Codeine analgesia is due to codeine-6-glucuronide, not morphine.
Eighty per cent of codeine is conjugated with glucuronic acid to codeine-6-glucuronide. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the 3- and 6-position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the mu-receptor to result in analgesia, codeine-6-glucuronide in analogy to morphine-6-glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O-demethylation to morphine, experience analgesia from codeine-6-glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype.
Vree
T B
TB
Institute for Anaesthesiology, Academic Hospital St Radboud, Nijmegen, The Netherlands.
van Dongen
R T
RT
Koopman-Kimenai
P M
PM
D000701:Analgesics, Opioid / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D003061:Codeine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D009020:Morphine / Q000737:chemistry / Q000378:metabolism; D010147:Pain Measurement; D011957:Receptors, Opioid / Q000737:chemistry
D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D009020:Morphine; C061773:codeine-6-glucuronide; D003061:Codeine