The liver is the major site of biotransformation for most opioids. Thus, th
e disposition of these drugs may be affected in patients with liver insuffi
ciency. The major metabolic pathway for most opioids is oxidation. The exce
ptions are morphine and buprenorphine, which primarily undergo glucuronidat
ion, and remifentanil, which is cleared by ester hydrolysis.
Oxidation of opioids is reduced in patients with hepatic cirrhosis, resulti
ng in decreased drug clearance [for pethidine (meperidine), dextroprogoxyph
ene, pentazocine, tramadol and alfentanil] and/or increased oral bioavailab
ility caused by a reduced first-pass metabolism (for pethidine, dextropropo
xyphene, pentazocine and dihydrocodeine). Although glucuronidation is thoug
ht to be less affected in liver cirrhosis, the clearance of morphine was fo
und to be decreased and oral bioavailability increased.
The consequence of reduced drug metabolism is the risk of accumulation in t
he body, especially with repeated administration. Lower doses or longer adm
inistration intervals should be used to remedy this risk. Special risks are
known for pethidine, with the potential for the accumulation of norpethidi
ne, a metabolite that can cause seizures, and for dextropropoxyphene, for w
hich several cases of hepatotoxicity have been reported. On the other hand,
the analgesic activity of codeine and tilidine depends on transformation i
nto the active metabolites, morphine and nortilidine, respectively. If meta
bolism is decreased in patients with chronic liver disease, the analgesic a
ction of these drugs may be compromised, Finally, the disposition of a few
opioids, such as fentanyl, sufentanil and remifentanil, appears to be unaff
ected in liver disease.