Clinical Pharmacokinetics and Pharmacodynamics of Opioid Analgesics in Infants and Children

CLINICAL PHARMACOKINETICS IN SPECIAL POPULATIONS
Clin . Phorm ocokinet. 28 (5): 385-404, 1995
0312-5963/95/OOO5-o385/S 10.00/0
Adis International limited. All rights reseNed .
Clinical Pharmacokinetics and

Pharmacodynamics of Opioid
Analgesics in Infants and Children
Klaus T. Olkkola,l Katri Hamunen 2 and Eeva-Liisa Maunuksela 2
1 Department of Anaesthesia, University of Helsinki, Helsinki, Finland
2 Helsinki University Eye Hospital, Helsinki, Finland
Contents
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. General Aspects of Pharmacokinetics In Infants and Children
2. Morphine . . . . . . . . . . . . . . . . . . . . . . . . ... .
2.1 Intravenous Pharmacokinetics .... . . . . . . . . .
2.2 Intramuscular and Subcutaneous Pharmacokinetics
2.3 Oral Pharmacokinetics . . . . . . . . . . . . .
2.4 Rectal Pharmacokinetics . . . . . . . ... .
2.5 Epidural and Intrathecal Pharmacokinetics
2.6 Pharmacodynamics . . . . . .
3. Pethidine (Meperidine) ... .. . . .
3.1 Intravenous Pharmacokinetics .
3.2 Intramuscular Pharmacokinetics
3.3 Rectal Pharmacokinetics
3.4 Pharmacodynamics
4. Buprenorphine
5. Methadone .
6. Oxycodone .
7. Pentazocine
8. Fentanyl
8.1 Intravenous Pharmacokinetics
9. Alfentanil . ... ... . . . . . . . .
10. Sufentanil . . . . . . . . . . . . . . .
10.2 Intranasal Pharmacokinetics
11. Conclusions . . . . . . . . . . . . .
~mma~
Summary
385
386
387
387
388
389
389
389
389
390
390
391
391
392
392
393
394
394
395
395
396
396
396
397
398
398
400
400
.400
Pain in childhood has not always been managed as actively as that in adults
because of the limited amount of research available to provide guidelines for the
management of paediatric pain. However, for many years now the pharmaco-
386
Olkkola et al.
kinetics and pharmacodynamics of opioid analgesics in infants and children have

been studied intensively.
Morphine is the standard for opioid analgesics and its pharmacology is the
best studied in paediatric patients. During the neonatal period, the volume of
distribution (V d) appears to be smaller in neonates than in adults, but adult values
are reached soon after the neonatal period. Although morphine is absorbed both
orally and rectally, there is little information on the pharmacokinetics of morphine
administered by these routes. The bioavailability of morphine after rectal administration appears to be highly variable.
For all the opioid analgesics studied, the elimination of the opioids is slower
in neonates than in adults. However, the rate of elimination usually reaches and
even exceeds adult values within the first year of life. The high rate of drug
metabolism means higher dosage requirements. In regard to the pharmacodynamics of opioid analgesics, infants and children do not appear to be more sensitive
to the effects of opioids than adults. Thus, except for the neonatal period, the
pharmacokinetics and pharmacodynamics of opioid analgesics are not markedly
different from those of adults, and the risk of using opioids in infants and children
is not higher.
Pain in childhood has not always been managed

as actively as that in adults. Although the neonate
displays distress in response to surgical stimuli,
postoperative pain appears to be undertreated both
in infants and in children.[ll This has been mainly
due to the limited research providing few guidelines for the management of pain in childhood.
The pharmacology of opioid analgesics has been
studied intensively over the last several decades.
This article reviews the available information on
the pharmacokinetics of opioids in infants and
children.
There is little information on the concentrationresponse relationship of opioids in young children,
but we have summarised the pharmacodynamic
profile of opioids in infants and children.
1. General Aspects of Pharmacokinetics

in Infants and Children
The pharmacokinetics and pharmacodynamics
of drugs are dependent on the age of the patient.
The largest differences between children and adults
are observed in the neonatal period. Due to both
pharmacokinetic and pharmacodynamic factors,
premature infants are especially susceptible to
many drugs. The pharmacological response of most
Adis International Limited. All rights reserved.
drugs is difficult to measure, and therefore there is

little information on the effect of age on pharmacodynamics. Because drug concentrations now can
be measured in very small samples of blood, the
influence of age on pharmacokinetics has been
studied more thoroughly.
The absorption of orally administered drugs is
influenced by the pharmaceutical formulation of
the drug in addition to patient factors. Liquid formulations are used most frequently in paediatric
practice and these may hasten the absorption of
orally administered drugs compared with the use
of tablets or capsules. The pH of the stomach of
neonates is more acidic than in older children and
in adults. This may somewhat accelerate the absorption of alkaline drugs, but in general physiological factors have little effect on absorption.!21
Diet is the most important factor affecting oral absorption of drugs. However, the effect of diet on an
individual drug is unpredictable,l31 Compared with
adults, the absorption of intramuscularly administered medication may be hastened in infants by the
relatively higher cardiac output, shorter circulation
time and the higher amount of blood circulating
through the muscles.!41
Drug distribution is influenced by such factors
Clin. Pharmacokinet. 28 (5) 1995
Opioid Analgesics in Infants and Children
as binding sites in tissues and plasma, and the relative proportions of components such as water, fat
and cell mass. During development, a child changes
both in outward dimensions and in the proportional
size of inner organs. The relative amount of water of
a neonate exceeds that of adults, mainly because of
the larger extracellular water compartment.[5] Adipose tissue increases during the first year of life,
thereafter decreasing.[6] The amount of plasma protein increases proportionally with age and shows
qualitative developmental differences. Many drugs
have lower protein binding in the neonate and for
some drugs adult values for protein binding are not
reached until the second decade of lifeP] The volume of distribution (V d) of water-soluble drugs
usually decreases during the early years owing to
the decrease in extracellular volume. The Vd of lipid
soluble drugs principally parallels the development
of fatty tissues. However, in many cases the V d
does not seem to be correlated to any age-related
changes in extracellular water, fat or cell mass.
Changes in drug metabolism are largest during
the first 10 years of life. Many enzymes are able to
metabolise certain foreign compounds during the
fetal period, but their activity is 10w.[S] The neonate
possesses an ability to metabolise some drugs, such
as paracetamol (acetaminophen), approximately as
rapidly as an adult. However, for most drugs metabolism is slower in neonates than later in life and
metabolism often reaches its maximal level during
the latter part of the first decade of life. The high
rate of drug metabolism in preschool and early
school age children, exceeding even the rate in
adults, means higher dosage requirements for these
individuals. In young children interindividual variation in metabolic clearance may be 2 to 10 times
greater than that in adults.[9.IO] This is not surprising since all pharmacokinetic studies in children
are done in patients suffering from severe illnesses
whereas pharmacokinetic studies in adults are often done in healthy volunteers.
The kidneys of neonates are functionally immature. However, the glomerular filtration rate reaches
and exceeds adult values within I month)lI] The
development of tubular function is slower.[12]
387
Physiological changes in renal function mean that

