On April 7, 2015 we blogged about a young boy who became comatose after receiving tramadol for post-tonsillectomy pain treatment. It was later learned that the boy was a CYP2D6 ultra rapid metabolizer. Then on July 21, 2015, we blogged about the risks of codeine in CYP2D6 ultra rapid metabolizers, especially children. Recently, a story was reported about a 9 year-old boy who allegedly experienced profound and fatal respiratory depression after two doses of oxycodone for the treatment of post-tonsillectomy pain. Although no mention of a metabolism-based drug-gene interaction was made, our team will be following this case closely. It is possible that a forensic toxicology report could reveal elevated plasma concentrations of the potent metabolite, oxymorphone. If this is indeed the outcome, then CYP2D6 ultra rapid metabolism should be strongly suspected and tested for.

The metabolism profile of codeine, oxycodone, hydrocodone and tramadol are very similar, and although codeine is the only one of the these agents not recommended in children for treatment of post-tonsillectomy pain, caution should be used with all four due to their similar metabolism and potential hazard in CYP2D6 ultra rapid metabolizers.

• Codeine is a prodrug with one-tenth the analgesic potency of its metabolite, morphine. Five to ten percent of codeine is metabolized by CYP2D6 to morphine, and then further conjugated to morphine-6-glucuronide. These metabolites are responsible for all of codeine’s analgesic properties. About 60% of codeine is conjugated to inactive codeine-6-glucuronide and ten percent is N-demethylated by CYP3A4 to inactive norcodeine. Codeine is subject to inhibition, induction and gene variations which may affect a patient’s therapeutic response.

• Oxycodone metabolism is not well understood.
  About 50% is N-demethylated by CYP3A4 to noroxycodone and 10%
  O-demethylated by CYP2D6 to oxymorphone. These metabolites are further metabolized to noroxymorphone by the same enzymes. Another 10% of oxycodone also undergoes 6-keto-reduction. Although oxymorphone has 10-60 times higher affinity for the mu-opioid receptor, it only accounts for 15% of oxycodone’s overall analgesia. This is hypothesized to be due to it achieving much lower concentrations at the mu-opioid receptor.

• Hydrocodone undergoes O- and N-demethylation by CYP2D6 and CYP3A4, respectively. The N-desmethyl metabolite, norhydrocodone is inactive, while the O-desmethyl metabolite, hydromorphone, has 30 times higher affinity for the mu-opioid receptor than hydrocodone.

• Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. Tramadol metabolite, O-desmethyltramadol (M1) has six times the analgesic properties that the parent drug has. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and gene variations, which may affect the therapeutic response.

See the chart below for a visual breakdown of opioid metabolism.