SPECIAL POPULATIONS Clin Pharmacokinet 1999 Jul; 37 (1): 17-40

0312-5963/99/0007-0017/$12.00/0

© Adis International Limited. All rights reserved.

Pharmacokinetics of Opioids in
Liver Disease
Irmgard Tegeder, Jörn Lötsch and Gerd Geisslinger
Center of Pharmacology, Institute of Clinical Pharmacology,
Johann Wolfgang Goethe-University of Frankfurt, Frankfurt am Main, Germany

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1. Overview of the Pharmacokinetics of Opioids in Patients with Normal Liver Function . . . . . . . . . 20
2. Pharmacokinetics of Specific Opioids in Patients with Liver Disease . . . . . . . . . . . . . . . . . 20
2.1 Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.2 Methadone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.3 Pethidine (Meperidine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.4 Dextropropoxyphene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.5 Codeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.6 Dihydrocodeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.7 Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.8 Pentazocine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.9 Tramadol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.10 Tilidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.11 Fentanyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.12 Sufentanil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.13 Alfentanil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.14 Remifentanil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Abstract The liver is the major site of biotransformation for most opioids. Thus, the
disposition of these drugs may be affected in patients with liver insufficiency.
The major metabolic pathway for most opioids is oxidation. The exceptions are
morphine and buprenorphine, which primarily undergo glucuronidation, and
remifentanil, which is cleared by ester hydrolysis.
Oxidation of opioids is reduced in patients with hepatic cirrhosis, resulting in
decreased drug clearance [for pethidine (meperidine), dextropropoxyphene, pen-
tazocine, tramadol and alfentanil] and/or increased oral bioavailability caused by
a reduced first-pass metabolism (for pethidine, dextropropoxyphene, pentazocine
and dihydrocodeine). Although glucuronidation is thought to be less affected in
liver cirrhosis, the clearance of morphine was found to be decreased and oral
bioavailability increased.
The consequence of reduced drug metabolism is the risk of accumulation in
the body, especially with repeated administration. Lower doses or longer admin-
istration intervals should be used to remedy this risk. Special risks are known for
pethidine, with the potential for the accumulation of norpethidine, a metabolite
18 Tegeder et al.

that can cause seizures, and for dextropropoxyphene, for which several cases of
hepatotoxicity have been reported. On the other hand, the analgesic activity of
codeine and tilidine depends on transformation into the active metabolites,
morphine and nortilidine, respectively. If metabolism is decreased in patients with
chronic liver disease, the analgesic action of these drugs may be compromised.
Finally, the disposition of a few opioids, such as fentanyl, sufentanil and
remifentanil, appears to be unaffected in liver disease.

Opioids are extensively used in the treatment of
pain in a diverse patient population. As the experi-
ence of pain varies greatly among patients, and op-
ioid effects may vary between individuals, therapy
needs to be individualised in order to achieve ade-
quate pain control. In addition to pain relief, opioids
induce several adverse effects, such as respiratory
depression and sedation, and have actions on the
gastrointestinal tract that induce nausea, vomiting
and constipation. A phenomenon still incompletely
understood but complicating the therapy is the de-
velopment of tolerance.
It has been suggested that patients with severe
liver disease have an increased sensitivity to opioid
analgesics. Administration of opioids may cause ce-
rebral dysfunction or worsen the condition of a pa-
tient with pre-existing hepatic encephalopathy.[1,2]
Additionally, impaired liver function may translate
into changes in pharmacokinetics. It is generally
accepted that opioid effects are initiated by the
binding of an opioid to specific receptors. The
higher the number of opioid receptors occupied by
opioid molecules, the higher the effect until a max-
imum is reached. The effect is thus a function of
the opioid concentration at the effect site. After sys-
temic administration, the time course of the con-
centration at the effect site (Ceff) is a function of the
plasma concentration (Cp):
Ceff = ke0 e−ke0t ∗ Cp
where ke0 is the rate constant for the transfer from
the site of drug effect to the environment[3] and the
asterisk denotes convolution (the mathematical op-
eration by which the time courses of drug concentra-
tion in plasma and at the effect site are combined).
When the plasma concentration time course changes,
the effect may also change with respect to its mag-
nitude and time course.
The rate of change of the amount (A) of drug in
the body can be described by:
dA/dt = –kA (Eq. 2)
where k is the elimination rate constant. The half-
life of a drug can be calculated as ln(2)/k. The
amount of drug in the body is related to the plasma
concentration by the volume of distribution (Vd):
A = Vd • Cp (Eq. 3)
If clearance (CL) = k • Vd, the rate of change of
amount A of drug in the body is related to the
plasma concentration by:
dA/dt = CL • Cp (Eq. 4)
The total clearance (CL) is a sum of several par-
tial clearances, named after the site or mechanism
of drug elimination, such as hepatic metabolic
clearance (CLH) or renal excretory clearance
(CLR).
The effect of liver impairment becomes more
pronounced as the contribution of hepatic clear-
ance to total clearance increases. The efficiency of
drug removal by the liver is determined by hepatic
blood flow, hepatic enzyme capacity and plasma
protein binding. Liver disease may affect any of
these conditions and, in addition, may lead to the
(Eq. 1) formation of porto-systemic shunts by which a
drug can be spared from hepatic elimination.
Hepatic clearance may be described as:
CLH = QH • EH (Eq. 5)
where QH is the hepatic blood flow and EH is the
hepatic extraction ratio describing the efficiency of
drug removal by the liver. When EH approaches 1,

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease 19

the hepatic clearance approximately equals the he-
patic blood flow (CLH ≈ QH). Thus, the clearance
of drugs highly extracted by the liver (EH > 0.7),
such as pethidine (meperidine), pentazocine and
dextropropoxyphene, largely depends on liver
blood flow.
In patients with liver disease, the clearance of
these drugs is mainly affected by reduced liver
blood flow or porto-systemic intra- and extra-hepatic
shunting. However, in liver cirrhosis the clearance
of some high-extraction drugs, such as propranolol,
were found to be reduced primarily by decreased
enzyme capacity.[4,5] Another effect of reduced
liver clearance is an increase in the oral bioavaila-
bility of high-extraction drugs because of reduced
first-pass metabolism and/or portal blood bypassing
the liver via porto-caval shunts.
In contrast to high-extraction drugs, the hepatic
clearance of drugs with a low extraction ratio (EH
< 0.3), such as methadone, largely depends on the
intrinsic hepatic clearance (CLint), which describes
the metabolic activity, and on plasma protein bind-
ing, because drug unbound to proteins is available
for elimination and the drop in drug concentration
across the liver is small. When EH is small, hepatic
clearance may be described as:
CLH = CLint • fu (Eq. 6)
where fu denotes the fraction of drug that is not
bound to proteins. Therefore, the clearance of low-
extraction drugs in patients with liver disease is
mainly affected by a reduced enzyme capacity or
altered protein binding (for drugs with fu < 0.1).
An increased free fraction of a drug caused by
a reduced level of plasma proteins may counter-

Table I. Pharmacokinetic parameters of commonly used opioids in patients with normal liver and renal function
Drug F (%) PB (%) CL (ml/min) Vss (L) t1⁄2β (h) References
Alfentanil 88-92 300-500a 30-70a 1.5-2 14-18
Buprenorphine 50-55b ~96 650-1300 200-400 3-6 (-23c) 19-24
Codeine 50-55 4-7 210-350a 2.5-3.5 25-29
O-Demethyl-tramadol ~9 30
Dextropropoxyphene 30-70 80 600-1200 700-1800 11-16 31-33
Dihydrocodeine 12-34 80-90a 3.3-4.5 34
Fentanyl 80-86 600-1000 200-560a 3-4 14, 35-39
(-15d)
(-8.7e)
Methadone 41-99 70-90 50-200 240-330a 19-58 40-44
Morphine 15-50 20-35 800-2000 70-330 1.5-4.5 (~2) 45-55
Morphine-3-glucuronide 150-190 8-30 1-2 47, 56
Norpethidine 12-24 57, 58
Norpropoxyphene 220-450 23-37 32, 33
Nortilidine 99 3.3-4.9 59
Pentazocine <20 1200-1700 350-500 2-5 (-10c) 8, 60-62
Pethidine (meperidine) 48-56 60-80 470-730a 260-320a 3-7 63-66
Remifentanil 3000-5000 25-40 10-20 min 67-70
Sufentanil 91-93 700-1500a 120-380a 2.5-3.5 (-12.8e) 14, 17, 71-75
Tilidine 6 59
Tramadol 65-75 440-490 200-300 5-6 30, 76
a Normalised for 70kg adult.
b Sublingual.
c Enterohepatic recirculation.
d Patients >60 years of age.
e Long sampling time to define the terminal elimination phase.
CL = clearance; F = oral bioavailability; PB = protein binding; t1⁄2β = terminal elimination half-life; Vss = volume of distribution at steady state.