renally excreted drugs are eliminated more slowly
during the first year of life. The differences between adults and newborn infants are most marked
during the first few weeks and months after birth.
However, there have been very few studies on the
differences in the pharmacokinetics of renally
eliminated drugs in neonates and adults.
2. Morphine
Morphine is an extract of opium and the standard opioid analgesic. Compared with other opioids,
its pharmacokinetics and clinical effects are probably the best studied in paediatric patients. It is a
pure agonist with its main effect at the Il-receptor,
but it also has K-activities.
2. 1. 1 Distribution
Morphine has low lipid solubility and a pKa

value of 8.0. At physiological pH over 20% is unionisedJl3] The binding of morphine to plasma protein is dependent on age. In premature infants less
than 20% is bound to plasma proteins,[14.15] but in
adults about 35% is bound)16] During long term
infusions for cancer pain it has been shown that the
unbound concentrations of morphine are comparable in plasma and cerebrospinal fluid.[17] The relationship between Vd and age is somewhat controversial (table I). Some studies have reported that
the Vd during steady-state (Vss) is similar in preterm and term infants)19] However, the Vd during
the elimination phase appears to be variable and
nonlinearly dependent on postnatal age during the
neonatal period in preterm babies)14] Within the
neonatal period for term infants, the Vd is linearly
proportional to age and body surface area)9] After
the neonatal period, the values for Vd remain approximately the same, which are smaller than,[24]
or the same as,[IO.25] those reported in adults.
2. 1.2 Elimination
Morphine is eliminated mainly by hepatic metabolism. The main metabolites are the pharmacologically inactive morphine-3-glucuronide and pharmacologically active morphine-6-glucuronide. Neonates
Olkkola et a/.
388
Table I. Summary of the principal pharmacokinetic data after intravenous administration of morphine
Age
CL
Vc
Vss
Vz
tlf;
(mllkg/min)
(Ukg)
(Ukg)
(Ukg)
(h)
References
1-7 days
preterm
2.7-9.6
2.0
1.8-5.2
7.4-10.6
14, 18-20
term
2.3-20.0
1.3-2.1
2.9-3.4
6.7-13.9
9, 14,15,19, 21,22
1.8
2.6
4.1-5.4
9, 15
11.4-33.5
0.87
2.0
2.4-4.8
1.2-4.5
9, 15,23-25
1-6 years
6.2-56.2
1.2
1.1-3.8
0.8-1.2
24-26
7 years
6.7-25.7
0.55
3.4
1.4-3.1
3.3
20,24,27
Adults
12.0-34.0
0.33
1.1-2.1
3.2
3.0-5.0
10,28
1 week to 2 months
2-12 months
7.4-9.0
Abbreviations: CL =total body clearance of drug from the plasma; t lf; =elimination half-life; Vc =apparent volume of distribution of the central
compartment; Vss
=apparent volume of distribution at steady-state; Vz =apparent volume of distribution during the terminal phase.
2.2 Intramuscular and Subcutaneous
Pharmacokinetics
appear to produce both glucuronides less effectively than do older children or aduits,l IS,19,20,23,29-3 I]
In children aged 1 day to 2.5 years it was observed
that the formation of morphine glucuronides was
correlated with age, whereas the formation ofmorphine sulphate and renal clearance of unchanged
morphine were independent of age)IS]
In acutely ill preterm infants, however, larger
amounts of morphine were excreted unchanged
than were excreted in older children and adults.[29]
In adults, less than 10% of morphine is excreted
unchanged.[32]
The total plasma clearance of morphine is dependent on the age of the patient (fig. I). Clearance
increases from values of between 0.5 and 3
ml/kg/min in preterm infants to values between 20
and 40 ml/kg/min in preschool children)9,14,15,18-27]
In adults, values for morphine clearance range from
10 to 20 ml/kg/min.[lO] Primarily due to changes in
clearance, the elimination half-life (tY2) changed
from values of 10 to 20 hours in preterm infants to
values of 1 to 2 hours in preschool children. In
adults the tY2 of morphine is normally 2 to 4 hours. [lO]
In addition to age, the pharmacokinetics of morphine are also dependent on concurrent diseases of
the children as demonstrated in children after cardiac surgery)33] Liver failure does not affect the
pharmacokinetics of morphine to any great extent,
but renal failure leads to accumulation of metabolites of morphineP4]
Although morphine is generally administered

intramuscularly or subcutaneously for postoperative pain, there is little information on the pharmacokinetics of intramuscular morphine in children. In adults, intramuscular morphine is absorbed
rapidly, peak plasma concentrations (C max ) being
reached within 15 minutes, and it is 100% bioavailable) lO]
The pharmacokinetics of subcutaneous morphine
have been studied in childrenPS] Continuous subcutaneous infusion of morphine in doses of 0.034
to 0.06 mg/kg/h produced plasma concentrations
ranging from 13 to 57 IlglL in these patients.
1000
<1 week old
o 1 week-2 months old
2-6 months old
~
~
5100
'E
Q)
u
c:
E 10
2Q)
rn
I
2
I
4
I
8
10
12
Time (h)
Fig. 1. Mean SEM serum morphine concentrations in 27 infants
after administration of a single dose of 0.1 mglkg.19l
389
2.3 Oral Pharmacokinetics
There appears to be only one report on the oral

