SPECIAL POPULATIONS Clin. Pha rmocokinet.

1996 Dec; 31 (6): 41 0-422

03 12-5963/ 96/001 2-D4 10/$06.5O/0

© Adis International Limited. All rights reseNed .

Pharmacokinetics of Opioids in
Renal Dysfunction
Graham Davies, Christopher Kingswood and Martin Street
University of Brighton and Royal Sussex County Hospital, Brighton, England

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . 410
1. Pharmacokinetic Properties of Opioid Analgesics in Individuals with
Normal Renal Function . . . . . . . . . . . . . . . . . . . . . . 411
2. Pharmacokinetic Properties of Opioid Analgesics in Patients
with Renal Insufficiency . . . . . . . 411
2.1 Morphine and its Metabolites . 411
2.2 Fentanyl . 414
2.3 Alfentanil .. . 415
2.4 Sufentanil .. 415
2.5 Remifentanil . 415
2.6 Codeine ... 416
2.7 Dihydrocodeine 417
2.8 Buprenorphine . 417
2.9 Pethidine (Meperidine) 417
2.10 Dextropropoxyphene (Propoxyphene) 418
2.11 Methadone 418
3. Conclusions . . . . . . . . . . . . . . . . . . . 418

Summary Patients with renal insufficiency commonly require the administration of an

opioid analgesic to provide adequate pain relief. The handling of morphine,
pethidine (meperidine) and dextropropoxyphene in patients with renal insuffi-
ciency is complicated by the potential accumulation of metabolites. While mor-
phine itself remains largely unaffected by renal failure, accumulation, as denoted by
an increase in both mean peak concentrations and the area under the concentration-
time curve, of both the active metabolite (morphine-6-glucuronide) and the prin-
cipal metabolite (morphine-3-glucuronide, thought to possess opiate antagonist
properties) have been reported. The increased elimination half-lives of the toxic
metabolites norpethidine and norpropoxyphene in patients with poor renal func-
tion administered pethidine and dextropropoxyphene, respectively, makes their
routine use ill advised.
Case reports of prolonged narcosis associated with the use of both codeine and
dihydrocodeine in patients with renal insufficiency call for care to be used when
prescribing these agents under such conditions. Although the pharmacokinetics
of buprenorphine, alfentanil , sufentanil and remifentanil change little in patients
with renal failure, the continuous administration of fentanyl can lead to prolonged
sedation.
Opioids in Renal Dysfunction
Opioid analgesics effectively control a spectrum
of different types of pain experienced by a diverse
patient population. However, pain is a very indi-
vidual response; effective pain relief, therefore, de-
mands a tailored approach to drug use to accommo-
date the variation in pain intensity, tolerance and
adverse effects experienced by patients. This can
best be achieved by an understanding of not only
the pharmacology of this group of agents but also
the likely impact of disease on their pharmacoki-
netic properties.
Research has described the importance of the
liver as a major site for the biotransformation of
these compounds, so that most prescribers demonstr-
ate caution when using opioids in patients with liver
dysfunction)l] However, although research has
shown a relationship between renal function and
the removal of some opioid metabolites, the area is
generally less well researched, resulting in a lack
of clear advice on how opioids should be used in
patients with renal impairment. This article reviews
the pharmacokinetics of the commonly used op-
ioids in patients with renal impairment and, where
possible, in those receiving conventional or contin-
uous renal support.
1. Pharmacokinetic Properties of
Opioid Analgesics in Individuals
with Normal Renal Function
While most opioids are well absorbed from the
gastrointestinal tract, their bioavailability is re-
duced, to some degree, by presystemic metabolism
in the gut wall or liver. Where systemic bioavaila-
bility is extensively reduced, as in the case of
buprenorphine where only 10% of the oral dose
reaches the systemic circulationp] administration
via the oral route is inappropriate. All opioids bind
to plasma proteins (both albumin and y-globulin)
although the extent varies from 7% (codeine) to
around 93% (sufentanil). Most opioids are readily
converted to more polar compounds, predomi-
nantly by the liver, although the extent of extrahep-
atic metabolism continues to be a focus for re-
search interest. Although these metabolites are
generally less active, some are more potent than the
© Adis International limited. All rights reserved.
411
parent compound (as with morphine-6-glucuronide)
while others produce adverse effects on accumula-
tion (as with norpethidine). While the majority of
metabolites are renally cleared, glucuronide conju-
gates may, in addition, be excreted via the biliary
system. Studies investigating the pharmacokinetic
properties of some of the commonly prescribed op-
ioids in individuals with normal renal function are
summarised in table I.l3-IS]
2. Pharmacokinetic Properties of
Opioid Analgesics in Patients with
Renal Insufficiency
2.1 Morphine and its Metabolites
2. 1. 1 Summary of Pharmacokinetics
Although morphine is widely distributed
throughout the body, great interindividual varia-
tion has been reported, ranging from a mean vol-
ume of distribution (Vd) of 1.1 Llkg in I study[16]
to 5.3 Llkg in another.[17] Morphine is highly ex-
tracted by the liver and undergoes rapid glucuron-
idation when administered parenterally and exten-
sive first-pass metabolism when given by mouth.
The high clearance (eL) values reported, for example
48 L· h- I in I study[ 18] to over 100 L. h- I in another, [9]
result in a short elimination half-life (tI/2~) of approx-
imately 2 hours.[9.10]
Two main metabolites have been described:
morphine-3-glucuronide (the principal metabolite)
and morphine-6-glucuronide which account for
approximately 40 and 10%, respectively, of the
morphine dose recovered in the urine following
intravenous administrationJ9,19] While morphine-
6-glucuronide is a more potent analgesic than mor-
phine,P 1,201 morphine-3-glucuronide has been shown,
in animal models, to antagonise the analgesic ef-
fects of both morphine[21] and morphine-6-glucu-
ronide. [22]
2.1.2 Effect of Renal Insufficiency
The main findings of studies involving patients
with renal failure and those requiring dialysis are
summarised in table 11.[ 18,23-29]
Several early reports, employing a specific radio-
immunoassay (RIA) technique to measure plasma
Clin. Pharmacokinet. 1996 Dec; 31 (6)
412 Davies et al.