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 Jul; 37 (1)
20
balance the effect of a decrease in enzyme activity.
In addition, when the protein binding of drugs that
are usually highly bound to proteins is reduced,
more than the normal amount of the drug can dis-
tribute into tissues. Since the amount of drug in the
body remains unaffected, the Vd can increase. In
addition, since the drug trapped in the tissues is not
eliminated, the half-life of those drugs may in-
crease.
With intermediately extracted drugs (0.3 < EH <
0.7), such as codeine and alfentanil, hepatic clear-
ance may be altered by liver blood flow, protein
binding and enzyme activity.
The function of various metabolising enzymes
appears to be differently affected in patients with
liver disease. It has been shown that the clearance
of low-extraction drugs oxidised by the micro-
somal cytochrome P450 (CYP) enzyme system is
reduced in patients with chronic liver disease.[4-8]
In contrast, the clearance of low-extraction drugs
that undergo predominantly glucuronidation was
not reduced.[9-12] However, in patients with severe
cirrhosis there is some evidence that glucuronida-
tion is also impaired.[13]
As the liver is the major site of opioid metabo-
lism, alterations in drug disposition may be expected
in patients with liver disease. This article reviews
the pharmacokinetics of the commonly used opioids
in patients with liver disease.
1. Overview of the Pharmacokinetics
of Opioids in Patients with Normal
Liver Function
The pharmacokinetic parameters of the com-
monly used opioids in patients with normal liver
and renal function are summarised in table I. When
not mentioned otherwise, half-life means terminal
elimination half-life (t1⁄2β) and Vd is at steady state
(i.e. Vss).
Although most opioids are quite well absorbed
from the gastrointestinal tract, their oral bioavaila-
bility is reduced by presystemic metabolism in the
gut wall and the liver (first-pass effect). All opioids
bind to plasma proteins, generally to albumin and
α1-acid glycoprotein (AAG); however, the extent
© Adis International Limited. All rights reserved.
Tegeder et al.
of binding varies from <10% for codeine to >95%
for buprenorphine. Opioids distribute rapidly in all
body tissues. Most opioids have a large Vd (of
about 3 to 6 L/kg).
Opioids are metabolised to more polar com-
pounds, predominantly by the liver, although extra-
hepatic metabolism, especially in the kidneys, con-
tinues to be a focus for research. Most of the
metabolites are less active than the parent com-
pounds and do not have clinically relevant pharma-
cological actions. Some metabolites, however, are
as or more potent as opioid agonists as the parent
drug (e.g. morphine as a metabolite of codeine,
morphine-6-glucuronide or O-demethyl-tramadol)
and may produce analgesic effects as well as ad-
verse effects such as respiratory depression. On ac-
cumulation, norpethidine may even cause severe
adverse effects not typical for pethidine itself.
The majority of metabolites are excreted via the
kidneys and may accumulate in patients with renal
failure. In addition to renal excretion, glucuronide
metabolites may be excreted via the biliary system;
enterohepatic recirculation has also been suggested
for some of these drugs (e.g. buprenorphine and
morphine).
2. Pharmacokinetics of Specific
Opioids in Patients with Liver Disease
2.1 Morphine
2.1.1 Pharmacokinetics
Morphine is well absorbed from the gastrointes-
tinal tract. However, it undergoes substantial first-
pass metabolism, predominantly in the liver, result-
ing in an oral bioavailability of only 20 to
40%.[45,77,78] Peak plasma drug concentrations (Cmax)
are reached within 15 to 20 minutes of intramuscu-
lar and subcutaneous administration, [40] and within
30 to 90 minutes of oral administration of a typical
immediate-release formulation.[45]
After absorption, morphine is rapidly distributed
in the body. It easily crosses the blood-brain bar-
rier, but at a considerably lower rate than more lipo-
philic opioids such as methadone or fentanyl.[79-81]
Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease
Approximately one-third of morphine binds to
plasma proteins.[40] Its Vd is 1 to 6 L/kg.[45,77,46,47,56]
The primary site of morphine metabolism is the
liver, where it undergoes rapid glucuronidation.
The high extraction of morphine (60 to 70%)[82,83]
results in a high systemic clearance (about 1.5 to 2
L/min) and a short t1⁄2β of approximately 2
hours.[47,77,84,85] Extrahepatic metabolism was found
to contribute considerably (up to 38%) to the total
body clearance of morphine.[83,86] A simple calcu-
lation shows that the assumption of extrahepatic
morphine metabolism is reasonable: assuming an
EH of 0.7 and a QH of 25 ml/min/kg,[87] hepatic
clearance as calculated by CLH = EH • QH should
not exceed 17.5 ml/min/kg. Systemic morphine
clearance, however, exceeds this value by about 30%,
strongly indicating that the liver cannot be the only
site of morphine metabolism, which is an indirect
evidence for extrahepatic metabolism of the drug.
The principal metabolite, morphine-3-glucuron-
ide (M3G), has no opioid agonistic effects.[88,89] Its
role is still controversial. There are several reports
that M3G antagonises the analgesic activity of
morphine and morphine-6-glucuronide (M6G),
contributing to morphine tolerance.[90-93] This an-
tagonism appears not to be mediated by opioid re-
ceptors.[94-98] On the other hand, several other re-
ports question the hyperalgesic action of M3G.[99-103]
M6G is produced in smaller amounts than M3G.
In contrast with M3G, the opioid agonist activity
of M6G is not in doubt. M6G appears to be at least
as potent as morphine.[104-108] Both M3G and M6G
are excreted primarily by the kidney and account
for between 55 and 60%, and approximately 10%,
respectively, of a given dose recovered in urine.
After the administration of oral morphine the area
under the plasma concentration-time curve (AUC)
of M6G exceeded that of morphine by a factor of
4 : 1[45,89,109] to 9 : 1.[77] In contrast, after the intra-
venous administration of morphine, the M6G :
morphine ratio is about 1 : 1 because of the ab-
sence of first-pass formation of M6G.[47]
M6G has a plasma clearance of about 10.2 L/h
and a Vd of 10 to 30L, resulting in a t1⁄2β of 1 to 2
hours.[47,56] Small amounts of morphine are meta-
© Adis International Limited. All rights reserved.
21
bolised to normorphine, another active metabo-
lite.[110] Its concentrations are usually too small to
be detected in plasma. However, normorphine may
be neurotoxic.[111] The amount of morphine ex-
creted unchanged in urine is less than 10%.[45,77]
Enterohepatic recirculation is thought to account
for traces of morphine still found in urine and fae-
ces several days after administration.[84,112] How-
ever, it is not clear whether this is of clinical im-
portance. In patients with renal insufficiency, the
glucuronide metabolites may accumulate because
they are mainly excreted by the kidneys.[48]
There is still controversy surrounding the con-
tribution of M6G to the effects seen after the ad-
ministration of morphine. M6G is a potent opioid[107]
and there is strong evidence that it contributes to
the clinical effects[113] of morphine in humans.[114]
After intrathecal administration in humans it pro-
duced analgesic effects with potency approxi-
mately 2.6 times greater than that of morphine.[104]
Although previous clinical investigations sug-
gested analgesic effects after systemic administra-
tion,[115,116] it was recently demonstrated in a study
with placebo and positive (morphine) control that
M6G had neither clinical nor analgesic effects
when administered as an intravenous bolus plus a
4-hour intravenous infusion.[117] This points to-
wards a slow and low brain uptake of plasma
M6G,[118] thereby challenging earlier reports of its
ability to easily cross the blood-brain barrier. This
had previously been explained by the existence of
2 energetically favourable conformations of the
M6G-molecule: extended in hydrophilic environ-
ments and folded in lipophilic environments.[119]
However, with the long-term administration of
morphine, more M6G might enter the brain with
time and it may thus become more relevant. This
view is supported by the observation that after
short-term administration oral morphine is only
one-sixth to one-eighth as potent as parenterally
administered morphine, but that after repeated oral
administration it is half to one-third as potent.[120]
In addition, M6G was reported to be a substrate of
P-glycoprotein,[121,122] as is morphine.[123] It is,
therefore, possible that coadministration of inhib-
Clin Pharmacokinet 1999 Jul; 37 (1)
22 Tegeder et al.

