33-fold greater affinity for μ-opioid receptors as compared with the parent drug. Relative to extensive metabolizers, poor metabolizers have been shown to have lower peak concentrations of hydromorphone after a dose of hydrocodone24
; however, CYP2D6 metabolizer status does not appear to affect response to hydrocodone.24
To date, there is no information on the pharmacokinetics of hydrocodone in CYP2D6 ultrarapid metabolizers. Therefore, there is insufficient evidence as to whether poor metabolizers can be expected to have decreased analgesia when treated with hydrocodone, and whether ultrarapid metabolizers have an increased risk of toxicity with normal doses of hydrocodone.
Approximately 11% of an oxycodone dose is O
-demethylated by CYP2D6 to the minor metabolite oxymorphone, which has a 40-fold higher affinity and eightfold higher potency for μ-opioid receptors as compared with the parent drug.10
As compared with extensive metabolizers, poor metabolizers have been shown to have lower peak concentrations of oxymorphone after a dose of oxycodone.27
However, prospective clinical studies have produced conflicting data pertaining to the associations between CYP2D6 metabolizer phenotype and the analgesic effect and toxicity of oxycodone. In two studies in healthy volunteers, differential analgesia response to experimental pain stimuli was observed between extensive and poor metabolizers and also between ultrarapid and extensive/poor metabolizers.29
However, clinical studies in postoperative patients and in patients with cancer failed to demonstrate a significant difference in analgesia or side effects in response to oxycodone across CYP2D6 phenotypes.27
Physiologic alterations (e.g., miosis) after dosing with oxycodone correlate best with exposure to the parent compound.31
It is therefore premature to recommend routine therapy adjustment for oxycodone on the basis of CYP2D6
The differing levels of evidence for the association of CYP2D6 phenotype with hydrocodone and oxycodone analgesia as compared with codeine and tramadol may be because of the difference in the relative roles of the parent drug and circulating metabolites in analgesia among these CYP2D6 substrates.31
To avoid treatment complications, opioids that are not metabolized by CYP2D6, including morphine, oxymorphone, buprenorphine, fentanyl, methadone, and hydromorphone,32
along with nonopioid analgesics, may be considered as alternatives for use in CYP2D6 poor metabolizers and in ultrarapid metabolizers, depending on the type and chronicity of the pain being treated.