Table I. Pharmacokinetic data for commonly used opioids in individuals with normal renal function
Dose (mg) n PB Cmax AUCo~ tl}z~ Cl Vss Reference
and route (%) (nmoVL) (nmoillo h) (h) (mllmin) (l)
Fentanyl
0.171V 7 83 3.1 5.46 335a 3
80 3.7 956 25 4
Alfentanil
O.UIV 7 79 1.6 0.84 27 3
Codeine
60 IV 6 4.0 1050a 244a 5
7 6
Pethidine
65-80 3-8 266a 7
Buprenorphine
0.3 IV 6 6.6 650.5 313 8
Morphine and metabolites
51V 10 273.2 ±65.2 228.7 ± 36.6 1.7 ± 0.8 1966±313 279.3 ± 99.5 9
M6G as a metabolite 10 79.5 ± 15.1 313.4 ± 87 2.6 ± 0.69 9
of morphine
0.12b1V 6 302.1 c ± 163.9 139.9d ± 48.9 2.0 ± 1.4 1057.4 ± 498.8 180.6 ± 81 .5 10
M6G as a metabolite 6 28.8c ± 16.1 96.7d ± 71.2 1.9± 1.3 10
of morphine
M6G
0.03b IV 6 155H ± 49.3 208.8d ± 55.4 2.1 ± 1.2 187.8 ± 37.4 29.4 ± 18.4 11
Sufentanil
0.005 b IV 10 92.5 2.7 ± 0.4 886 ± 55 a 122 ± 13a 12
Remifentanil
0.002-0.03 b IV 24 92 0.17-0.34 4117-4950 25-40 14,15
a Normalised for 70kg adult.
b mg/kg.
c ng/ml.
d ng/ml o h.
Abbreviations and symbols: AUCo~ = area under the concentration-time curve from zero to infinity; Cl = total body clearance of drug from
plasma; Cmax = peak plasma drug concentrations aiter a single-dose administration; IV = intravenous; M6G = morphine-6-glucuronide; n =
number of participants; PB =protein binding; tl2P =elimination half-life; Vss =apparent volume of distribution at steady-state.

concentrations, suggested that morphine accumu- of high-performance liquid chromatography has

lated in patients with renal failure[30-32] and led the
authors to postulate that the kidney may play an
important role in the metabolism of the drug. How-
ever the findings of other workers,[23,25,33] using
chromatographic analytical techniques, high-
lighted the problem of crossreactivity between the
parent compound and its metabolites when the RIA
technique was used.
This, therefore, cast doubt over the accuracy of
the plasma morphine concentrations measured in
earlier studies and consequently the clearance val-
ues reported. The speed, precision and specificity
subsequently made it the method of choice in the
analysis of morphine and its metabolitesp4]
More recent work has confirmed the accumula-
tion of the glucuronide metabolites in patients with
renal failure following the administration of intra-
venous morphine as a bolus dose (table II). Whilst
patients with end-stage renal disease (ESRD)
demonstrate a significant reduction in both mor-
phine Vd[26.27] and CL,[27] the difference in t1;2~ was
not significant when compared with healthy indi-
viduals. However, the maximum plasma concen-
trations and area under the concentration-time

© Adis International Limited . All rights reserved. Clin. Pharmacokinet. 1996 Dec; 31 (6)
Opioids in Renal Dysfunction 413

curve for both morphine-6-glucuronide and morphine-
3-glucuronide were significantly higher in patients
with ESRD when compared with those measured
in the control groups suggesting a decrease in
clearance of these metabolitesJ26.27] Subsequent
work has demonstrated a significant linear relation-
ship between creatinine clearance (CLCR) and the
renal clearances of both glucuronides,l35.36] Inter-
estingly, peritoneal dialysis appears to have no sig-
nificant effect on the pharmacokinetic behaviour of
morphine, morphine-3-glucuronide or morphine-
6-glucuronide when compared with patients with
ESRD.[27]
Other workers have demonstrated that the in-
creased plasma concentrations of the glucuronides
reported in patients with renal failure leads to a
significant increase in cerebrospinal fluid (CSF)
concentrationP7] The CSF morphine-6-glucuron-
ide concentrations, 24 hours post-dose, were up to
15 times greater in patients with renal failure, lead-
ing the authors to conclude that the accumulation
of morphine-6-glucuronide in the plasma, because
of renal failure, leads to progressive accumulation
in the CSF, which may partially explain the re-
ported sensitivity of renal failure patients to mor-
phine.[37]
Further evidence of the accumulation of mor-
phine-6-glucuronide when renal function is com-
promised is provided by a study of patients admin-
istered an intravenous bolus of the compound)29]
The authors compared the disposition of the drug
in patients with ESRD, those requiring peritoneal
dialysis and renal transplant patients with good
kidney function. The ty, was significantly shorter

Table II. Pharmacokinetic data for morphine and morphine-6-glucuronide (M6G) in patients with renal insufficiency
Dose n Renal AUCo~ tlr"p Cl Vss Reference
(mg) function (mg/l· h) (h) (mllmin) (l)
0.125" IV 11 NR 3.5 (1.7-7.4) 805b (539-1218) 196 (116-307) 18
0.125" IV 9 ESRD 3.2 (1.0-6.6) 721 (371 -1428) 126.7 (41.3-256.9) 18
13.3-15.3c 1M 3 NR 134.6 ± 14.3 2.2 ±0.1 1493b ± 163 281 b ± 30.1 23
10-14.7c 1M 4 ESRD 101 .5 ± 5.7 1.2 ± 0.2 1948b ±222 214b ± 38.5 23
0.2" IV 7 NR 3.1 ±0.9 1491 b ±441 259b ±84 24
0.2" IV 9 ESRD 3.1 ±0.9 1197b ± 294 196b ± 70 24
41V 6 NR 1.7±0.8 1960b ±392 280b ± 161 25
41V 7 ESRD 2.4±1.1 1477b ± 434 308b ± 119 25
10lV 5 NR 4.8±0.9 741 ± 169 240.8 ± 55.1 26
9 ESRD 4.8±3.2 533 ±298 140.9 ± 37.8 26
0.1" IV 10 NR 228.7d ± 36.6 1.7±0.8 1966±313 232.2 ±76.5 27
0.1" IV 8 ESRD 398d ± 95.2 2.3 ± 0.8 1171 ± 337 127.3 ± 19.4 27
0.1" IV 9 PO 469.1d ± 101.4 2.0 ± 0.4 971 ± 184 135.1 ±20 27
0.1" IV 9 Trans 302.1d±105.3 2.0±0.9 1596 ± 468 175.4 ±95.3 27
3.3" ± 1.41V 4 CAVH 5.7 ±3.1 1127b ± 504 28
0.03" (M6G) IV 6 ESRD 27.1 ± 15.8 10.6 ± 5.6 17.5b ±4.2 29
0.03 (M6G) IV 6 PO 17.3 ± 4.6 14.3±6.2 18.9b ±4.2 29
0.03 (M6G) IV 6 Trans 2.1 ±0.7 96.0 ± 34.9 13.3b ± 2.1 29
a mglkg.
b Normalised for 70kg adult.
c Papaveretum administered.
d nmolll· h.
e Morphine given as a continuous infusion.
Abbreviations and symbols: AUCo·_ = area under the concentration-time curve from time zero to infinity. CAVH = continuous arteriovenous
haemofiltration; Cl =total body clearance of drug from plasma; ESRD = end stage renal disease; 1M = intramuscular administration; IV =
intravenous administration; M6G =morphine-6-glucuronide; n =number of patients; NR =normal renal function ; PO =peritoneal dialysis;
hr"p =elimination half-life; Trans =post kidney transplant; Vss =apparent volume of distribution at steady-state.