Table II. Pharmacokinetics of morphine in patients with hepatic cirrhosis

Route Dose n Liver function F (%) CL (ml/min) Vss (L) t1⁄2β (h) Reference
Intravenous 0.1 mg/kg 6 NL 2345a ± 560 295a ± 65 1.85 ± 0.53 49
8 LCI 1470a ± 525 314a ± 62 3.35 ± 0.65 49
0.15 mg/kg 6 NL 1233 ± 427 203a ± 168 2.5 ± 1.5 124
6 LCI 1153 ± 345 161a ± 91 2.2 ± 1.3 124
1mg 8 NL 735a ± 98 1.67 ± 0.37 83
8 LCI 546a ± 49 2.02 ± 0.23 83
4mg 6 NL 1960a ± 161 287a ± 35 4.2 ± 0.2 125
7 LCI 798a ± 91 280a ± 70 1.7 ± 0.3 125
Oral 20mg 6 NL 47 ± 5.8 3.3 ± 0.6 125
10mg 6 LCI 101 ± 16.4 5.5 ± 0.8 125
a Normalised for 70kg adult.
CL = clearance; F = oral bioavailability; LCI = liver cirrhosis; NL = normal liver function; t1⁄2β = terminal elimination half-life; Vss = volume of
distribution at steady state.

itors of P-glycoprotein, such as verapamil or cyclo-
sporin, lead to an increased brain uptake of M6G,
thereby enhancing its effects on the central nervous
system.
2.1.2 Effect of Liver Disease
The main findings of studies involving patients
with hepatic cirrhosis are summarised in table II.
An early report suggested that morphine can cause
hepatic encephalopathy in patients with liver cir-
rhosis.[1] Although this was not confirmed by a
more recent study,[125] several authors have shown
that the metabolism of morphine is significantly
impaired in patients with severe hepatic cirrho-
sis.[49,83,125,126] The t1⁄2β was prolonged in those pa-
tients with cirrhosis who had marked decreases in
hepatic function. Compared with controls, t1⁄2β was
approximately doubled (3 to 4 vs 1.5 to 2h),[49,125]
which was attributable to a reduction in total body
clearance. Vd was not significantly altered. [49,125]
Hasselstrom et al.[125] have also reported that the
bioavailability of oral morphine increased to 100%
in patients with cirrhosis as compared with a bio-
availability of about 30% in the control group. In
contrast to these results, Patwardhan et al.[124]
found that the systemic clearance and t1⁄2β of mor-
phine after intravenous administration were similar
in both patients with cirrhosis and healthy volun-
teers. These contradictory findings may be ex-
plained by differences in the severity of liver dis-
ease in the patients enrolled in the studies. The
clinical data presented by Patwardhan et al.[124]
suggest that their patients had less severe hepatic
dysfunction (hypoalbuminaemia and hyperbilirubin-
aemia, normal prothrombin time, 3 patients with
ascites) compared with other studies that included
patients in Child-Pugh class C, encephalopathy or
bleeding from oesophageal or gastric varices.[83,125]
Using hepatic vein catheterisation, Crotty et al.[83]
have provided a direct measurement of morphine
hepatic extraction in 8 patients with hepatic cirrho-
sis and 8 controls. The extraction ratio was 0.52 in
the control group and was reduced by 25% in those
with cirrhosis. The hepatic plasma flow was almost
identical in both patient groups, so that the reduc-
tion in extraction ratio was probably because of
impaired enzyme capacity and/or the presence of
intrahepatic shunts. However, the effect of cirrho-
sis was less than that reported in similar studies of
high-extraction oxidised drugs such as proprano-
lol[5] and lidocaine[4] (44 and 52% reduction of he-
patic extraction in cirrhosis, respectively). This
supports the concept that glucuronidation may be
relatively spared in cirrhosis. Specifically, the sys-
temic clearance of low-extraction drugs that are
metabolised exclusively by glucuronidation was
not reduced in cirrhosis.[9-11]
At present, this phenomenon may be explained
as follows. The isoenzymes of glucuronyltrans-
ferase are thought to be located in the membrane
of the endoplasmic reticulum.[127] The addition of