pharmacokinetics of morphine in children. [36] Two
children with chronic pain were given controlled
release tablets of morphine every 12 hours or regular tablets every 4 hours. The bioavailability was
not determined but the time taken to achieve C max
(t max ) was 2 and 2.5 hours after administration of
controlled release tablets and 0.25 and 1.5 hours
after administration of regular tablets. The minimum plasma morphine concentrations (C min ) and
the area under the plasma concentration-time curve
(AVC) normalised for dose were comparable for
the 2 preparations.
The bioavailability of rectal morphine in children is approximately 30% (range from 6 to 99%)
and C max values are normally achieved within 30
minutes when morphine is administered dissolved
in propylene glycol and within 60 to 90 minutes
when an aqueous morphine solution is mixed with
dry starch hydrogel. [37-39] When morphine 0.5 mg/kg
in hydrogel was given rectally to children, aged 4
to 8 years, a mean ( SD) Cmax of 25 6 IlglL was
observed.[39] Because of greatly variable absorption, rectal administration of morphine can result
in morphine plasma concentrations that may cause
potentially serious toxicity.[40]
2.5 Epidural and Intrathecal
Pharmacokinetics
In children aged from 2 to 15 years, epidural administration of morphine resulted in rapid achievement of C max (t max was 10 minutes).[41] The mean
Vd during elimination (V z), 2.9 0.9 Llkg ( SD),
was similar to that in adults, but clearance, 28.3
3.4 ml/min/kg, was higher than that in adults.f 42 ]
Caudally administered morphine appears to be
absorbed as fast as after lumbar epidural administration.[43] After an intrathecal injection of 0.02
mg/kg of morphine the mean cerebrospinal fluid
concentration of morphine after 6 hours is 2860
540 IlglL ( SD); after 18 hours the concentration
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of morphine in cerebrospinal fluid was 220 150

Ilg/L, but no morphine could be detected in
plasma.f44 ] This is most likely due to the small dose
administered and the slow absorption of morphine
into the systemic circulation.
2.6. 1 Analgesia and Sedation
The plasma concentrations of morphine required to attain analgesia or adequate sedation during long term infusions in patients under intensive
care appear to be dependent on the age of the patient. After thoracic or extensive orthopaedic surgery, found that the mean concentration of morphine necessary to provide an analgesic response
was 26 IlglL in infants compared with 4 IlglL in
children 2 to 6 years of ageP5] The 2 youngest
patients aged 11 days and 2 months, respectively,
differed from the others; their plasma morphine
concentrations were 28 and 64 IlglL at reappearance of pain. This finding was confirmed later in
the study by Chay et aJ.f19] who found that neonates were less sensitive to the analgesic effect of
morphine. In that study, the neonates required morphine plasma concentrations of 125 Ilg/L for adequate analgesia and sedation (fig. 2). Other investigators have reported effective analgesic plasma
concentrations to be 121lg/L for postoperative analgesia[45] and 65 IlglL for intraoperative analgesia
in children.[24]
During subcutaneous infusion the median effective concentration for analgesic effect in children
with terminal malignancy was 20 IlglL.l35] In
adults the mean ( SD) minimum effective analgesic morphine concentration was 16 9 IlglL.l46]
2.6.2 Ventilation
Compared with adults, infants have been

claimed to be at an increased risk of ventilatory
depression after administration of morphine.f 47 ]
However, this claim has been questioned recently.
Lynn et al.[48] evaluated the ventilatory effects of
intravenous morphine in 30 patients, aged 2 to 570
days and noted no age-related differences in respiratory effects at the same plasma morphine concentrations. This observation was supported by the
Olkkola et a/.
390
100
o Term
Preterm
80
~60
!!!
Q)
"0
C
Q.
lfi 40
a:
20
0
100
10
1000
Plasma concentration (J.lg/L)
Fig. 2. Relationship between plasma morphine concentration

and analgesic effect expressed as a cumulative frequency of
patients attaining adequate analgesia. 1191
results of 2 other studies.r 2s .44 ] However, for pharmacokinetic reasons neonates and, particularly, preterm neonates may be susceptible to the effects of
morphine, which emphasises the importance of individual dosage titration.
3. Pethidine (Meperidine)
Pethidine (meperidine) is a synthetic opioid agonist. It is frequently used for pain management in
children and as paediatric premedication alone or
in combination with promethazine and chlorpromazine (lytic cocktail). The analgesic effect and adverse effects of pethidine are comparable with
those of morphine, but it has a shorter duration of
action than morphine.r 49 ]
Pethidine has a lipid solubility higher than that