© Adis Internaftonal Umited. All rights reserved. Clin. Pharmacokinet. 1996 Dec; 31 (6)
414
and the clearance significantly greater in the trans-
plant patients compared with both ESRD and peri-
toneal dialysis groups, but no difference in clear-
ance was found between the 2 renal failure groups
(ESRD and peritoneal dialysis). The clinical impli-
cations of this finding are, as yet, unresolved; how-
ever, it is interesting to note that no prolonged re-
spiratory depression was observed in the patients
studied.
Research investigating the profile of morphine
in critically ill patients suggests a complex rela-
tionship between the drug's pharmacokinetic and
pharmacodynamic profile and the severity of the
patients' condition. Although morphine clearance
appears to vary considerably in the presence of
acute renal failure, [28.38] the influence of critical ill-
ness and acute renal failure on the pharmacology
of the glucuronides has not been described. How-
ever, the influence of a variety of renal replacement
therapies on the clearance of both morphine and
morphine-6-glucuronide has been studied.l 28 .38]
Intermittent haemodialysis for between 3 and 5
hours produced significant falls in morphine con-
centrations; a mean of 75% (47 to 100%) when
combined with a period of haemofiltration and a
mean of 48% (24 to 84%) when dialysis alone was
used.l 28 ] In addition a significant correlation was
found between morphine tY2 and the haemofiltrate
volumes collected. Both continuous haemofiltra-
tion and continuous haemodiafiltration techniques
(commonly used in the management of acute renal
failure) appear to extract both morphine and mor-
phine-6-glucuronide efficiently.f3 8] The mean siev-
ing coefficient reported (a measure of the fraction
of the drug which is able to pass through the artifi-
cial kidney membrane) for morphine and mor-
phine-6-glucuronide exceeded 0.5 when either
technique was used. However, the authors con-
cluded that methods used to provide continuous
renal support make only a minor contribution to the
overall clearance of morphine (less than 1%) but
may be responsible for a larger proportion of mor-
phine-6-glucuronide clearance.!38]
Although morphine itself does not accumulate
in patients with renal failure, morphine-6-glucu-
© Adis International Umited. All rights reserved.
Davies et al.
ronide and morphine-3 -glucuronide clearly do.
Further data on the pharmacodynamics of both
glucuronides are required in order to establish their
relative clinical merits and the nature of their inter-
action with both morphine and each other. Until
such data become available, morphine should be
used with caution in patients with severe renal im-
pairment or those requiring renal replacement
therapy.
2.2 Fentanyl
2.2.1 Summary of Pharmacokinetics
Fentanyl is a potent, highly lipid-soluble, syn-
thetic opioid which is commonly used as an adjunct
to general anaesthesia. It has a short duration of
action (0.5 to 1 hours) when given as a single in-
travenous bolus because it is rapidly distributed,
metabolised and excreted (tY2 approximately 3.5
hours). Fentanyl is metabolised in the liver by N-
dealkylation and hydroxylation to compounds that
are both inactive and nontoxic. The main metabo-
lites, 4-N-(N-propionylanilo )piperidine and 4-N-
(N-hydroxypropionylanilo )piperidine are excreted
in the urine. Less than 10% of the drug is excreted
unchanged in the urine.
The pharmacokinetic properties of fentanyl
vary greatly within healthy volunteers!3] and pa-
tients,l39] Its initial short duration of action is
thought to be concentration-dependent, so that re-
peated doses lead to higher plasma concentrations
and consequently a longer duration of action.!40]
The second peak plasma concentration observed
following fentanyl administration was initially
thought to be caused by the enterohepatic recircu-
lation of the drug,f411 However, this hypothesis ap-
pears unlikely due to the high first-pass extraction
of the drug, and is probably related to the redistri-
bution of the drug from certain body stores.
2.2.2 effect of Renal Insufficiency
The clearance of fentanyl has been found to be
normal in surgical patients with renal failure,! 42 1
although studies involving the critically ill have
reported an increase in both tl/2 (25 hours) and Vd
(over 1700L).l43 1 No dosage modification appears
necessary when fentanyl is administered as a bolus
Clin. Pharmacokinet. 1996 Dec; 31 (6)
Opioids in Renal Dysfunction
dose in patients with ESRD, although it would ap-
pear prudent to closely monitor this group of pa-
tients for signs of intoxication when it is used as a
continuous infusion. Due to the reportedly increased
tY2 and the lack of data relating to the clearance of
fentanyl (when administered as a continuous in-
fusion), fentanyl should be used with caution in
critically ill patients with acute renal failure and
consideration should be given to the use of an alter-
native agent.
2.3 Alfentonil
2.3. 7 Summary of Pharmacokinetics
Alfentanil is a very short acting opioid with an
analgesic effect lasting between 5 and 10 minutes;
although related to fentanyl, it is less potent and
less lipid soluble. When compared with fentanyl it
possesses a faster onset and shorter duration of ac-
tion; a result of its smaller Vd (30L compared with
over 300L) and shorter tY2 (l.5 hours compared
with over 3 hours).[2 l
Alfentanil is metabolised in the liver, mainly by
N- and O-dealkylation,[44 l to inactive compounds
which are renally cleared.
2.3.2 Effect of Renal Insufficiency
Although patients with chronic renal failure ap-
pear to exhibit a reduced protein binding of alfen-
tanil, both Vd (28L in ESRD compared with 20L
in healthy individuals) and tY2 (l.8 hours in ESRD
compared with l.5 hours in healthy individuals),
values were found to be no different to values ob-
tained from patients with normal renal function) 45 l
Similar results have been reported elsewhere)46,47l
No alteration to the administration regimen of al-
fentanil is required for patients with renal impair-
ment.
2.4 Sufentonil
2.4. 7 Summary of Pharmacokinetics
Sufentanil is a highly potent thienyl analogue of
fentanyl. It is up to 10 times as potent as fen-
tanyl[ 48 l and more lipophilic (partition coefficient
between n-octanol and water of 1754, twice the
value quoted for fentanyl»)1 3l. It is rapidly distrib-
uted into most tissues, with 98 % of an injected dose
© Adis Internatio nal Limited. All rights reserved .