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease
detergents or other membrane-perturbing agents
produces an increase in the enzyme activity in
vitro.[128] It has been postulated that the sparing of
glucuronidation in liver disease may be because of
a similar activation of the enzyme by the disease
process.[129-133]
Crotty et al.[83] found a discrepancy between the
systemic clearance and the hepatic clearance in
both the controls and patients with cirrhosis. The
percentage of systemic clearance unaccounted for
by hepatic clearance was greater in the patients
with liver disease (33%) than in the control group
(10%). In a study by Mazoit et al.,[86] total body
clearance exceeded hepatic clearance by 38%. These
findings provide indirect support for the idea that
morphine has an extrahepatic metabolism; this is
further substantiated by several studies that have
shown that morphine is conjugated with glucuronic
acid in homogenates of human intestine,[134,135]
kidney microsomes[136,137] and brain tissue.[138]
Thus, extrahepatic metabolism might contribute sub-
stantially to the overall clearance of morphine, es-
pecially in patients with liver cirrhosis.
Olsen et al.[139] have shown that the plasma pro-
tein binding of morphine was decreased in patients
with hepatic failure. The decreased binding was
attributed to lower albumin levels and the displace-
ment of the bound drug caused by the high binding
affinity of bilirubin. The higher free fraction of
morphine in plasma, however, is not expected to
increase the Vd because morphine is only moder-
ately protein bound.[124]
Because the metabolism of morphine is reduced
in patients with liver cirrhosis, it should be used
with caution in these patients to avoid accumula-
tion of the drug. A 1.5- to 2-fold increase in the
administration interval has been suggested.[49] If
administered orally, the increased bioavailability
has to be considered. Whether the lower formation
of M6G in patients with cirrhosis is associated with
a lower pharmacological effect has not yet been
evaluated.
© Adis International Limited. All rights reserved.
23
2.2 Methadone
2.2.1 Pharmacokinetics
The analgesic activity of methadone is almost
entirely produced by l-methadone, which is much
more potent as an opioid agonist than the d-iso-
mer.[140] Most kinetic studies are performed with
racemic methadone. It is well absorbed from the
gastrointestinal tract, and unlike many other opioid
analgesics it has a considerably high oral bioavail-
ability (approximately 80%)[41,42] because its he-
patic extraction is low (0.09).[43]
At therapeutic concentrations, about 90% of
methadone is bound to plasma proteins.[43] Metha-
done has a long t1⁄2β of about 30 hours (with a range
of 8.5 to 58h).[43,44,141,142] It appears to be firmly
bound to proteins in various tissues with a gradual
accumulation after repeated administration.[142,143]
Its Vd is about 2 to 5.5 L/kg.[42,43] Methadone
undergoes extensive biotransformation in the liver.
The major metabolic pathways are N-demethyla-
tion and cyclisation to pyrrolidines and pyrrolines.
The metabolites are excreted in urine and bile along
with small amounts of unchanged drug.[144,145] The
mean total plasma clearance is about 3 to 12 L/h,
renal clearance accounting only for 0.24 to 1.8
L/h.[43,146]
2.2.2 Effect of Liver Disease
Kreek et al.[147] reported that the total 24-hour
urinary excretion of methadone and its metabolites
was significantly lower (32.6%) in patients with
liver disease compared with controls (48.3%). The
urinary excretion of the pyrrolidone metabolite, an
end-product of 2 pathways of methadone metabo-
lism, was also reduced. In a second study the same
authors found the faecal excretion of methadone
and its unconjugated metabolites to be unaltered in
patients with liver disease as compared with a
control group.[148] The patients in these 2 studies
had chronic active, chronic persistent or alcoholic
hepatitis without severe liver dysfunction.[147,148]
In patients with biopsy-proven mild to moder-
ate chronic liver disease, Novick et al.[149] found
no change in the pharmacokinetic parameters of
methadone compared with healthy individuals. In
patients with more severe liver disease, the t1⁄2β was
Clin Pharmacokinet 1999 Jul; 37 (1)
24
somewhat longer, but drug disposition was not sig-
nificantly altered.[149] In patients with severe alco-
holic liver cirrhosis, however, the t1⁄2β of methadone
was significantly prolonged (32h) compared with
a control group of methadone-maintained alcohol
abusers with normal liver function tests (t1⁄2β
19.7h).[150] The Vd was larger in patients with cir-
rhosis than in controls (716 vs 438L) whereas the
apparent clearance after oral administration was
similar in both groups.[150] The patients with cirrhosis
had somewhat lower dose-adjusted mean plasma
concentrations than the controls (2.8 vs 3.6 μg/L/
mg),[150] which might have been a consequence of
the greater Vd and possibly increased tissue storage
of the drug. None of the patients with severe liver
cirrhosis had signs or symptoms of methadone
overdosage.[150]
Since most disposition parameters of methadone
were normal in patients with hepatic cirrhosis,
Novick et al.[150] suggested that the usual metha-
done maintenance dosage may be continued even
in patients with severe hepatic dysfunction. How-
ever, with alcohol abusers as controls the pharmaco-
kinetic differences between patients with and with-
out cirrhosis might have been underestimated,
because this kind of control is more likely to have
compensated cirrhosis with normal liver function
tests than truly healthy individuals.[151] On the
other hand, long-term excessive alcohol (ethanol)
ingestion appears to increase the metabolism of
methadone by stimulating its degradation in liver
microsomes, whereas acute alcohol intake inhibits
the metabolism of methadone at liver microsomal
sites,[152] leading to elevated methadone plasma
concentrations.[153] These potential interactions
and a missing second control group of truly healthy
individuals makes it difficult to interpret the results
presented by Novick et al.[149,150]
It has been demonstrated that 4 heterologously
expressed CYP enzymes were able to catalyse the
N-demethylation of methadone. Referring to their
relative content in the liver, however, it can be as-
serted that CYP3A4 is the major enzyme involved
in the N-demethylation of methadone.[154] It has
been shown that both the CYP3A4 mRNA and pro-
© Adis International Limited. All rights reserved.
Tegeder et al.
tein were reduced in livers from patients with
hepatocellular diseases.[155] Since excessive long
term alcohol consumption may induce enzymes,
the results obtained in patients with alcoholic liver
cirrhosis might not be representative of patients
with severe liver cirrhosis of other aetiologies.
2.3 Pethidine (Meperidine)
2.3.1 Pharmacokinetics
Pethidine was one of the first synthetic opioid
analgesics introduced into clinical practice. It is
less potent than morphine. Pethidine is metabo-
lised predominantly by the liver; its t1⁄2β is about 3.5
hours.[63,64] The major metabolic pathway is hydro-
lysis to meperidinic acid, which is consecutively
conjugated with glucuronic acid and excreted by
the kidney. Pethidine is also N-demethylated to
norpethidine which is either metabolised to nor-
meperidinic acid or excreted unchanged in urine
(about 6%).[65] Elimination of the pharmacologi-
cally active norpethidine is slower (t1⁄2β 12 to 24h)
than that of pethidine, and the metabolite can accu-
mulate in patients receiving repeated doses of
pethidine.[57,58] High plasma concentrations of
norpethidine have been related to the development
of neuromuscular irritability and seizures.[58]
At normal urine pH, less than 5% of an admin-
istered pethidine dose is excreted unchanged in
urine.
Taken orally, pethidine is subject to extensive
first-pass metabolism with a mean oral bioavaila-
bility of about 50%.[156] Approximately 60 to 80%
of pethidine in plasma is bound to proteins, mainly
to AAG.[157] When AAG levels increase (as in
stress) pethidine binding may also increase.[157]
Pethidine has a large Vd (3 to 5 L/kg).[63,64]
2.3.2 Effect of Liver Disease
Using isolated perfused rat livers, Callaghan et
al.[158] have examined the effect of liver disease on
the hepatic extraction and clearance of pethidine,
using chronic carbon tetrachloride-induced cirrho-
sis as a model of liver disease. The extraction ratio
of pethidine was reduced from 0.91 in controls to
0.79 in cirrhosis, and the intrinsic hepatic clearance
was reduced from approximately 10.8 to 4.2 L/h.
Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease
In patients with cirrhosis, it has been shown that
the presystemic metabolism of pethidine is strik-
ingly impaired, and its oral bioavailability may in-
crease to as much as 80%.[159] The reduced hepatic
extraction of pethidine in cirrhosis results in a de-
crease of approximately 50% in plasma clearance
and approximate doubling of the half-life of the
parent compound.[160] A prolonged half-life was
also noticed in patients with acute viral hepati-
tis.[161] The use of normal doses of pethidine in these
patients may result in excessive sedation, respira-
tory depression or other adverse opioid effects.
Pond et al.[159] have shown that the generation
of norpethidine is impaired in patients with cirrho-
sis, suggesting that these patients may be relatively
protected from its toxicity. Mean norpethidine
plasma concentrations after intravenous and oral
pethidine were 36 and 45% of the concentrations
in healthy individuals. However, further elimina-
tion of norpethidine was slower than in healthy
individuals, leading to an increased risk of cumu-
lative toxicity when repeated doses are adminis-
tered. This is substantiated by a case of CNS tox-
icity in a patient with cirrhosis after multiple days
of pethidine use. The patient was receiving approx-
imately 400mg daily of intramuscular pethidine
when symptoms of CNS toxicity (diaphoresis, ag-
itation, tremors and muscle spasms) occurred. The
patient had normal renal function.[162]
Since the Vd of pethidine in patients with cir-
rhosis was not affected[159] a single intravenous
dose should not be changed. When taken orally, the
dose of pethidine should be reduced as the bio-
availability is increased. Because the elimination
of norpethidine is decreased in patients with liver
disease, those patients may be at risk of norpethid-
ine accumulation and neurotoxicity with repeated
doses, although less norpethidine is produced.
Therefore, pethidine should not be used for long
term pain management in any patient.
2.4 Dextropropoxyphene
2.4.1 Pharmacokinetics
Dextropropoxyphene is chemically related to
methadone but has a low analgesic activity. It is
© Adis International Limited. All rights reserved.
25
widely prescribed, often in combination with para-
cetamol (acetaminophen) or aspirin (acetylsali-
cylic acid), for the treatment of mild to moderate
pain. The analgesic effect is produced by the dextro
isomer of propoxyphene, which is thought to be
half as potent as an analgesic as codeine when
given orally.
Following oral administration, about 30 to 70%
of the drug escapes first-pass metabolism to enter
the circulation.[31] Plasma concentrations vary
widely between individuals.[31] Dextropropoxy-
phene is about 80% bound to proteins[163] and has
a large Vd (approximately 16 L/kg).[31,164] The ma-
jor route of metabolism is N-demethylation to
norpropoxyphene, which is excreted by the kid-
neys.[32] Norpropoxyphene is pharmacologically
active. It has, however, substantially lower CNS-
depressant effects than dextropropoxyphene but is
thought to have a greater local anaesthetic ef-
fect.[165]
The t1⁄2β of the parent compound and the meta-
bolite range from 11 to 16 hours and 23 to 37 hours,
respectively,[31-33] with much longer half-lives re-
ported in elderly patients (dextropropoxyphene 24
to 50h, norpropoxyphene 25 to 76h).[166] After re-
peated doses, the accumulation of norpropoxy-
phene may be responsible for some of the observed
toxicity, such as cardiac dysrhythmias.[165,167-169]
Patients with cardiac diseases may be at a higher
risk for this adverse effect.
2.4.2 Effect of Liver Disease
After oral administration of dextropropoxy-
phene in patients with cirrhosis, plasma concentra-
tions of dextropropoxyphene were considerably
higher and norpropoxyphene concentrations were
much lower than in control patients.[170] This is
probably because of a decreased first-pass metabo-
lism of orally administered dextropropoxyphene
in these patients. The AUC ratio of norpropoxy-
phene : dextropropoxyphene was significantly lower
in patients with cirrhosis (0.5 to 0.9) than in con-
trols (2.5 to 4)[170,171] and was significantly corre-
lated with the liver function.[171] The reduction of
norpropoxyphene generation may reflect both
Clin Pharmacokinet 1999 Jul; 37 (1)
26
porto- systemic shunting and reduced liver enzyme
capacity.
Patients with cirrhosis, unlike healthy individuals,
experienced considerable sedation after oral dextro-
propoxyphene,[170] probably because of increased
bioavailability. Several cases of hepatotoxicity
with jaundice, upper abdominal pain and malaise
attributable to dextropropoxyphene have been re-
ported.[172-175] The histological changes seen at bio-
psy consisted of centrilobular cholestasis, portal
tract inflammation and bile duct abnormalities,
mimicking large bile duct obstruction.[172] Dextro-
propoxyphene, therefore, should be avoided in pa-
tients with hepatic insufficiency.
2.5 Codeine
2.5.1 Pharmacokinetics
Codeine, which is chemically methylmorphine,
is a naturally occurring phenanthrene alkaloid. Co-
deine is principally metabolised by the liver to co-
deine-6-glucuronide (approximately 60%) which
is excreted by the kidneys.[25] The drug also under-
goes N-demethylation to norcodeine.[176] A small
fraction (about 10%) of codeine is O-demethylated
to morphine.[176] Both morphine and its glucuronide
conjugates can be found in the urine after therapeu-
tic doses of codeine.[177]
Only 4 to 12% of a given codeine dose is ex-
creted unchanged in urine.[176,177] Codeine has an
exceptionally low affinity for opioid receptors.[178]
Its analgesic effect is thought to be caused by its
conversion to morphine.[179-183] However, its anti-
tussive actions might involve distinct receptors that
interact with codeine itself.[184] Probably because
of first-pass metabolism, morphine : codeine AUC
ratios were greater after oral than intramuscular ad-
ministration.[25]
The bioavailability of orally administered codeine
is approximately 50 to 55%.[25,26,185] In plasma,
less than 10% of codeine is bound to proteins.[164]
Codeine has a Vd of 3 to 4 L/kg. The t1⁄2β is 2 to 4
hours.[26,27]
2.5.2 Effect of Liver Disease
As mentioned in section 2.5.1, codeine analge-
sia requires the formation of morphine.[179,180] The
© Adis International Limited. All rights reserved.
Tegeder et al.
O-demethylation of codeine to morphine is catalysed
by the genetically polymorphic CYP2D6,[179,180,186]
which is expressed in phenotypes, the most impor-
tant of which are extensive (EMs) and poor (PMs)
metabolisers of sparteine and debrisoquine. PMs
account for about 7% of the healthy Caucasian pop-
ulation. PMs produce only trace amounts of mor-
phine and, therefore, no analgesia is achieved after
the administration of codeine.[180,182,187,188]
Conflicting results have been reported concern-
ing adverse drug reactions in EMs and PMs. In the
study of Poulsen et al.,[188] only EMs experienced
adverse drug reactions, whereas Eckhardt et al.[180]
found no difference between the phenotypes. Since
the oxidative enzyme capacity of the liver has been
shown to be impaired in patients with hepatic cir-
rhosis[4-8] it can be assumed that patients with cir-
rhosis will experience little or no analgesia from
codeine. Even worse, the use of codeine in these
patients might expose them to the adverse effects
caused by codeine itself. However, this is chal-
lenged by reports that the CYP isoenzymes are af-
fected to a different extent by cirrhosis,[189,190] with
CYP2D6 being relatively spared.[190] Thus, until
data on the pharmacokinetics and analgesic effects
of codeine in patients with cirrhosis become avail-
able, alternative analgesics should be preferred in
these patients.
2.6 Dihydrocodeine
2.6.1 Pharmacokinetics
Dihydrocodeine has elimination pathways sim-
ilar to codeine, that is, glucuronidation and de-
methylation. In EMs of sparteine and debrisoquine
(CYP2D6), the following metabolites were recov-
ered in urine after oral administration of dihydro-
codeine 60mg: dihydrocodeine glucuronide (27.7%),
nordihydrocodeine (15.8%), nordihydrocodeine
glucuronide (6.3%) dihydromorphine (0.5%) and
dihydromorphine glucuronide (8.4%). Approxi-
mately 30% of the dihydrocodeine dose was excreted
unchanged in the urine.[191] In PMs of sparteine,
dihydrocodeine O-demethylation to dihydromor-
phine was found to be impaired.[191]
Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease
Orally administered dihydrocodeine undergoes
extensive first-pass metabolism, resulting in a bio-
availability of approximately 20%.[34] The half-life
varies between 3.3 and 4.5 hours.[34]
2.6.2 Effect of Liver Disease
In contrast to codeine, quinidine, an inhibitor of
CYP2D6, did not change the effects of dihydro-
codeine on pain thresholds.[192] From that it was
concluded that dihydrocodeine produces analgesia
independent of its biotransformation to dihydro-
morphine.[192,193] Patients with cirrhosis can, there-
fore, be expected to experience pain relief from
dihydrocodeine. However, since oral bioavailabil-
ity may be increased and hepatic clearance de-
creased in patients with cirrhosis, dihydrocodeine
should be used with caution in these patients.
2.7 Buprenorphine
2.7.1 Pharmacokinetics
Buprenorphine is a semisynthetic, highly lipo-
philic, opioid derived from thebaine which has
been categorised as a partial agonist at μ opioid
receptors. It appears to display a ceiling of its ef-
fects at high doses.
When administered orally, buprenorphine under-
goes extensive first-pass metabolism and its oral
bioavailability is insufficient to achieve analgesic
drug concentrations. Administered sublingually,
however, about 50 to 55% of a buprenorphine dose
may escape first-pass metabolism and enter the
systemic circulation.[19-21] Buprenorphine is meta-
bolised by glucuronidation and dealkylation pre-
dominantly in the liver to buprenorphine-3-glucu-
ronide, which is inactive, and norbuprenorphine,
which has an analgesic effect of approximately
one-fiftieth of that of the parent drug.[194] Both the
N-dealkylated and conjugated metabolites can be
detected in the urine (about 10% of a dose).[195]
However, most of the drug (approximately 80 to
90%) is excreted as its metabolites via the biliary
system,[195] and enterohepatic recirculation was
suggested.[195]
After intravenous administration, the t1⁄2β of
buprenorphine and norbuprenorphine have been
reported to be approximately 3 to 6 hours,[20,22] and
© Adis International Limited. All rights reserved.
27
approximately 35 hours,[19] respectively. About
96% of the circulating drug is bound to protein,[23]