of morphine, but lower than that of the newer opioids fentanyl, alfentanil and sufentanil.[13,SO] In neonates, the plasma protein binding of pethidine is
52%[SI] and in infants aged 3 to ] 8 months it is
85%.rS2] In adults, approximately 60 to 80% of
pethidine is bound to plasma proteins.[SI ,S3] An important determinant of pethidine plasma binding is
the concentration of ai-acid glycoprotein, which is
lower in neonates.r SI ,S3]
Because pethidine is the opioid most often used
for the treatment of obstetric pain,!54] there much
information on the disposition of pethidine in neonates at birth. Pethidine administered to the mother
is rapidly transferred through the placenta to the
fetus.r ss .62 ] The amount of pethidine and norpethidine transferred to the fetus is related to the dose
administered to the mother, the dose-delivery interval (i.e. the time between administration of the
drug and delivery of the neonate) and the metabolic
capacity of the mother.lss ,s7.61 .62]
At delivery, concentrations of pethidine in cord
blood are about 70 to 90% of maternal concentrations, but these can be even higher in the neonate
than in the mother.l sl ,s761] This may depend on the
fact that the blood in the neonate is more acidic than
that of mother, which leads to passive diffusion of
basic pethidine to the fetal side.ls4 ] At birth,
norpethidine concentrations in the neonate are approximately 80 to 90% of maternal pethidine concentration.[S9,60] C max values for norpethidine are
reached 24 to 36 hours after birth.[63,64)
Pharmacokinetic parameters for pethidine are
summarised in table II . In neonates and young infants the volume of the central compartment (Vc)
and Vss are larger than in older children and
adults.l 6s .67 ,69] In the youngest age groups (i.e. infants aged less than 3 months) there was large interindividual variation in Vd (fig. 3) and this variability was not correlated with either age or
bodyweight.l6S ] In children 5 to 8 years of age, Vc
and Vss are equal to those reported in adults.l 66 ,67,69]
3. 1.2 Elimination
Pethidine is metabolised in the liver mainly by
hydrolysis to pethidine acid and by N-demethylation to norpethidine. Norpethidine is subsequently
hydrolysed to norpethidine acid. Urinary excretion
of pethidine and norpethidine is dependent on pH.
In adults, when urine pH is uncontrolled approximately 5% of a dose is excreted unchanged. Acidification of urine increases the amount of unchanged
391
Table II. Summary of the principal pharmacokinetic data after intravenous administration of pethidine
Age
CL
Vc
Vss
Vz
(ml/kg/min)
(Ukg)
(Ukg)
(Ukg)
Reference
t 1"
(h)
1-7 days
preterm
3.5
2.1
8.8
11.9
65
term
7.2
2.0
5.6
10.7-22.7
57, 65
9.7
3.1
8.0
8.2
5.0
2.3
52
3.0
66
3-1-4.4
67-69
1 week to 2 months
3-18 months
5.5 years
10.4
1.0
2.8
Adults
10.0-12.0
0.7-1.2
3.0-4.0
3.0
65
Abbreviations: CL =total body clearance of drug from the plasma; t1" =elimination half-life; Vc =apparent volume of distribution of the central
compartment; Vss =apparent volume of distribution at steady-state; Vz =apparent volume of distribution during the terminal phase.
pethidine to 25% and alkalinisation decreases it to

1 to 2% of the total dose.f 531
Studies in neonates whose mothers have been
given pethidine during delivery indicate that neonates have prolonged elimination of pethidine. 1561
During the first days oflife, the major excretion product is unchanged pethidine. On the third day more
norpethidine than pethidine is excreted.l 56 ,59,70]
During the first 24 hours of life the elimination of
pethidine is limited not only by diminished metabolic capacity, but also by the very low urinary
flow rate.[63,64) In neonates whose mothers have
been given pethidine during delivery, the mean t';2
of pethidine is 13 to 23 hours (range 10 to 45
hours))57.6o,63)
In neonates and young infants, the elimination
of pethidine is slower than in older children and
adults, and it is subject to great interindividual
variation.165-69] In neonates and infants, clearance
of pethidine is correlated with age, gestational age,
bodyweight and body surface area, while Viz is not.
Values for tl/2 range from 3 to 59 hours (fig. 3).
Pharmacokinetic parameters do not appear to differ between preterm and term infants, but interindividual variation in parameters is greater among
preterm babies.l65 ) In children aged 5 to 8 years, VI2
[3.0 0.5 hours ( SD)] and clearance (l0.4 1.7
mllkg/min) are comparable with these parameters
in adults.l 66-69 ) Elimination of pethidine is linear,
at least for intravenous doses of up to 5 mg/kg in
adults l67 ] and 3 to 5 mg/kg, rectally, in children.l 66 )
Norpethidine undergoes slower elimination than
pethidine.l71-73) The role of norpethidine in con Adis International Limited. All rights reserved.
tributing to the pharmacological effect of pethidine

is not quite clear, but after repeated administration
of pethidine, norpethidine has been reported to
cause CNS excitatory effects, including tremors,
twitches and convulsions.l7 4 ] In children, plasma
concentrations of norpethidine appear more rapidly after rectal administration than after the drug
is given by intravenous or intramuscular administration. 175 ]
In the neonate, the tl/z values for norpethidine
range from 30 to 85 hours,160.70] whereas the corresponding values in adults range from 8 to 16
hours .l71-73]
3.2 Intramuscular Pharmacokinetics
After intramuscular injection of pethidine in

adult patients, C max varied 3- to 5-fold and t max
varied 3- to 7 -fold.l76 ) In children aged 7 to 13
years, intramuscular injection of pethidine 1 mg/kg
resulted in a mean C max of 1609 nmollL 10 minutes
after injection.l7 5] In adults, C max was reached more
slowly.l76]
The mean bioavailability of rectally administered pethidine varies from 40 to 55% in children
aged from 4 to 13 years. 166 ,75] Rectal administration of pethidine produces unpredictable and
highly varying concentrations. After administration of a pethidine suppository of 100mg, individual C max values varied from 88 to 1050 IlglL and
were not correlated with the mg/kg dose. C max valClin. Pharmacokinet. 28 (5) 1995
392
Olkkola et al.
40
tremely steep. Plasma pethidine concentrations of

0.5 to 0.7 mg/L are required for analgesia.l7 6,77] In
children given pethidine during eye surgery, postoperative pain occurred at mean pethidine concentrations of 0.15 and 0.20 mg/L in patients receiving
the drug intravenously and rectally, respectively.[66]
30
...J
10
r.
3.4.2 Ventilation
:- I
04--------r------~------._----_,
80
60
.P
40
20
~.
O~----~~~----._------._~--_,
12
,.
-U\
04-------,-------~------r_----_,
20
40
60
80
Weight (kg)
Fig. 3. Pharmacokinetic variables [plasma clearance (el), elimination half-life (t>,;) and volume of distribution during the terminal
phase (Vz)] of pethidine (meperidine) as a function of patient
bodyweight.165.66.69J
ues appeared relatively late: 147 44 minutes (