415
having left the plasma within 30 minutes.[12]
Sufentanil is highly protein bound (92.5%, mainly
to (XI-acid glycoprotein)[13] and has a large appar-
ent Vd (approximately 120L)[12] suggesting exten-
sive uptake of the drug into body tissues . The com-
pound is extensively metabolised by the liver
(hepatic extraction ratio = 0.8) by N-dealkylation,
to products thought to be inactive, O-demethyla-
tion, to a metabolite possessing approximately
10% of the activity of the parent compound, and
some additional conjugation)49] Although very lit-
tle sufentanil is excreted unchanged, the metabo-
lites are found in both the urine and faeces.
The t l/2~ of sufentanil (approximately 3 hours)[12,50]
is greater than values reported for alfentanil but
less than those offentanyl; some variation has been
observed in patients undergoing cardiac surgery
(approximately 10 hours)[ 5I l and hyperventilated
surgical patients (approximately 4 hours»)52 l
2.4.2 Effect of Renal Insufficiency
Although a case report observed that a patient
with ESRD experienced prolonged postoperative
respiratory depression as a result of elevated
plasma concentrations of sufentanil,[ 49 l other stud-
ies have found no significant differences between
the clearance, t Y2 ~ or apparent Vd at steady-state
(V d ss ) of the drug when comparing patients with
ESRD to those possessing normal renal func-
tion. [53.55l One study[53l has suggests that, because
of the wide variability in both clearance and tl/2~
observed in their study,[53] administration of
sufentanil should be individualised in patients with
renal failure . However, this variation may, in part,
be explained by the population studied, namely,
patients aged between 10 and 15 years.
2.5 Remifentonil
2.5. 7 Summary of Pharmacokinetics
Although remifentanil is another fentanyl de-
rivative its unique structure makes it a novel agent
within the phenylpiperidine group of drugs. The
incorporation of a methyl ester into the N-acyl moi-
ety renders it susceptible to hydrolysis by blood
and tissue nonspecific esterases. This structural
manipulation makes remifentanil the first ultra-
Clin. Pharmaco kinet. 1996 Dec; 31 (6)
416
short-acting opioid available to supplement gen-
eral anaesthesia. It is rapidly de-esterified to the
primary carboxylic acid metabolite (GI-90291)
while N-dealkylation (to carboxylic acid) is only a
minor metabolic pathway in humans.f 56 ] Approxi-
mately 90% of the drug is recovered in the urine as
the carboxylic acid metabolite.f 57 ] This is consider-
ably less active than its parent compound (it pos-
sesses only 0.1 to 0.3% of the relative potency of
remifentanil), but mean steady-state plasma con-
centrations have been reported to be 12 times greater
than those measured for remifentanil.[l4]
A recent study investigating the pharmacokinet-
ics of remifentanil in patients receiving elective
surgery[14] assigned individuals to 4 groups (of 6
patients) in order to compare different remifentanil
doses (2,5, 15 and 30 Ilg/kg) administered as a I-min-
ute infusion. The pharmacokinetics of remifentanil
were described using a 3-compartment model.
Clearance was found to lie between 4 and 5 Llmin,
apparent Vd ss between 25 and 40L and the terminal
tl/2 between 10 and 21 minutes. Both CL and V dss
were independent of dose while CL was not signif-
icantly affected by body weight or gender. The tl/2
of the carboxylic acid was found to lie between 88
and 137 minutes.
2.5.2 Effect of Renal Insufficiency
A recent study compared the pharmacokinetics
of remifentanil (administered as an infusion over 4
hours) in patients receiving renal dialysis and
healthy volunteers. The authors concluded that re-
nal failure had no significant effect on the pharmaco-
kinetics of remifentanil, with no significant differ-
ence between the 2 groups for both CL or Vd values,
although the terminal tl/2P of the metabolite carbo-
xylic acid was significantly longer in the group
with renal failure.[58] Shlugman and colleagues[59]
reported that patients with renal failure [defined as
a CLCR of < 1.8 Lih «30 ml/min)] are not more
sensitive to the respiratory depressant effects of
remifentanil and suggested that it may be an ideal
agent for use in such patients.
2.5.3 Phenylpiperidine Derivatives: A Special Note
Recent work investigating the pharmacokinetic
and pharmacodynamic relationship of the phenyl-
© Adis International Limited. All rights reserved.
Davies et al.
piperidine derivatives in attempting to achieve a
balanced anaesthesia suggests that a knowledge of
the (l/2P of the drug is of limited value.[60] The au-
thors suggest that using computer simulations to
select an appropriate agent based on the pharmaco-
kinetic and pharmacodynamic properties of the
drugs, together with a knowledge of the intended
duration of infusion, may be a more rational ap-
proach, although more reliable measures of opioid
effect during general anaesthesia need to be devel-
oped.
2.6 Codeine
2.6.7 Summary of Pharmacokinetics
Codeine, a naturally occurring phenathrene al-
kaloid, is principally metabolised by the liver to
codeine-6-glucuronide.f 61 ] The drug also under-
goes N-demethylation to norcodeine, which has a
similar potency to the parent drug, and approximately
10% of the drug is desmethylated to morphine.[62]
The terminal tl/2of codeine in healthy volunteers
lies between 2.5 and 3.5 hours[63] with only 3 to
16% of the parent drug being excreted unchanged
in the urine.f 64 ] Codeine is less than 10% protein
bound[6J with a Vd of between 3 to 4 Llkg.
2.6.2 Effect of Renal Insufficiency
Codeine is known to cause profound hypoten-
sion[65] as well as both central nervous system
(CNS) and respiratory depression. [66] Patients with
renal failure given conventional doses of codeine
have been reported to develop narcosis.[67,68]
Guay et aI.l5] studied the removal of codeine in
6 patients receiving haemodialysis and 6 healthy
volunteers, The tyzPof codeine was found to be 18,7
+ 9,0 hours in the haemodialysis group compared
with 4 + 0.6 hours in those individuals with normal
kidney function.
This unexpected accumulation of codeine in re-
nal failure may represent not only a change in the
pharmacokinetic properties of the drug but also an
enhanced dynamic response. The influence of both
conventional and continuous renal replacement
therapies on the removal of codeine is unknown.
Clin. Pharmac okinet. 1996 Dec; 31 (6)
Opioids in Renal Dysfunction 417