and its Vd is 200 to 400L.[19,22,24]
2.7.2 Effect of Liver Disease
The N-dealkylation of buprenorphine to nor-
buprenorphine is catalysed by the hepatic CYP en-
zyme system, with CYP3A4 as the major isoen-
zyme.[196,197] Since it has been shown that the
expression of the CYP3A proteins is significantly
reduced in patients with severe chronic liver dis-
ease,[189] the metabolism of buprenorphine is sus-
pected to be altered in liver cirrhosis. Therefore,
dosage adjustments may be required in patients
with liver insufficiency. Until sufficient pharmaco-
kinetic data on buprenorphine and its metabolites
in patients with liver disease become available, the
drug should be used cautiously in these patients.
2.8 Pentazocine
2.8.1 Pharmacokinetics
Pentazocine acts as a κ agonist and a partial ag-
onist at μ opioid receptors. Its analgesic actions are
produced by the l isomer; the d-isomer has little
affinity for opioid receptors.
Pentazocine is well absorbed from the gastroin-
testinal tract, but first-pass metabolism in the liver
is extensive. Less than 20% of a dose of pentazo-
cine enters the systemic circulation after oral ad-
ministration.[60] The half-life in plasma is approx-
imately 3 hours[60,61] and the Vd is 4 to 5 L/kg.[60,61]
The action of the drug is terminated largely by
biotransformation in the liver, with only 5 to 8% of
a dose excreted unchanged in the urine. The meta-
bolites, products of the oxidation of the terminal
methyl groups and glucuronide conjugates, are ex-
creted largely by the kidney.[198] Individuals who
smoke metabolise pentazocine 40% more than
nonsmokers.[199] There is a considerable interindi-
vidual variability of the rate of pentazocine meta-
bolism. This may account for the variability of the
analgesic response, which has been found to be
quite unpredictable when the drug was adminis-
tered orally.[200]
Clin Pharmacokinet 1999 Jul; 37 (1)
28
2.8.2 Effects of Liver Disease
In patients with hepatic cirrhosis, a 2- to 3-fold
increase in the bioavailability of orally adminis-
tered pentazocine has been reported, i.e. approxi-
mately 70% of a given dose entered the circulation
in patients with cirrhosis compared with approxi-
mately 20% in a healthy control group.[8,201] Com-
pared with healthy individuals, systemic clearance
was approximately halved and t1⁄2β doubled, whereas
Vd was unchanged.[8,201] The AUC ratio between
patients with healthy liver function and patients
with cirrhosis (AUChealthy : AUCcirrhosis) was 2.0
after intravenous administration and 8.3 when pen-
tazocine was taken orally.[8]
Assuming that the total response is related to the
AUC, a remarkable increase of the effects of pen-
tazocine is expected in patients with cirrhosis, es-
pecially when the drug is given orally. This agrees
with the observations that hepatic insufficiency ap-
pears to predispose patients to more pronounced
pentazocine adverse effects (marked apprehension,
anxiety, dizziness and sleepiness).[202]
Because of a higher bioavailability, oral doses
of pentazocine should be reduced substantially in
patients with cirrhosis. When multiple oral or par-
enteral doses are required, administration intervals
should be lengthened or subsequent doses should
be reduced below the initial dose because of the
lower systemic clearance of the drug.[201]
2.9 Tramadol
2.9.1 Pharmacokinetics
Tramadol, a racemic mixture of 2 enantiomers,
is a synthetic 4-phenylpiperidine analogue of co-
deine. It is a central analgesic with low affinity for
opioid receptors. Its analgesic effects result in large
part from activation of monoaminergic spinal inhi-
bition of pain pathways.[203,204]
Oral tramadol is rapidly absorbed, with a bio-
availability of 65 to 75%. Cmax is reached within 2
hours. Plasma protein binding is 20% and Vd about
200 to 300L.[30,76]
Tramadol undergoes extensive biotransforma-
tion in the liver via 2 main metabolic pathways to
O- and N-demethylated compounds. The O-de-
© Adis International Limited. All rights reserved.
Tegeder et al.
methylated compounds undergo further sulpha-
tion or glucuronidation.[205] 5 metabolites arising
from phase I reactions and 6 from phase II reactions
are known.[205] The main metabolite (M1), O-
demethyl-tramadol, is an agonist at the μ opioid
receptor with a higher affinity than the parent com-
pound.[178] Tramadol and its metabolites are
mainly excreted via the kidneys (90%); the remain-
ing 10% appear in faeces.[205] Approximately 15%
of a dose of tramadol is excreted unchanged in the
urine.[205] The t1⁄2β of tramadol and its O-demethyl
derivative (M1) were reported to be 5 to 6 and 9
hours, respectively.[30,76,206,207] Pharmacokinetic
differences between the enantiomers have not been
reported.
2.9.2 Effects of Liver Disease
O-Demethylation of tramadol to the active M1
metabolite seems to depend on the polymorphic
enzyme CYP2D6.[206] O-Demethyl-tramadol has a
higher affinity for opioid receptors than tramadol
itself, and has been shown to have analgesic activ-
ity in mice and rats as assessed by the tail flick
response.[178] In PMs of sparteine, analgesic effects
of tramadol on experimental pain were reduced
compared with those seen with EMs.[208] From that,
it was concluded that the opioid activity of tramadol
may well be a consequence of the metabolism of
the parent drug to the active demethylated metabo-
lite.[208] Since the oxidative enzyme capacity ap-
pears to be reduced in patients with liver cirrhosis,
the analgesic activity of tramadol might be less
than expected in patients with severe liver disease.
However, this has not yet been shown directly.
The plasma concentration and t1⁄2β of tramadol
in patients with liver cirrhosis was increased by a
factor of 2 to 3 compared with volunteers with
healthy liver function.[209] The same source reports
an increase in the renal clearance of unchanged
drug to 30% in these patients, compared with ap-
proximately 10% in healthy volunteers.
Since it is not yet known whether patients with
liver cirrhosis experience sufficient pain relief after
recommended doses of tramadol, and because of
the potential for delayed elimination and accumu-
lation of the drug, it appears advisable to consider
Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease
alternative agents until more information becomes
available.
2.10 Tilidine
2.10.1 Pharmacokinetics
Tilidine is a prodrug from which the active met-
abolite nortilidine is formed by demethylation,
mainly during first-pass metabolism in the liver
after oral administration of the drug.[59,210] The
systemic oral bioavailability is only about 6% for
the parent substance. About 99% is converted into
the active metabolite nortilidine.[59] Nortilidine is
further metabolised in the liver to bisnortilidine
and other polar compounds, which are eliminated
by the kidneys. Only 3% of an oral dose of tilidine
is recovered in the urine as nortilidine and less than
0.1% as tilidine.[59] The t1⁄2β of nortilidine and
bisnortilidine are 3.5 to 5 hours, and 5 to 7 hours,
respectively.[59]
Tilidine is often combined with naloxone as an
oral formulation in order to prevent intravenous
abuse. Because of a high first-pass metabolism,
naloxone normally does not reach the systemic cir-
culation after oral administration. Therefore, given
orally, it does not interfere with the analgesic effects
of nortilidine. However, with intravenous admin-
istration, the opioid agonistic affects of nortilidine
would be antagonised by naloxone.
2.10.2 Effects of Liver Disease
Data presented here were obtained from the
manufacturer.[211] In a nonblind single-dose trial,
the pharmacokinetic parameters of tilidine + nalox-
one were evaluated in 8 patients with compensated
hepatic cirrhosis. Compared with the results of pre-
vious studies in healthy individuals, the AUC (812
vs 993 μg/L • h in patients with cirrhosis and
healthy individuals, respectively) and the Cmax of
nortilidine (88.6 vs 158.0 μg/L) were reduced in
the patients with cirrhosis, whereas the t1⁄2β was
prolonged (9.9 vs 4.6h). In contrast to studies with
healthy individuals, naloxone could be measured
in plasma from patients with liver cirrhosis. Thus,
it can be assumed that the capacity for oxidative
metabolism of tilidine and for glucuronidation of
naloxone is reduced in these patients.
© Adis International Limited. All rights reserved.
29
Since the analgesic effects of tilidine depend on
demethylation to nortilidine, and since systemically
available naloxone antagonises analgesic effects of
nortilidine, it may be assumed that patients with
severe liver cirrhosis experience none, or only mi-
nor, analgesia after the administration of tilidine.
Although this assumption has not yet been confirmed
by clinical studies, it appears wise to use alterna-
tive analgesics in patients with severe liver disease.
2.11 Fentanyl
2.11.1 Pharmacokinetics
Fentanyl is a highly lipid-soluble synthetic op-
ioid related to the phenylpiperidines, and is com-
monly used as a supplement to general anaesthesia.
It is primarily a μ agonist and is estimated to be 80
times as potent as morphine as an analgesic.[212]
Following intravenous administration of fen-
tanyl, the onset of action is within one circulation
time, suggesting a rapid and extensive uptake by
the brain, the site of action.[213] The short duration
of effect (about 30 min) after the administration of
a single intravenous bolus dose is because of its
rapid redistribution from the sites of action in the
brain to storage sites (muscle and fat) and biotrans-
formation (liver).[213] With repeated administra-
tion, continuous infusion or high doses, accumula-
tion may lead to a prolonged duration of action.
The apparent Vd of fentanyl is about 3 to 5
L/kg[35,214] but has been shown to increase with
continuous infusion resulting in a prolongation of
the t1⁄2β.[215-217] Additionally, after prolonged con-
tinuous infusion of fentanyl, the duration of effect
may not be limited by redistribution, but by the
clearance of the drug which is much slower than
redistribution.[37] In plasma, about 85% of fentanyl
is bound to proteins, mainly to albumin (50 to
60%);[14,218] binding to AAG is of minor impor-
tance.[218]
The elimination of fentanyl from the body is
governed by its reuptake from storage sites and its
metabolism in the liver. Fentanyl undergoes N-
dealkylation and hydroxylation to compounds that
are both inactive and nontoxic. The main metabo-
lites, 4-N-(N-propionylanilino)-piperidine and 4-N-
Clin Pharmacokinet 1999 Jul; 37 (1)
30
(N-hydroxypropionylanilino)-piperidine, and a small
amount of unchanged drug (<10%) are excreted in
the urine.[38,219] Fentanyl is eliminated with a half-life
of about 3.5 hours,[35,36,38,220] but there is consider-
able variability interindividually.[221,222] In patients
undergoing cardiac[223,224] or abdominal aortic[39]
surgery, longer t1⁄2β values of 5 to 7 and 8.7 hours,
respectively, have been reported.
Studies investigating the pharmacokinetic and
pharmacodynamic relationship of the phenylpiper-
idine derivatives, however, suggest that a knowl-
edge of the terminal elimination half-life of the
drug is of limited value[225] because it does not help
to predict to what extent the concentration decline
of a drug might be prolonged after repetitive dos-
ages or drug infusion. Hughes et al.[226] therefore
proposed the use of a ‘context-sensitive half-time’,
defined as the time required for the plasma drug
concentration to decline by 50% starting from the
plasma concentration found at the end of the infu-
sion. The word ‘context’ refers to the infusion du-
ration. ‘Context-sensitive half-time’ means how
long it takes for the plasma concentration measured
at the end of an infusion of a certain duration to
drop by 50%.
2.11.2 Effects of Liver Disease
In patients with histologically confirmed he-
patic cirrhosis who underwent surgery, Haberer et
al.[35] found no change in the pharmacokinetics of
fentanyl compared with controls with healthy liver
and kidney function. However, none of the patients
had profound hepatic insufficiency, as indicated by
the clinical data of the patients presented in that
paper (normal serum albumin and total protein lev-
els, only minor reductions of the prothrombin time
in most patients).[35]
In patients undergoing abdominal aortic surgery,
Hudson et al.[39] reported a lower total body clear-
ance and larger Vd of fentanyl resulting in a pro-
longed t1⁄2β (8.7h), compared with previously reported
mean values (3 to 4h). The aortic cross-clamping
in that study might have altered the distribution and
elimination of fentanyl. Aortic cross-clamping ac-
tivates the renin-angiotensin system[227] which can
result in a decrease of the mesenteric and hepatic
© Adis International Limited. All rights reserved.
Tegeder et al.
blood flow.[228] Since fentanyl is a high-extraction
drug, its clearance will be relatively sensitive to
changes of liver blood flow.
The disposition of fentanyl appears to be rela-
tively unaffected by hepatic cirrhosis, although
pharmacokinetic alterations might occur with se-
vere liver dysfunction or reduced hepatic blood
flow. It is not yet known whether accumulation of
fentanyl during continuous infusion is more pro-
nounced in patients with liver cirrhosis compared
with patients with normal liver function.
2.12 Sufentanil
2.12.1 Pharmacokinetics
Sufentanil is a synthetic, highly lipophilic. op-
ioid chemically related to fentanyl. It is approxi-
mately 5 to 10 times more potent than fentanyl as
an analgesic.[229]
Sufentanil distributes rapidly and extensively to
all tissues, with a Vd of about 3 to 5 L/kg.[71,72,230]
In plasma, sufentanil is 90 to 93% bound to pro-
teins, mainly to AAG.[14,231] In neonates, protein
binding is only about 80% because of lower AAG
plasma levels.[232] Protein binding is independent
of sufentanil plasma concentration but is affected
by plasma pH. An increase in plasma pH from 7.4
to 7.8 decreases binding by 28%, and conversely,
lowering the pH increases the binding.[14]
Sufentanil is extensively metabolised by the
liver (hepatic extraction ratio 0.8) by N-dealkylat-
ion to products thought to be inactive, by O-de-
methylation to a metabolite possessing approxi-
mately 10% of the activity of the parent compound
and by some additional conjugation reactions. The
metabolites are found in both urine and faeces.
Only 1 to 2% of an injected dose of sufentanil is
recovered unchanged in urine.[233]
The t1⁄2β in patients who underwent general sur-
gery was reported to be about 3 hours[71,72,230] and
approximately 5 hours in adults undergoing car-
diac surgery.[234] However, the t1⁄2β might have been
underestimated because the duration of sampling
(8 hours or less) might have missed the last expo-
nential of the disposition function. In a study where
blood samples were taken up to 48 hours after the
Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease
administration of sufentanil, the terminal elimina-
tion half-life was approximately 13 to 16 hours.[73,235]
2.12.2 Effects of Liver Disease
In patients with liver cirrhosis undergoing sur-
gery, Chauvin et al.[74] found no change in sufen-
tanil kinetics compared with age-matched con-
trols. Plasma protein binding was similar in the
control group (91.7%) and in patients with cirrho-
sis (90.4%). However, neither the plasma albumin
nor AAG plasma levels in these patients with cir-
rhosis differed from those of the controls, which
may partly explain why the sufentanil free fraction
remained unaffected.
In addition to plasma protein concentrations,
binding of sufentanil may be influenced by pH
changes possibly leading to alterations of tissue
distribution. Sufentanil has a pKa of 8.0, and there-
fore at physiological pH only a small fraction (ap-
proximately 1.6%) is in the un-ionised form. With
alkalosis, which may occur in patients with severe
liver dysfunction because of elevated ammonia
levels, the proportion of the un-ionised form in-
creases and protein binding decreases. In neurosur-
gical patients undergoing hyperventilation, it has
been shown that an increase in the plasma pH from
7.37 in controls to 7.51 in the patients with hypo-
capnia resulted in an increase in the total Vd (5.4
vs 3.5 L/kg in controls) and a prolongation of the
t1⁄2β (3.9 vs 2.4h in controls).[236]
The results of Chauvin et al.[74] suggest that sin-
gle dose sufentanil should have a similar duration
of action in patients with cirrhosis and patients
with healthy liver function. In patients with cirrho-
sis with reduced plasma proteins or alkalosis, the
Vd and t1⁄2β might increase.
2.13 Alfentanil
2.13.1 Pharmacokinetics
Alfentanil is a very short acting opioid; its an-
algesic effects last 5 to 10 minutes after adminis-
tration of a single intravenous dose. Its analgesic
potency is only one-third to one-quarter of that of
fentanyl and it is less lipid soluble than fentanyl.
When compared with fentanyl and sufentanil, al-
fentanil has a faster equilibration between blood
© Adis International Limited. All rights reserved.
31
and brain (t1⁄2,ke0 0.96 min[237] compared with 6.6
and 6.2 min for fentanyl and sufentanil[238,239]),
which leads to a faster onset of effects. The Vd of
alfentanil is smaller than that of fentanyl, ranging
between 0.3 and 1 L/kg.[15,16,225,240-243] In plasma,
alfentanil is 88 to 92% bound to proteins, [14,244]
mostly to AAG.[14] This proportion is independent
of plasma alfentanil concentrations or changes in
plasma pH,[14] but may be affected by changes in
plasma levels of AAG.[244]
Alfentanil is almost exclusively eliminated by
metabolism. Only 0.4% of a dose is recovered in
urine as unchanged drug.[245] The main metabolic
pathways are oxidative N- and O-dealkylation,[243]
leading to inactive compounds that are cleared by
the kidneys.[243] The enzyme primarily responsible
for the metabolism is CYP3A4.[246] The estimated
hepatic extraction ratio of 0.3 to 0.5[247] suggests
that the total body clearance of alfentanil could be
influenced by changes in both hepatic blood flow
and intrinsic clearance. In contrast to fentanyl, the
duration of effect of a single dose of alfentanil de-
pends more on total body clearance than on redis-
tribution to tissues, probably because of its lower
lipid solubility when compared with fentanyl.
The t1⁄2β of alfentanil is approximately 1.5 hours
after a single intravenous dose.[15,16,225,241-243,248]
And with continuous infusion in critically ill patients
needing intensive care the t1⁄2β was 2.5 to 3
hours.[249-251]
2.13.2 Effects of Liver Disease
In patients with liver dysfunction, disposition of
alfentanil is affected in several ways. This con-
trasts to the reports of unaltered kinetics of fentanyl
and sufentanil in patients with cirrhosis. Ferrier et
al.[241] reported that patients with biopsy-proven
liver cirrhosis had an t1⁄2β of 3.65 hours compared
with 1.5 hours in controls, and plasma protein
binding was significantly reduced from 88.5% in
controls to 81.4% in patients with liver disease.
Similar results were demonstrated by Bower et
al.[240] The increase in the free fraction might be
attributable to lower AAG levels or alterations of
binding sites in patients with cirrhosis.[241] When
the pharmacokinetic parameters were corrected for
Clin Pharmacokinet 1999 Jul; 37 (1)
32 Tegeder et al.