SO) after administration of pethidine.l66]
3.4. 7 Analgesia
In adults the minimum analgesic concentration

of pethidine is highly variable among patients, and
the concentration-analgesic response curve is ex Adls International Limited. All rights reserved.
Although neonates at birth appeared to be clinically unaffected by the pethidine given to the
mother during delivery, 40% of neonates had increased ventilatory rates in response to administration of naloxone.l 55 ] Pethidine administered to the
mother intravenously or intramuscularly less than
1 hour before delivery does not seem to be associated with neonatal depression.[55,6J ,62] With a drugdelivery interval of 1 to 3 hours, depression of the
neonate is related to the metabolic pattern of the
mother; with an interval of 3 to 6 hours all neonates
are depressed to some degree.l 61 ] These findings
correlate well with concentrations of pethidine in
the neonatal plasma and urine.[59,60]
There is some controversy over the role of pethidine and its metabolite norpethidine in producing
ventilatory depression in the neonate. [55,61,62,64] After a few doses of pethidine it seems very unlikely
that neonatal ventilatory depression would be related to the concentration of norpethidine since
plasma norpethidine concentrations are low and
norpethidine has low pharmacological activity with
greater excitatory than depressant effects. However, the neonatal norpethidine concentration may
become clinically significant when the mother has
received multiple doses with a long dose-delivery
intervaP60,78]
4_ Buprenorphine
Buprenorphine is a semi-synthetic partial flagonist. It possesses high affinity to the fl-receptor
and subsequently has a slow dissociation rate,
which accounts for the prolonged duration of action.l 79 ] The use of buprenorphine in the paediatric
population is interesting because it has a relatively
long duration of effect and can be given sublingually. In the management of moderate to severe postoperative pain in children, it has an analgesic effect
Clin. Phormacokinet. 28 (5) 1995
393
Table III. Summary of the principal pharmacokinetic data aiter intravenous administration of buprenorphine, methadone, oxycodone and
pentazocine
Age
CL
(ml/kg/min)
Vc
Vss
Vz
(Ukg)
(Ukg)
(Ukg)
tl;"
(h)
Reference
Buprenorphine
5-8 years
60.0
3.2
1.0
82
Adults
13.0-19.0
1.0-3.0
2.0-3.0
83
Methadone
1-18 years
5.4
0.7
7.1
19.2
84
Adults
3.0
1.1
6.0
35
85
Oxycodone
2-10 years
15.2
0.8
Adults
11.0
Pentazocine
4-9 years
21.8
Adults
19.0
0.7
2.1
1.8
86
2.6
3.7
87
4.0
5.3
3.0
88
5.0-6.0
2.0-3.0
89,90
Abbreviations: CL = total body clearance of drug from the plasma; tl;" = elimination half-life; Vc = apparent volume of distribution of the central
compartment; V's = apparent volume of distribution at steady-state; Vz = apparent volume of distribution during the terminal phase.
comparable to that of morphine, but it tends to cause

more sedation.[80,8!]
Buprenorphine is highly lipophilic and about
96% of the circulating drug is bound to plasma
proteins.[49] There is only one study of the pharmacokinetics of buprenorphine in children)82] In children aged 4 to 7 years given buprenorphine 3 )lg/kg
intravenously, the mean ty, was 1.0 0.2 hours (
SD) compared with 3.1 0.6 hours in adults (table
III). Clearance of buprenorphine in children is
about 3-fold greater than that in adultsJ82, 83 1
The pharmacokinetics of intramuscular and
sublingual buprenorphine have not been studied in
children, but studies in adults demonstrate that
buprenorphine is absorbed rapidly and completely
after intramuscular administration.l 83 ] After sublingual administration of buprenorphine to adults,
tmax varies greatly between patients, ranging from
20 to 360 minutes, the mean being approximately
3 hours. Bioavailability of sublingually administered buprenorphine is approximately 55%, but
there is appreciable interpatient variation (from 16
to 94%))91]
There is no information on the concentration-response relationship of buprenorphine in children.
In animal models buprenorphine exhibits a ceiling
effect in dose-response curvesp9] However, it is not
Adis International Limited. All rights reserved .
clear if the ceiling effect exists for both analgesic

and ventilatory depressant effects in humans.[49,79]
In children aged 5 to 8 years intravenous buprenorphine produces greater and longer-lasting
ventilatory depression than intravenous morphine
in doses considered to be equianalgesic)92]
5. Methadone
Methadone is a synthetic )l-agonist with a long
duration of action because it is slowly eliminated.[85] Its analgesic effect in children appears to
be comparable with that of morphine.l 84 ] During
recent years methadone has been promoted for the
management of postoperative pain,l84,93] and in
some countries it is the basic opioid in the treatment of cancer pain in childrenJ94,95 1
Methadone is highly lipid soluble[l3] and approximately 85% of the drug is bound to plasma
proteins in adults.[49) Because of its good lipid solubility, it has a large Vd: the mean ( SD) values
being 7.1 2.5 L/kg in children and 6.1 2.4 L/kg
in adults)85,96] It is metabolised by N-demethylation and cyclisation in the liver to inactive substances that are excreted in the urine and bile along
with small amounts of unchanged drug. In adults,
the amount of methadone excreted in the urine is
increased when the urine is acidifiedJ49] Because
Olkkola et al.
394
of its higher plasma clearance, the t1;2 of methadone

in children aged 1 to 18 years is shorter than that
in adults (table III). However, there is substantial
variation in the pharmacokinetic parameters of
methadone among both children and adults. For
instance the mean ( SD) values for the t1;2 are 19
14 hours in children and 35 22 hours in adults
(and the reported values range from 4 to 62 hours
in children and from 9 to 87 hours in adults, respectively). [85,96] Oral bioavailability of methadone has
not been studied in children. In adults it is as high
as 79% (range 60 to 95%).[97]
There is no information on the concentration-response relationship in children. In adults, the doseresponse curve for analgesic effect of methadone
appears to be steep.[93] In children, intravenous
methadone produces greater acute decreases in peripheral arteriolar oxygen saturation and greater
and longer-lasting increases in end-tidal carbon dioxide concentration than the same dose of intravenous morphine,f98]
6.0xycodone
Oxycodone is a semi-synthetic f,.l-agonist that in
adults produces postoperative analgesia more rapidly than morphine and with a lower dose,f99] Furthermore, the analgesic effect is somewhat longer
lasting than that observed after administration of
morphineP9] It can be used in the management of
postoperative and cancer pain.[IOO] In many countries oxycodone is available only as an oral preparation combined with nonsteroidal anti-inflammatory drugs or as a suppository,flOl]
The physicochemical properties of oxycodone
resemble those of morphine. Lipid solubility is relatively low and protein binding is approximately
38%.[102] The pharmacokinetic parameters of oxycodone are summarised in table III. The values for
the Vss range from 1.2 to 3.7 L/kg in children aged
2 to 10 years[86] and they are similar to those observed previously in adults.[I03] According to studies in adults, oxycodone is metabolised in the liver.
Its main metabolites are oxymorphone and
noroxycodone,f87.103] About 7% of the intramuscular dose is excreted unchanged in urine. [87] Because
Adis
Interna~onal
Limited. All rights reserved.
of its higher clearance, the t1;2 values for oxycodone