2.7 Dihydrocodeine longer t \l2 (but not statistically significant) in those

with normal renal function (mean 6.6 hours) com-
2.7. 1 Summary of Pharmacokinetics
pared with those with renal impairment (mean 4
Dihydrocodeine is thought to have similar elim-
hours). Plasma concentrations of the metabolites,
ination pathways to codeine, via glucuronidation
particularly buprenorphine-3-glucuronide, increase
and demethylation in the liver, although this has
dramatically in patients with significant renal im-
not been fully evaluated. Rowell et aJ.l69) reported
pairment. The 4-fold rise in the plasma concentra-
a mean v/,~ of 3.9 hours in patients with normal
tion of norbuprenorphine, the active metabolite,
renal function.
in renal failure patients is unlikely to result in clin-
2.7.2 Effect of Rena//nsufficiency ically significant prolongation of the drug's action.
Although the renal clearance of dihydrocodeine
has not been measured, reports exist of prolonged 2.9 Pethidine (Meperidine)
narcosis in patients with renal failure taking the
2.9. 1 Summary of Pharmacokinetics
drug.l70.7I) Both patients described in the case re-
Pethidine was one of the first synthetic opioid
ports responded to multiple doses of naloxone. In
analgesics to be used in clinical practice and is less
a pharmacokinetic study of oral dihydrocodeine,
potent than morphine itself. It is subject to exten-
Barnes et al.[72) found similar tl/2~ in patients with
sive first-pass metabolism with a mean oral bio-
renal failure compared with normal individuals.
availability of 56%.[73) The drug is demethylated
However, the authors observed significantly
in the liver to its sole active metabolite norpethid-
higher peak plasma concentrations and AUC in re-
ine, which is either further hydrolysed to norpeth-
nal failure patients. They postulated that this find-
idinic acid and its conjugates or excreted un-
ing may reflect a reduction in the systemic clear-
changed in the urine.[74) Some of the drug is also
ance of the drug or an increase in its bioavailability.
hydrolysed to pethidinic acid. Although less than
The administration of therapeutic doses of di-
5% of an administered dose of the parent drug is
hydrocodeine, appropriate for those with normal recovered from the urine at normal pH «5%),[75)
renal function, to patients with renal failure may, in
acidification of the urine increases the recovery of
some patients, result in adverse effects developing.
both pethidine and norpethidine,l76)
Pethidine is extensively protein bound (be-
2.8 Buprenorphine
tween 60 and 80%), mainly to <Xl-acid glycopro-
2.8.1 Summary of Pharmacokinetics tein,(77) has a large Vd (4 to 5 Llkg) and a t\l2 of
This is a partial opioid agonist, 30 times more approximately 3.5 hours. l77 ) The terminal t \l, of
potent than morphine. It undergoes extensive first- norpethidine ranges between 14 and 21 hours in
pass metabolism when administered orally. It is individuals with good renal function.l 78 )
metabolised, by glucuronidation and dealkylation,
2.9.2 Effect of Rena/Insufficiency
in the liver to produce buprenorphine-3-glucuron-
Although the terminal t\l2 of pethidine appears
ide, which is inactive, and norbuprenorphine
to be unaffected by changes in renal function,
which is 40 times less potent than the parent drug.
norpethidine clearance is significantly correlated
Both products are principally excreted via the bil-
with CLCR l79) and consequently accumulates in re-
iary system.
nal failure patients (terminal t\l2 of 35 hours).[78)
2.8.2 Effect of Rena//nsufficiency Although norpethidine is a CNS depressant,
A recent study comparing the clearance of intra- possessing twice the proconvulsant potency of
venous buprenorphine, both single bolus and con- pethidine,(77) individual susceptibility to the cen-
tinuous infusion, in patients with impaired and nor- tral effects of stupor and convulsions varies. For
mal renal function reported no significant difference example, in a study of 9 patients with moderate to
between the 2 groups. [7) The authors reported a severe renal failure (serum creatinine 300 to 2160

© Adis International Limite d. All rights reserve d. Clin. Pharmaco kine t. 1996 Dec; 31 (6)
418
mmoIlL), only 2 patients developed seizures. One
had mild and the other severe renal impairment.[SO]
Kaiko et aUSl] studied 48 patients with
norpethidine-induced neurological adverse effects.
Although 14 of this group had some degree of renal
impairment (as measured by raised urea level),
only 5 of the 10 patients who experienced a seizure
were from this group. The authors commented that
although renal failure may predispose patients re-
ceiving pethidine to neurological problems, other
factors (such as the degree of exposure and plasma
norpethidine : pethidine ratios) may be as impor-
tant. One fatality, due to seizures associated with
high norpethidine plasma concentrations, has been
reported in an addict with renal failure who re-
ceived repeated doses of the drug.f s2 ]
Although little research has been undertaken, it
would seem wise to use pethidine with caution in
patients with renal failure. Whilst the administra-
tion of a single dose appears to carry little risk for
patients with renal failure, its administration on a
regular basis should be avoided. Pethidine clear-
ance in patients receiving conventional or contin-
uous dialysis has not been studied.
2.10 Dextropropoxyphene
(Propoxyphene)
2. 10.1 Summary of Pharmacokinetics
Dextropropoxyphene is structurally similar to
methadone and is commonly used, in combination
with paracetamol, for the control of mild-to-mod-
erate pain. The drug is primarily demethylated in
the liver to yield, norpropoxyphene which is ex-
creted by the kidneys.[S3] The terminal tl/2 of the
parent compound and metabolite range between
11.8 and 14.6 hours and 22.9 to 36.6 hours, respec-
tively.f s4 ,S5] Dextropropoxyphene is approximately
80% protein bound and is widely distributed (Vd
16 Llkg).f6]
2. 10.2 Effect of Renal Insufficiency
The peak plasma concentrations and AUe for
both dextropropoxyphene and norpropoxyphene
have been reported to be increased in anephric pa-
tients.[S6] While the tl/ 2 of norpropoxyphene was
prolonged, that for dextropropoxyphene remained
© Adis International Limited. All rights reserved.
Davies et al.
unchanged. [S4] The authors postulated that a reduc-
tion in presystemic clearance may explain the in-
creased AUe reported for dextropropoxyphene.
Studies involving animals have shown that the ac-
cumulation of dextropropoxyphene can cause both
eNS and respiratory depression, while both com-
pounds, in overdose, contribute to the depressed
cardiac conduction witnessed.[S7]
Haemodialysis appears to inefficiently remove
dextropropoxyphene and its metaboliteJSSl The re-
moval of the drug by other renal replacement tech-
niques has not been studied.
2.11 Methadone
2. 11. 1 Summary of Pharmacokinetics
Unlike many opioid analgesics, methadone pos-
sesses a high oral bioavailability (mean of approx-
imately 80%),[S9] is highly protein bound (between
71 and 87%)[90] and has an t1/2~ in excess of 30
hours.[91] Methadone is metabolised, mainly by N-
methylation, in the liver to 1,5-dimethyl-2-ethyl-
3,3-diphenyl-1-pyrroline, the main metabolite.
However, renal excretion of the unchanged drug is
an important route of methadone elimination, ac-
counting for approximately 20% of an adminis-
tered single oral doseJ92] The majority of metha-
done (as the metabolite) is excreted in the faeces.
2.11 .2 Effect of Renal Insufficiency
In a case report detailing 2 patients with chronic
renal failure receiving maintenance methadone
therapy, the plasma concentrations reported were
similar to those seen in patients with normal renal
functionJ93] This has led to speculation that pa-
tients with poor renal function are able to effec-
tively eliminate methadone (as the primary meta-
bolite) by increasing the quantity excreted through
the faeces. Until studies have been undertaken to
confirm this hypothesis some authors recommend
that the dose of methadone administered in ESRD
should be reduced by up to 50% of normaU6]
3. Conclusions
The relationship between renal impairment and
the use of opioid analgesics remains a complex is-
sue because of the paucity of research. Sufficient
Clin. Phormac okinet. 1996 Dec; 31 (6)
Opioids in Renal Dysfunction 419

