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9 Analgesicsto 10 mg morphine. It is not given via the intrathecal or epidural route due to preser-
vatives. Its effects are essentially the same as morphine and are antagonized by
naloxone.Methadone
The notable features of methadone are its relatively low first-pass metabolism result-
ing in a relatively high oral bioavailability of 75% and a long plasma half-life. Thus
it may be used orally, and as such it is used to treat those addicted to intravenous
opioids, that is, diamorphine, by means of slow weaning programs. It is less sedative
than morphine.
Methadone may also act as an antagonist at the NMDA receptor and this is thought
to be especially beneficial in the treatment of certain neuropathic pain that would
be otherwise resistant to typical opioids.Kinetics
Methadone is 90% plasma protein bound and metabolism occurs in the liver to a
number of inactive metabolites. Its plasma half-life is 18–36 hours. Up to 40% is
excreted as unchanged drug in the urine, which is enhanced in acidic conditions.Codeine
Codeine (methylmorphine) is 10 times less potent than morphine and not suitable
for severe pain. The oral and intramuscular adult dose is 30–60 mg, the paediatric
dose is 0.5–1 mg.kg−^1 The intravenous route tends to cause hypotension probably
via histamine release and is therefore avoided. It has been suggested codeine acts as
no more than a prodrug for morphine.Kinetics
The presence of a methyl group reduces hepatic conjugation resulting in an oral
bioavailability of 50%. Post-operative oral bioavailability is much more variable and
ranges from 20% to 80%.
Asmall proportion (5–15%) of codeine is eliminated unchanged in the urine while
the remainder is eliminated via one of three metabolic pathways in the liver. The pre-
dominant metabolic pathway is 6-hydroxy glucuronidation, although 10–20% under-
goes N-demethylation to norcodeine, and 5–15% undergoes O-demethylation to
morphine. A number of other metabolites, such as normorphine and hydrocodone,
have also been identified. Of these metabolites only morphine has significant activ-
ity atμ-receptors. O-demethylation is dependent on the non-inducible cytochrome
P450 (CYP2D6), which exhibits genetic polymorphism so that poor metabolizers
experience little pain relief. The frequency of poor metabolizers varies and is esti-
mated at 9% of the UK population but 30% in the Hong Kong Chinese population.