i have, for quite a while now, been trying to elucidate the actual mechanism
by which promethazine potentiates the effects of codeine.
im lead to believe that its pharmacokinetic in origin.
promethazine is a CYP2D6 inhibitor, which would imply that it inhibits
CYP2D6 mediated metabolism of codeine >> morphine.
so why is it a potentiator of codeine?
i found something on pubmed implicating promethazine as an inducer of CYP2D6
(aswell as an inhibitor,) but that would only explain codeine potentiation
by pretreatment, not concurrent administration.
diphenhydramine and assorted other anticholinergics and antihistamines
increase the effects of narcotics via a proposed (but not mentioned)
pharmacodynamic pathway. (from http://adhpage.tripod.com/potentiators.htm
which is where im getting some of my info from)
the above site also cites quinine as a potentiator, however ive found
elsewhere that quinine administration will block 2D6 activity and therefore
codeine metabolism >> morphine. this leads me to doubt the reliability of
the explanations of potentiator mechanisms on this site.
a friend on IRC just mentioned something to do with blood-brain-barrier
permeability of narcotics being enhanced by promethazine. he cant provide
any worthy refefences at the moment though, citing 'too wasted on codeine
and promethazine to give a sh.t right now' as his reason. ill post the refs
for this as an addendum if he decides he wants to find them

there is also the other possibility that codeine's analgesic effect is quite
significantly a result of its (proposed) active metabolite
codeine-6-glucuronide.
morphine-6-glucuronide is apparently ~50x more potent than morphine. more
research apparently needs to be done (and may have been done by now) on
codeine-6-glucuronide and its properties. maybe promethazine interacts with
it...
id be interested to find out whether morphine-6-gluc is actively transported
thru the blood-brain-barrier - or if not, how does it get through, the gluc
group being quite polar....