Table III. Recommendations for prescribing opioids in patients with renal insufficiency
Drug Problem in renal insufficiency
Pethidine Active metabolite (norpethidine) accumulates. Can cause
seizures
Dextropropoxyphene Both parent compound and its main metabolite
(norpropoxyphene) accumulate in renal insufficiency. May
cause CNS or respiratory depression or cardiotoxicity
Morphine Accumulation of morphine-6-glucuronide, a metabolite more
potent (as an analgesic) than morphine and renally cleared
Fentanyl Prolonged sedation may occur when continuously
administered to patients with chronic renal failure
Codeine Case reports of patients with renal failure developing narcosis
Buprenorphine No significant changes in pharmacokinetic parameters in
patients with renal insufficiency
Methadone Potential for accumulation of methadone and its primary
metabolite in renal failure. Postulated increase in faecal
excretion of methadone in patients with renal insufficiency
Dihydrocodeine Reports of raised peak plasma concentrations and AUC in
patients with renal failure, although t;;.~ remained the same
as for patients with normal renal function. Prolonged narcosis
reported in some patients with renal failure
Remifentanil No significant changes reported in the pharmacokinetics of
remifentanil in patients with renal failure. Accumulation of
active metabolite [carboxylic acid metabolite (GI-90291);
0.1-0.3% potency of remifentanil] in patients with renal
impairment. However, the degree of accumulation is unlikely
to result in the patient experiencing significant pharmacological
effects
Sufentanil No significant changes in pharmacokinetic parameters in
patients with renal failure. Possible accumulation of less
potent metabolite (desmethyl-sufentanil; 10% activity of
sufentanil). Clinical significance of such accumulation is
unknown
Alfentanil Reduced protein binding
Abbreviations: AUC = area under the concentration-time curve; CRRT = continuous renal replacement therapies; ESRD = end-stage renal
disease; IHD = intermittent haemodialysis; PD = peritoneal dialysis; tlf.1~ = elimination half-life.
Suggested action
Avoid regular use of conventional doses on
patients with ESRD, IHD, PD and CRRT
Avoid use in patients with ESRD, IHD, PD and
CRRT
Use with care in patients with ESRD, IHD, PD
andCRRT
When continuous administration is required in
patients with poor renal function close
monitoring is required. Consider use of an
alternative agent
Use lower doses or an alternative analgesic for
patients with renal insufficiency
Normal dose can be used
Reduce dose by up to 50% in ESRD or
dialysis patients
Use lower doses or an alternative analgesic for
patients with renal insufficiency
Rapid breakdown of remifentanil by plasma
and tissue esterases makes it potentially the
ideal agent for use in patients with renal
insufficiency
Case report of prolonged respiratory
depression in a patient with chronic renal
failure. Use with caution in such patients until
further information on the use of sufentanil in
patients with renal failure becomes available
Its short duration of action and lack of active
metabolites make it an ideal agent for use in
patients with renal impairment

evidence exists, especially in relation to morphine, Acknowledgements

to suggest that patients with renal insufficiency
are more sensitive to the effects of these agents.
This increased sensitivity may, in part, result from
the accumulation of active metabolites in addition
to the pharmacokinetic changes conferred on the
parent compound by renal impairment itself.
Although table III attempts to summarise the
findings of the research to date, dosage regimens
should always be titrated against the response of
the individual patient.
We acknowledge Mrs S. Gotham for preparation of the
manuscript, and 2 anonymous referees for helpful comments
on an earlier draft.
References
I. Corall I, Williams R. Management of liver failure. Br J Anaesth
1986;58: 234-45
2. Hughes TJ. A pharmacological basis to the rational use of potent
analgesics. Hosp Update 1988 Nov; 14 (II): 2159-69
3. Bower S, Hull CJ. Comparative pharmacokinetics of fentanyl
and alfentanil. Br J Anaesth 1982; 54: 871-7