protein binding, the unbound Vd and free drug
clearance were decreased significantly in both
studies.[240,241] These changes in pharmacokinetics
were observed in patients with a moderate degree
of hepatic insufficiency; a more delayed elimina-
tion can be expected in patients with pronounced
hepatic failure.
In patients with liver dysfunction, alfentanil
should be administered with caution. Its effects
may not only be prolonged but also enhanced, be-
cause of the increased free fraction of the drug.
2.14 Remifentanil
2.14.1 Pharmacokinetics
Remifentanil is a synthetic μ opioid agonist[252]
with an analgesic potency 20 to 30 times higher
than that of alfentanil.[237,253] Although chemically
related to the fentanyl family of short-acting 4-an-
ilidopiperidine derivatives, remifentanil is struc-
turally unique among currently available opioids
because of an ester linkage that is crucial to its
opioid activity. As an ester, remifentanil is suscep-
tible to hydrolysis by blood and tissue nonspecific
esterases, resulting in rapid metabolism to essen-
tially inactive compounds. The primary carboxylic
acid metabolite (GI-90291) had only 1/4600 of the
μ opioid agonist potency of the parent compound
in anaesthetised dogs.[254]
GI-90291 is eliminated primarily by renal ex-
cretion, with a t1⁄2β of approximately 1.5 to 2
hours[67,255] and steady-state plasma concentra-
tions about 12 times higher than those measured for
remifentanil.[67] In addition to ester hydrolysis as