are shorter in children than in adults.[86,103]
The intramuscular and oral pharmacokinetics of
oxycodone have not been studied in children. In
adults C max values are reached in about 1 hour
(range 0.5 to 1.5 hours) after intramuscular injection.[87,104,I05] In adults the oral bioavailability of
oxycodone is 60 to 87%.[87,104]
It has been suggested that oxymorphone, whose
analgesic potency is lO-fold greater than that of
morphine,[49] accounts for some of the effects produced by oxycodone, but this has not been confirmed in studies undertaken in humans,fI06] There
is little information on the oxycodone plasma concentration-analgesic effect relationship. In children,[86] the mean concentration at which children
emerging from halothane anaesthesia needed additional analgesics after eye surgery was 12 8 IlglL
( SD). In adults suffering from severe cancer pain,
the mean effective analgesic concentration of oxycodone was 101 Ilg/L.[107 ] The ventilatory depression observed in children after administration of
oxycodone 0.1 mg/kg appears to be greater than
following morphine (0.1 mg/kg), pethidine (0.67
mg/kg), methadone (0.1 mg/kg) and buprenorphine (0.003 mg/kg) in doses presumed to be equianalgesic. [86,92,98]
7. Pentazocine
Pentazocine is a synthetic weak f,.l-antagonist
and partial K- and 8-agonist.[49] In adults it has a
shorter duration of action than morphine and its
time-effect profile is also different.[108] In children,
pentazocine has been considered to be a well tolerated and effective premedication and postoperative
analgesic,fI09-111]
Pentazocine is approximately 50 to 80% bound
to plasma proteins in adults,f1l2] In children 4 to 8
years of age, the mean ( SD) Vz is 5.3 2.1 L/kg,
which is similar to values previously reported in
adults (table III). Correspondingly, the plasma
clearance and tl/2 are of the same order of magnitude
as those in adults,f88,90] According to studies in
adults, the metabolism of pentazocine involves oxidation and conjugation in liver with considerClin. Pharmacokinet. 28 (5) 1995
395
able interindividual variation in the rate of metabolism. Inactive metabolites together with small
amounts of unchanged drug are excreted in the
urine. Less than 2% of the administered dose
undergoes biliary excretion. 149,108] The pharmacokinetics of oral pentazocine have not been studied
in children, but in adults the oral bioavailability of
pentazocine is about 20% and C max values are
achieved within 1 to 2 hours of oral administration .190,113]
There is no information on the concentrationresponse relationship of pentazocine in children.
In our own studies in children, 0.5 mg/kg of intravenous pentazocine produced steeper changes in
end-tidal carbon dioxide and peripheral oxygen
saturation than 0.1 mg/kg of intravenous morphine.188 ]
8. Fentanyl
Fentanyl is a synthetic opioid with a potency
approximately 100-fold greater than that morphine. 1114 ] It is probably the most widely used intraoperative analgesic in paediatric patients.
8. 1.1 Distribution
Fentanyl has a pKa value of 8.4 and less than