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1996 Dec; 31 (6)
420
4. McClain DA , Hugg Cc. Intravenous fentanyl kinetics. Clin
Pharmacol Ther 1980; 28: 106-14
5. Guay DRP, Matzke GR, Findlay JWA: et al. Codeine pharma-
cokinetics and pharmacodynamics in hemodialysis patients
[abstract]. Clin Pharmacol ther 1987; 41 : 222
6. Jusko WJ, Gretch M. Plasma and tissue protein binding of drugs
in pharmacokinetics. Drug Metab Rev 1976; 5: 43-140
7. Bennett WM, Aronoff GR, Morrison G, et al. Drug prescribing
in renal failure: dosing guidelines for adults. Am J Kidney Dis
1983; 3: 155-93
8. Hand CW, Sear JW, Uppington J, et al. Buprenorphine disposi-
tion in patients with renal impairment: single and continuous
dosing with special reference to metabolites. Br J Anaesth-
esiol 1990; 64: 276-82
9. Osborne R, Joel S, Trew D, et al. Morphine and metabolite
behavior after different routes of morphine administration:
demonstration of the importance of the active metabolite mor-
phine-6-glucuronide. Clin Pharmacol Ther 1990; 47: 12-9
10. Hanna MH, Peat SJ , Knibb AA, et al. Disposition of morphine-
6-glucuronide and morphine in healthy volunteers. Br J An-
aesth 1991 ; 66: 103-7
II. Hanna MH , Peat SJ , Woodham M, et al. Analgesic efficacy
and CSF pharmacokinetics of intrathecal morphine-6-glu-
curonide: comparison with morphine. Br J Anaesth 1990;
64: 547-50
12. Bovill JG, Sebel PS, Blackburn CL, et al. The pharmokinetics
of sufentanil in surgical patients. Anesthesiology 1984; 61:
502-6
13. Meuldermans WEG, Hurkmans RMA, Heykants JJP. Plasma
protein binding and distribution of fentanyl, sufentanil , al-
fentanil and lofentanil in blood. Arch Int Pharmacodyn Ther
1982; 257:4-19
14. Westmoreland CL, Hoke JF, Sebel PS, et al. Pharmokinetics of
remifentanil (GI87084B) and its major metabolite (GI9029I )
in patients undergoing inpatient surgery. Anesthesiology
1993; 79: 893-903
15. Lemmens HJM. Pharmacokinetic-pharmacodynamic relation-
ships for opioids in balanced anaesthesia. Clin Pharmacokinet
1995; 29 (4): 231-42
16. Moore A, Sear J, Baldwin D, et al. Morphine kinetics during
and after renal transplantation. Clin Pharmacol Ther 1984; 35:
641-5
17. Hoskin PJ, Hanks GW, Aherne GW, et al. The bioavailability
and pharmacokinetics of morphine after intravenous, oral and
buccal administration in healthy volunteers [abstract]. Br J
Clin Pharmacol 1989; 27: 499
18. Aitkinhead AR, Vater M, Achola K, et al. Pharmacokinetics of
single-dose IV morphine in normal volunteers and patients
with end-stage renal failure. Br J Anaesth 1984; 56: 813-9
19. Sawe J. Morphine and its 3- and 6-glucuronides in plasma and
urine during chronic oral administration in cancer patients. In :
Foley KM,lnturrisi CE, editors. Opioid analgesics in the man-
agement of cancer pain. New York: Raven Press, 1986: 45-55
20. Osborne R, Joel S, Trew D, et al. Analgesic activity of mor-
phine-6-glucuronide. Lancet 1988; II : 828
21. Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a
potent antagonist of morphine analgesia. Life Sci 1990; 47:
579-85
© Adis International Umited. All rights reserved.
Davies et al.
22. Watt JA, Cramond T, Smith MT. Morphine-6-glucuronide: an-
algesic effects antagonised by morphine-3-glucuronide [ab-
stract]. Clin Exp Pharmacol Physiol 1990; 17: 83
23. Woolner DF, Winter D, Frendin TJ, et al. Renal failure does not
impair the metabolism of morphine. Br J Clin Pharmacol
1986; 22: 55-9
24. Chauvin M, Sandouk P, Scherrmann JM , et al. Morphine
pharmacokinetics in renal failure. Anesthesiology 1987;
66: 327-31
25. Sawe J, Odar-Cederlof I. Kinetics of morphine in patients with
renal failure. Eur J Clin Pharmacol 1987; 32: 377-82
26. Sear JW, Hand CW, Moore RA, et al. Studies on morphine
disposition: influence of renal failure on the kinetics of mor-
phine and its metabolites. Br J Anaesth 1989; 62: 28-32
27. Osborne R, Joel S, Grebenik K, et al. The pharmokinetics of
morphine and morphine glucuronides in kidney failure. Clin
Pharmacol Ther 1993; 54: 158-67
28. Bion JF, Logan BK, Newman PM, et al. Sedation in intensive
care: morphine and renal function . Intensive Care Med 1986;
12: 359-65
29. Hanna MH, D'Costa F, Peat SJ , et al. Morphine-6-glucuronide
disposition in renal impairment. Br J Anaesth 1993; 70: 511-4
30. Moore RA, Sear JW, Bullingham RES, et al. Morphine kinetics
in renal failure. In: Foley KM, Inturrisi CE, editors. Opioid
analgesics in the management of cancer pain. New York: Ra-
ven Press, 1986; 65-72
31. Ball M, McQuay HJ, Moore RA, et al. Renal failure and the use
of morphine in intensive care. Lancet 1985 Apr 6; I: 784-6
32. Shelly M, Park GR. Renal failure and use of morphine in inten-
sive care [letter]. Lancet 1985 May 1\; I: 1100
33. Osborne RJ, Joel SP, Slevin ML. Morphine intoxication in renal
failure : the role of morphine-6-glucuronide. BMJ 1986 Jun
14; 292: 1548-9
34. Glare PA, Walsh TD. Clinical pharmacokinetics of morphine.
Ther Drug Monit 1991; 13: 1-23
35. Milne RW, Nation RL, Somogyi AA, et al. The influence of
renal function on the renal clearance of morphine and its glu-
curonide metabolites in intensive-care patients. Br J Clin
Pharmacol 1992; 34: 53-9
36. Peterson GM, Randall CTC, Paterson J. Plasma levels of mor-
phine and morphine glucuronides in the treatment of cancer
pain: relationship to renal function and route of administra-
tion. EurJ Clin Pharmacol 1990; 38: 121-4
37. D' Honneur G, Gilton A, Sandouk P, et al. Plasma and cerebro-
spinal fluid concentrations of morphine and morphine glucu-
ron ides after oral morphine. Anesthesiology 1994 Jul; 81:
87-93
38. Davies JG, Coombes ID, Kingswood C, et al. The clearance of
morphine and morphine-6-glucuronide in critically ill pa-
tients receiving continuous renal replacement therapies [ab-
stract). J Pharm Pharmacol 1994; 46 Suppl2: 1045
39. Bentley JB, Borel JD, Nenad RE, et al. Age and fentanyl phar-
macokinetics. Anesth Analg 1982; 61: 968-71
40. Hug CC, Murphy MR. Fentanyl disposition in cerebrospinal
fluid and plasma and its relationship to ventilatory depression
in the dog. Anesthesiology 1979; 50: 342-9
41. Stoeckel H, Hengstmann JH, Schuttler J. Pharmacokinetics of
fentanyl as a possible explanation for recurrence of respira-
tory depression. B J Anaesth 1979; 51: 741-5
Clin. Pharmacokinet. 1996 Dec: 31 (6)
Opioids in Renal Dysfunction
42. Coral 1M, Moore AR, Strunin L. Plasma concentrations of fen-
tanyl in normal surgical patients with severe renal failure . Br
J Anaesth 1980; 52: 10 I P
43. Alazia M, Levron JC, Guidon C, et al. Pharmacokinetics of
fentanyl during continuous infusion in critically ill patients
[abstract]. Anesthesiology 1987; 67: 665
44. Meuldermans W, Van Peer A, Hendricks J, et al. Alfentanil
pharmacokinetics and metabolism in humans. Anesthesiol-
ogy 1988; 69: 527-34
45. Chauvin M, Lebrault C, Levron JC, et al. Pharmacokinetics of
alfentanil in chronic renal failure . Anesth Analg 1987; 66:
53-6
46. Bower S, Sear Jw. Disposition of alfentanil in patients receiv-
ing a renal transplant. J Pharm Pharmacol 1989; 41 : 654-7
47. Davis PJ, Stiller RL, Cook DR, et al. Effects of cholestatic
hepatic disease and chronic renal failure on alfentanil phar-
macokinetics in children. Anesth Analg 1989; 68: 579-83
