How does time-released codeine work?

[Starshowers]

I was just curious about this, and through the search function I couldn't find discussion about the mechanism of action, only discussion regarding breaking the time release. The most relevant post about this I could find: http://www.bluelight.ru/vb/threads/38135-Extended-release-codeine?p=346073&viewfull=1#post346073

It is a well-accepted notion that codeine inhibits hepatic enzyme Cytochrome P450 2D6 (CYP2D6) immediately after it is absorbed by said enzyme. Could anyone explain why ER codeine seems to work as well as IR codeine?

And yes, it comes in 100mg ER tablets in Canada.

Thanks

 

[Poodles!]

For starters, codeines opiod analgesic effects come predominantly from codeine-6-glucuronide, not morphine.

UGT2B7: codeine --> C6G (~80% )

CYP2D6: codeine --> morphine (≤5% )

On top of this, the morphine will be further metabolised to morphine-6-glucuronide and morphine-3-glucoronide via UGT2B7 and UGT1A3. 2B7 prefers to produce M6G and 1A3 prefers M3G, with more of the 3-conjugate being produced. Of these, only M6G is active as a an opoid analgesic and M3G is a convulsant. It's also interesting to note that M6G is 50 times more potent as an analgesic than morphine which would mean it's responsible for a significant portion of morphines effects, especially when administered orally when the vast majority of the morphine will be hit by first-pass metabolism.


I've no doubt that CYP2D6 inhibition (or a lack of the enzyme in poor metabolisers) will affect codeines analgesic potential to a degree, I really doubt it's all that significant. Or at least not as significant as a lot of people asssume. Anyoe taking timed-release codeine will be on the medication for longish periods of time, at which point they'd always have some level of CYP2D6 inhibition regardless of whether they're using timed or immediate realease. This would effectively make everyone poor metabolisers. For occaisional analgesic use, or for recreational use, then IR codeine will have the advantage as CYP2D6 will (assuming no other inhibitors have been used) be at full strength and it's unlikely you'd ever need a TR formula for either of these uses.