Codeine
Codeine is very similar in structure to morphine. It simply adds a methyl group on the 3-carbon hydroxyl group of morphine (from an –OH to a -OCH3). Indeed, codeine is found naturally along with morphine in the poppy seed. Therefore it is not semi-synthetic, although it can be easily manufactured.
Codeine is a weak analgesic with a weak affinity to the µ receptor, 300 times less than morphine.2 In 1948, Sanfilippo.3 identified that codeine is metabolized to morphine. Because of this, up until recently, it had generally been accepted that codeine's conversion to morphine is the main reason for codeine's analgesic properties. In the early 1990s, several studies indicated that the CYP450 2D6 enzyme was responsible for the conversion of codeine to morphine.4,5 One of these studies5 also showed that within a laboratory pain model, either inhibition of 2D6 by a competitive inhibitor (quinidine in this study) or a poor 2D6 metabolism phenotype would decrease the amount of morphine measured and the subjective ratings of analgesia.
However, despite the case reports that would follow these studies, some researchers have had difficulty accepting that codeine's conversion to morphine by 2D6 is the reason for its efficacy as an analgesic. The main problem with this supposition is that very little of the total dose of codeine is actually metabolized by 2D6 into morphine. Indeed, the range has been between 0.5%6 to 2–3%.7 Generally, these studies and others have shown that 80% of codeine is actually directly glucuronidated by UGT 2B7 to codeine-6-glucuronide (C6G), 5% or less is metabolized to morphine by 2D6, and the rest is metabolized by the CYP450 3A4 enzyme into norcodeine, a compound that is inactive as an analgesic. The products of codeine's metabolism from both 2D6 and 3A4 are quickly glucuronidated, with the 2D6/morphine product going to morphine-6-glucuronide (M6G), an active analgesic, and morphine-3-glucuronide (M3G).1