Table III. Recommendations for prescribing opioids in patients with hepatic insufficiency
Drug Problem in liver disease Suggested action
Alfentanil Reduced protein binding. CL decreased by ~50% and t1⁄2β Reduce dose in patients with severe liver
prolonged dysfunction
Buprenorphine Insufficient data
Codeine O-Demethylation to form morphine, the active compound, may Do not use for analgesia
be reduced
Dextropropoxyphene Increased F of oral dextropropoxyphene. Several reports of Avoid in patients with liver disease
hepatotoxicity due to dextropropoxyphene
Dihydrocodeine Insufficient data
Fentanyl Pharmacokinetics of a single intravenous dose unaltered Normal single dose can be used. With
continuous administration, recovery time after
termination of the infusion may be prolonged
Methadone Prolongation of t1⁄2β and increase of Vd in patients with severe Normal dosage can be used in mild to moderate
hepatic dysfunction. Chronic alcohol abuse may increase liver disease. In severe liver dysfunction
methadone metabolism accumulation may occur
Morphine Reduced hepatic glucuronidation leads to an increase of oral F, Use with care in patients with severe liver
decrease of CL and prolongation of t1⁄2β cirrhosis and reduce oral dosage
Pentazocine 2- to 3-fold increase in F. CL reduced by ~50% and t1⁄2β doubled Use lower dosage or an alternative analgesic
Pethidine Reduced hepatic CL of pethidine and norpethidine resulting in Reduce oral dosage and avoid regular use
(meperidine) an increased F of oral pethidine and prolongation of t1⁄2β of
pethidine and norpethidine. Accumulation of norpethidine may
occur. Can cause seizures
Remifentanil Pharmacokinetics unaltered Normal dose can be used
Sufentanil Pharmacokinetics unaltered. Reduced protein binding with Normal dose can be used. Use with care when
alkalosis associated with an increase of Vd and t1⁄2β plasma pH is elevated
Tilidine Generation of the active compound nortilidine reduced (tilidine is Do not use as an analgesic in severe liver
a prodrug). Probably no analgesic effects cirrhosis
Tramadol Reduced generation of the main metabolite O-demethyl-tramadol Prefer alternative analgesic until analgesic
that appears to be responsible for some of the analgesic actions. activity of tramadol in patients with liver disease
t1⁄2β of tramadol and O-demethyl-tramadol approximately doubled has been confirmed
CL = clearance; F = oral bioavailability; t1⁄2β = terminal elimination half-life; Vd = volume of distribution.