48. Rolly G, Kay B, Cockx F. A double-blind comparison of high
doses of fentanyl and sufentanil in man. Acta Anaesthesiol
Belg 1979; 30: 247-56
49. Wiggum DC, Cork RC, Weldon ST, et al. Postoperative respi-
ratory depression and elevated sufentanil levels in a patient
with chronic renal failure . Anesthesiology 1985; 63: 708-10
50. Lehmann KA, Sipakis K, Gasparini R, et al. Pharmacokinetics
of sufentanil in general surgical patients under different con-
ditions of anaesthesia. Acta Anaesthesiol Scand 1993; 37 (2):
176-80
51. Howie MB, Smith OF, Harrington K, et al. Serum concentra-
tions of sufentanil and fentanyl in the post-operative course
in cardiac surgery patients. Anesthesiology 1984; 61: A 131
52. Schwartz AE, Matteo RS, Ornsteine, et al. Pharmacokinetics of
sufentanil in hyperventilated patients [abstract]. Anaesth An-
alg 1987; 66 Suppl: 151
53. Davis PJ , Stiller RL, Cook DR, et al. Pharmacokinetics of
sufentanil in adolescent patients with chronic renal failure.
Anesth Analg 1988; 67: 268-71
54. Fyman P, Avitable M, Moser F, et al. Sufentanil pharmacokinet-
ics in patients undergoing renal transplantation [abstract]. An-
esth Analg 1987 ; 66 Suppl.: 62
55. Sear Jw. Sufentanil disposition in patients undergoing renal
transplantation: influence of choice of kinetic model. Br J
Anaesth 1989; 63: 60-7
56. Egan TO, Lemmens HJM , Fiset P, et al. The pharmacokinet-
ics of the new short-acting opioid remifentanil (GI87084B)
in healthy adult male volunteers. Anesthesiology 1993; 79:
881-92
57. Glass PSA, Hardman 0 , Kamiyama Y, et al. Preliminary phar-
macokinetics and pharmacodynamics of an ultra-short acting
opioid: remifentanil (GI87084B). Anesth Analg 1993; 77:
1031-40
58. Hoke J, Muir K, Glass P, et al. Pharmacokinetics of remifentanil
and its metabolite (G19029I ) in subjects with renal disease
[abstract]. Clin Pharmacol Ther 1995; 57: PI55
59. Shlugman 0 , Dufore S, Dershwitz M, et al. Respiratory effects
of remifentanil in subjects with severe renal impairment com-
pared to matched controls [abstract]. Anesthesiology 1994;
81: 1417
60. Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics,
and rational opioid selection. Anesthesiology 1991; 74: 53-63
© Adis International Limited. All rights reserved.
421
61. Hull JH, Findlay JWA, Rogers JF, et al. An evaluation of the
effects of smoking on codeine pharmacokinetics and bio-
availability in normal human voluneteers. Drug Intell Clin
Pharm 1982; 16: 849-54
62. Posey BL, Kimble SN . High-performance liquid chromato-
graphic study of codeine, norcodeine and morphine as indi-
cators of codeine ingestion. J Anal Toxicol 1984; 8: 68-74
63. Gilman AG, Goodman LS, Rail TW, et aI. , editors. Goodman
and Gilman's the pharmacological basis of therapeutics. 7th
ed. New York: Macmillan, 1985
64. Way EL, Adler TK. The pharmacologic implications of the
fate of morphine and its surrogates. Pharmacol Rev 1968;
12: 383-446
65. Parke TJ, Nandi PR, Bird KJ, et al. Profound hypotension fol-
lowing intravenous codeine phosphate. Anaesthesia 1992; 47:
852-4
66. Pearson MA. A fatality due to the ingestion of codeine
(methylmorphine). Clin Toxicol1979; 15: 267-71
67. Levine OF. Hypocalcaemia increases the narcotic effect of co-
deine. Postgrad Med J 1980; 56: 736-7
68. Matzke GR, Chan GLC, Abrahim PA. Codeine dosage in renal
failure. Clin Pharm 1986; 5: 15-6
69. Rowell FJ, Seymour RA, Rawlins MD. Pharmacokinetics of
intravenous and oral dihydrocodeine and its acid metabolites.
Eur J Clin Pharmacol 1983; 25: 419-24
70. Barnes IN, Goodwin FJ. Dihydrocodeine narcosis in renal fail-
ure . BMJ 1983; 286: 438-9
71. Redfern N. Dihydrocodeine overdose treated with naloxone in-
fusion . BMJ 1983; 287: 751-2
72. Barnes IN, Williams AJ, Tomson MJF, et al. Dihydrocodeine in
renal failure: further evidence for an important role of the
kidney in the handling of opioid drugs. BM] 1985; 290: 740-2
73. Mather LE, Tucker GT. Systemic availability of orally admin-
istered meperidine. Clin Pharmacol Ther 1976; 20: 535-40
74. Mather LE, Meffin Pl Clinical pharmacokinetics of pethidine.
Clin Pharmacokinet 1978; 3: 352-68
75. Stambaugh JE, Wainer IW, Sanstead JK, et al. The clinical phar-
macology of meperidine: comparison of routes of administra-
tion. J Clin Pharmacol 1976; 16: 245-56
76. Asatoor AM , London DR , Milne MD, et al. The excretion of
pethidine and its derivatives. Br J Pharmacol 1963; 20:
285-98
77. Edwards OJ, Svensson CK, Visco JP, et al. Clinical pharmaco-
kinetics of pethidine. Clio Pharmacokinet 1982; 7: 421-33
78. Tang R, Shimomura SK, Rotblatt M. Meperidine-induced sei-
zures in sickle cell patients. Hosp Formul 1980; 15: 764-72
79. Odar-Cederlof I, Boreus LO, Bondesson U, et al. Comparison
of renal excretion of pethidine (meperidine) and its metabo-
lites in old and young patients. Eur J Clin Pharmacol 1985;
28: 171-5
80. Szeto HH , Inturrisi E, Houde E, et al. Accumulation of
normeperidine, an active metabolite of meperidine, in pa-
tients with renal failure or cancer. Ann Intern Med 1977; 86:
738-41
81. Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous sys-
tem excitatory effects of meperidine in cancer patients. Ann
Neurol 1982; 13: 180-5
82. Jiraki K. Lethal effects of normeperidine. Am J Forensic Med
Pathol 1992; 13 (I): 42-3
Clin. Pharmacokinet. 1996 Dec; 31 (6)
422
83. Inturrisi CE, Colburn WA, Verebely K, et al. Propoxyphene and
norpropoxyphene kinetics after single and repeated doses of
propoxyphene. Clin Pharmacol Ther 1982; 31: 157-67
84. Wolen RL, Ziege EA, Gruber CM. Determination of propoxy-
phene and norproxyphene by chemical ionization mass
fragmentography. Clin Pharmacol Ther 1974; 17: 15-20
85. Gram LF, Schou J, Way WL, et al. d-Propxyphene kinetics after
single oral and intravenous doses in man. Clin Pharmacol
Ther 1979; 26: 473-82
86. Gibson TP, Giacomini KM , Briggs WA, et al. Propoxyphene and
norpropoxyphene plasma concentrations in the anephric pa-
tient. Clin Pharmacol Ther 1980; 27: 665-70
87. Nickander R, Smits SE, Steinberg MI. Propoxyphene and
norpropoxyphene: pharmacologic and toxic effects in animals.
J Pharmacol Exp ther 1977; 200: 245-53
88. Giacomini KM, Gibson TP, Levy G. Effect of hemodialysis on
propoxyphene and norpropoxyphene concentrations in blood
of anephric patients. Clin Pharmacol Ther 1980; 27: 508-14
© Adis International Umited. All rights reserved.
Davies et al.
89. Nilsson MI, Meresaar V, Anggard E. Clinical pharmacokinetics
of methadone. Acta Anaesthesiol 1982; 74 Suppl: 66-9
90. Berkowitz BA. The relationship of pharmacokinetics to phar-
macological activity: morphine, methadone and naloxone.
Clin Pharmacokinet 1976; I: 219-30
91. Gourley GK, Wilson PR, Glynn CJ. Pharmacodynamics and
pharmacokinetics of methadone during the perioperative pe-
riod. Anesthesiology 1982; 57: 458-67
92. Inturrisi CE, Verebely K. Disposition of methadone in man after
a single oral dose. Clin Pharmacol Ther 1972; 13: 923-30
93. Kreek MJ, Schecter AJ, Gutjahar CL, et al. Methadone use in
patients with chronic renal disease. Drug Alcohol Depend
1980; 5: 197-205
Correspondence and reprints: Graham Davies, Department
of Pharmacy, University of Brighton, Moulsecoomb, Brigh- .
ton BN2 4GJ, England.
Clin. Pharmacokinet. 1996 Dec; 31 (6)