10% is unionised at physiological pH. On the basis
of octanol/water partition coefficients, it is over
500 times more lipid soluble than morphine.l 50]
Because of its good lipid solubility, fentanyl is
widely distributed in tissues (table IV). In neonates
the reported values for V ss have ranged from 3 to
14 Llkg mean values being 4 to 6 Llkg.1117-119]
Table IV. Summary of the principal pharmacokinetic data after intravenous administration of fentanyl, alfentanil and sufentanil
Age
CL
(ml/kg/min)
vc
vss
vz
11,;,
(L/kg)
(Ukg)
(Ukg)
(h)
0.9-2.2
3.1-7.9
3.1-7.9
117.118
8.3
5.4
119
References
Fentanyl
1-7 days
preterm
term
1 week to 2 months
12.1
9.0-28.0
17.7
22.4
115.116
2-12 monlhs
18.1-30.6
0.2-0.9
2.3-4.5
1.1-3.9
117.120
1-6 years
11.5-12.8
0.8
1.4-3.1
2.4-4.1
117. 121
0.3
1.9
3.5
117
3.6-4.4
122. 123
7 years
Adults
7.1
12.0-15.0
0.3-0.4
4.0-5.0
Alfentanil
1-7 days
preterm
0.9-2.9
0.3-0.8
5.4-8.8
124-127
term
1.7
0.8
5.5
125
0.8-1.3
128. 129
0.7-1.4
124.128.130-133
0.7
130
1.2-1.6
134-135
2-12 months
8.2-11.5
0.2-0.3
0.5-0.6
1-6 years
4.7-11.1
0.1-0.2
0.2-0.6
7 years
8.2
Adults
5.4-8.3
0.5-1.0
4.2
2.7
1 week to 2 months
6.7-17.0
3.4-4.2
21.5-27.5
1-6 years
16.9-30.5
7 years
12.8-16.4
Adulls
12.7
0.3-1.0
0.5
0.17-0.22
Sufentanil
1-7 days
2-12 monlhs
0.5-1.0
0.7
2.7-3.1
10.6
136. 137
1.6-3.7
0.9-2.0
138
3.0-3.9
0.9-3.6
137-139
1.3-3.5
137-140
2.7
141
1.3-2.8
0.16
1.7
136
3.6-12.3
2.9
Abbreviations: CL = lolal body clearance of drug from the plasma; 1,f.1 = eliminalion half-life; Vc= apparent volume of distribution of the central
compartment; Vss = apparent volume of distribution at steady-state; Vz = apparent volume of distribution during the terminal phase.
396
Olkkola et al.
Adult values appear to be reached during adolescence. [117] Children undergoing cardiac surgery appear to have lower Vss than adultsJI21-123]
8. 1.2 Elimination
Fentanyl is eliminated almost entirely by hepatic metabolism; in adults less than 8% of the dose
is excreted unchanged in urine.[123] The tY2 is prolonged in preterm infants undergoing ligation of
patent ductus arteriosus,l' 15] but values comparable
with those in adults are reached within the first
months oflife.[I I7.119.121 .142] Compared with adults,
the clearance of fentanyl appears to be higher in
infants and young children.[1l7119]
Interestingly, it has been observed that the type
of surgery affects the pharmacokinetics offentanyl
in infants. The elimination of fentanyl is decreased
in the presence of increased intra-abdominal pressure such as that which occurs during abdominal
surgeryJ"8."9] It has been speculated that this
could be due to the impaired liver blood flow because of increased intra-abdominal pressure. Renal
failure does not appear to affect the pharmacokinetics of fentanyl during cardiac surgery in children and adolescents, which is not surprising since
fentanyl is primarily metabolised)143]
There is very little information on the relationship between plasma fentanyl concentrations and
analgesia in paediatric patients. Roth et al.[1l6] related analgesia and sedation in the neonatal intensive care unit with plasma fentanyl concentrations
produced by continuous infusion. Duration of infusion ranged from 53 to 245 hours. Neonates
whose gestational age was less than 34 weeks appeared to need less fentanyl for adequate sedation:
the mean plasma concentration was 1.7 Ilg/L,
whereas in neonates whose gestational age was
over 34 weeks the mean concentration was 2.1
Ilg/L. In adults the mean effective concentration for
postoperative analgesia has been reported to be
somewhat lower, 0.6 Ilg/L.[l44]
8.2.2 Ventilation
The effect of fentanyl on ventilation is somewhat controversial. On one hand it has been shown
that preterm infants move and breathe spontaneously in a relatively rapid manner after administration of a bolus of 30 Ilg/kg of fentanyl given during
anaesthesia for ligation of patent ductus arteriosusJ"5] On the other hand in the study of Koehntop
et aLl"8] it was observed that ventilatory depression was evident in neonates at lower concentrations than those needed in adults. The mean fentanyl concentration at the time of extubation
ranged from 0.05 to 0.77 Ilg/L.
Some studies have suggested that adults tolerate
higher concentrations of drug than do children before ventilatory depression is seen.[145] However,
the latest studies have shown that that is not the
case. Hertzka et aLl146] have studied the effect of
age on fentanyl-induced ventilatory depression.
Three groups of patients were studied: infants 1 to
12 months, children 1 to 5 years and adults 22 to
38 years. Elevation of skin surface C02 correlated
with increasing plasma fentanyl concentrations.
The incidence of apnoea determined with pneumography increased with age of the patient as did
the number of episodes of apnoea per patient (fig.
4). Thus, infants older than 1 month do not appear
to be more sensitive than older patients to the ventilatory depressant effect of fentanyl. However,
care should be exercised when administering fentanyl to neonates during the first days of life.
9. Alfentanil
Alfentanil is a derivative of fentanyl that has
lower lipid solubility and potency that is approximately one-seventh of that of fentanyl. Compared
with fentanyl, it also has a more rapid onset and
shorter duration of actionJ1l4] Due to its pharmacokinetic and pharmacodynamic characteristics, it
has become very popular in day-case surgery.
Alfentanil is a tertiary amine with a lower lipid

solubility than that of fentanyl. It has a pKa value
397
30
",10
0>
0.
'"
...
0>
"0
'"
'0.
UJ
o
0.1
9. 7.2 Elimination
.... _...
0.3
10
30
Age (y)
Fig. 4. The number of episodes of fentyl-induced apnoea per

patient plotted against age. Values for episodes of apnoea are
plotted logarithmically (except for 0). Both the overall incidence
of apnoea as well as the number of episodes of apnoea per
patient increase with age.l 146J
of 6.5 and less than 10% of alfentanil is ionised at

physiological pH. [50] Following intravenous administration, the concentrations of alfentanil in
plasma decline rapidly. Compared with adults, one
study has reported that the mean values for the initial Vd, Vss and V z are smaller in children aged
between 4 and 8 years than those in adults.[132] Because the binding of alfentanil to plasma proteins
was similar in children and adults, this difference
was explained by the lower percentage of fat tissue
in children. Alfentanil is bound to plasma proteins
and to ai-acid glycoprotein to a larger extent than
to albumin. In the study of Meistelman et al.,[1 32]
at a concentration of 50 f-LglL, 94.4 l.5% ( SD)
of alfentanil was bound to plasma proteins in children. In another study comparing pharmacokinetics of alfentanil in children aged between 10
months and 6.5 years and in adults, no difference
was seen in the Vz (table IV). In fact, the mean
value was a little higher in children than in
adults.[133] Plasma protein binding was similar in
children and adults with mean free fractions of 11.5
0.9% ( SD) and 1l.8 3.9%, respectively.
In preterm infants the values of V ss and V z
appear to be larger than in older children and
adults.[124-126.128,134,135] Interestingly, in preterm

infants gestational age does not affect the distribution kinetics of alfentanil.[125] Cardiopulmonary
bypass increases the value for the initial Vd, at
least, but probably also values for other measures
of V d in infants and children.[131]
Alfentanil is eliminated mainly by metabolism.
Only about 0.4% of the administered dose is excreted unchanged in the urine during the 24-hour
period after intravenous bolus administration to
adults.[I35] The elimination of alfentanil is clearly
dependent on the age of the patient. In preterm and
term infants the mean clearance of alfentanil has been
reported to be between I and 2 mllkg/min,[124-127]
which is considerably lower than the values observed in older children and adults.[128,132,133] Together with an increased V d, the smaller clearance
of alfentanil in infants results in greatly prolonged
t\l2 values.
In infants the t\l2 values vary largely and mean
values between 6 and 10 hours have been reported.[124-126] However, the elimination of alfentanil
in children appears to be comparable with that in
adults before the end of the first year of life.
Preschool children eliminate alfentanil faster
than adults (fig. 5).[128,132-135] Neither cholestatic
hepatic disease nor chronic renal failure affects the
pharmacokinetics of alfentanil in children. [130]
There appears to be no information on the analgesic concentrations of alfentanil in infants and