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 Jul; 37 (1)
Opioids in Liver Disease
the major metabolic pathway, a minor proportion
of remifentanil undergoes N-dealkylation.[68]
Remifentanil distributes rapidly into tissues, as
indicated by the very short time required for equil-
ibration between blood and effect site (t1⁄2,ke0 0.75
to 1.3 min).[69,70,237] Its Vd is 25 to 40L, similar to
that of alfentanil (30 to 60 L/kg).[237,68-70] Its clear-
ance is about an order of magnitude higher than
that of alfentanil (about 180 vs about 18 L/h).[67,237]
Because of its high clearance and small Vd,
remifentanil has a very short t1⁄2β of 10 to 20 min-
utes.[67,256] As a result, recovery from the effects of
remifentanil is rapid and almost independent of
dose or duration of infusion.[68]
2.14.2 Effects of Liver Disease
Data on the influence of liver disease on the
pharmacokinetics of remifentanil are limited. In
patients awaiting liver transplantation, Dershwitz
et al.[257] showed that the disposition of remifen-
tanil was unaltered. Hepatic function in these pa-
tients was severely compromised, as indicated by
hypoalbuminemia, prolongation of prothrombin
time and portal hypertension. There were also no
differences in the disposition of the main metabo-
lite GI-90291 between the control group and pa-
tients with liver disease. However, in the hepatic
dysfunction group the remifentanil concentration
needed to depress CO2-stimulated ventilation by
50% was significantly reduced (1.56 vs 2.52 μg/L),
suggesting that the patients with liver disease were
more sensitive to the opioid effects of remifentanil.
Because the drug is cleared so rapidly, regardless
of the presence of liver disease, the apparent dif-
ference in sensitivity to the ventilatory depres-
sant effect of remifentanil is unlikely to cause
meaningful changes in the safety of the drug in the
recovery period. At present, dose adjustment of
remifentanil appears to be unnecessary in pa-
tients with hepatic dysfunction.
3. Conclusion
The relationship between liver impairment and
the use of opioid analgesics remains a complex
issue, partly because of the paucity of research for
some opioid analgesics such as dihydrocodeine,
© Adis International Limited. All rights reserved.
33
tramadol or tilidine. However, there is sufficient
evidence that the hepatic metabolism of morphine,
pethidine, pentazocine and alfentanil is signifi-
cantly reduced in patients with cirrhosis, leading to
changes in drug disposition that should be consid-
ered in dosage regimens. Table III summarises the
findings of the research to date and attempts to give
some practical advice. The choice of the most ap-
propriate drug and dose, however, depends on the
individual situation of the patient and the kind of
pain to be treated.
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Correspondence and reprints: Dr Gerd Geisslinger, Center of
Pharmacology, Institute of Clinical Pharmacology, Johann
Wolfgang Goethe-University, Theodor Stern Kai 7, 60590
Frankfurt am Main, Germany.
E-mail: geisslinger@em.uni-frankfurt.de
Clin Pharmacokinet 1999 Jul; 37 (1)