children. However, one study has estimated the effective concentrations of alfentanil for sedation in
infants and small children during cardiac catheterisation.l 147 ] Altogether 14 patients were studied.
Seven patients were cyanotic, 10 were digitalised
and 6 received furosemide (frusemide). The patients were given flunitrazepam 0.1 mg/kg orally I
hour before catheterisation for premedication. The
mean duration of catheterisation was 2.4 0.6
hours ( SD). During stable sedation, plasma alfentanil concentrations ranged from 50 to 220 f-LglL,
Clin. Phormacokinet. 28 (5) 1995
398
Olkkola et al.
1000
100
~
0,
.3
c
.2
li!
C
Q)
u
c
0
u
10
'c
~
.lE
c;;
ca
E
If)
ca
ii:
0.1-+---.-----.-----,---.-----.-----,---
Time (h)
Fig. 5. Mean SO plasma alfentanil concentration decay curves
for children aged 4 to 8 years and adults following administration
of a single intravenous bolus dose of 20 llg/kg.[132]
the mean value being 79 J..LglL. There is no information on the sedative concentrations of alfentanil
in adults. However, for skin closure after general
surgery, the value of the plasma concentration of
alfentanil for which the probability of no response
is 50% is 150 J..LglL.148]
9.2.2 Ventilation
One study has evaluated the ventilatory effects

of alfentanil after repair of congenital heart defects
in infants and children.[I29] Six infants, aged 4 to
11 months, and 5 children aged 2 to 8 years were
anaesthetised with 50% nitrous oxide in oxygen
and halothane and neuromuscular relaxation was
provided with pancuronium bromide. During induction of anaesthesia, the patients were given an
intravenous bolus of 20 J..Lg/kg of alfentanil followed by an infusion of 1 J..Lg/kg/min. In the case of
Adis International Lirnited. All rights reserved.
insufficient anaesthesia during surgery, additional

bolus doses of 5 J..Lg/kg were administered. The infusion of alfentanil was stopped after closure of the
sternum. The patients were extubated when the
ventilatory rate was above 25 breaths per minute in
the infants and 20 breaths per minute in the children and when the end-tidal carbon dioxide concentration was lower than 6.5%. The patients were
extubated 20 to 50 minutes after stopping the alfentanil infusion. In infants the mean ( SD) plasma
concentration at extubation was 42 17 J..LglL and in
children it was 58 11 J..Lg/L.
The duration of postoperative analgesia, determined by the time between stopping the infusion
of alfentanil and the first administration of opioid
in the intensive care unit, ranged from 188 to 808
minutes in infants and from 106 to 878 minutes in
children.[129] These findings have been later confirmed by another study from the same group.[131]
In adults it has been shown that the concentration
threshold for resumption of spontaneous breathing
varies from 100 to 200 J..Lg/UI48]
10. Sufentanil
Sufentanil is the most potent opioid available
for clinical use, being 5 to 10 times more potent
than fentanyl. Although its pharmacokinetic profile resembles that of fentanyl, it has a slightly
more rapid onset of effect and a shorter duration of
action.114]
Sufentanil is a tertiary amine with a better lipid

solubility than that of fentanyl. It has a pKa value
of 8.0 and 80% of sufentanil is ionised at physiological pH.50] Sufentanil is highly bound to ai-acid
glycoprotein in plasma.[50] At physiological pH the
free fraction of sufentanil, 19.5 2.7% ( SD), is
significantly higher in neonates than in infants
(11.5 3.2%), children (8.1 1.4%) and adults (7.8
1.5%). The free fraction is also significantly
higher in infants than in children or in adults. The
free fraction of sufentanil is strongly correlated
with the plasma ai-acid glycoprotein levePl49]
Clin. Pharrnacokinet. 28 (5) 1995
399
The Vss is higher than that of alfentanil, but approximately at the same level as that of fentanyl (table
IV). The Vss has been reported to be greater in
neonates than in infants, children and adolescents.ll371 However, V z , on the other hand, has been
reported to be smaller in infants younger than 10
months undergoing cardiac surgery than in children older than to months,l l38 1
On average, childrenll36-1391 appear to have
larger values for Vss and V z than do adults.ll411 Adolescents appear to have pharmacokinetic variables comparable to those of adults,l l40 1
Week 1
Weeks 34
20
15
C
~
0>
""
10
...J
()
0
1200
10. 1.2 Elimination
Animal and human studies have suggested that

sufentanil is eliminated by O-demethylation and
N-dealkylation.lI501 Less than 2% of the dose is excreted unchanged in urine. Metabolites do not contribute to the analgesic activity of sufentaniLl l51 1
The elimination rate of sufentanil is dependent on
the age of the patient. In neonates, sufentanil clearance has been reported to vary from I to 8 ml/kg/rnin.
The clearance is considerably less than that reported for older children and adults,l136.137. 141 1
Greeley and de Bruijnll361 studied the pharmacokinetics of sufentanil within the neonatal period
in a crossover manner in 3 neonates. The first experiments were done at the age of 2 to 7 days and
the second experiment was undertaken during the
3rd or 4th week of life. The clearance of sufentanil
ranged from 1.7 to 6.7 ml/kg/min in the younger
infants (in the first experiment) and reached values
ranging from 12.9 to 18.8 mllkg/min in the older
patients (in the second experiment) [fig. 6]. Accordingly, the clearance of sufentanil exceeded
adult values at the age of a few weeks. In infants
and children, the clearance of sufentanil is higher
than that in adolescents and adults.lI37.139.1411 This
means that during long term infusion, higher maintenance doses must be used in infants and children
if the concentration-response relationship is similar both in children and adults. In neonates, the
tY2 has been reported to vary from 6 to 20
hours,l136.1371Values comparable to or even shorter
than those in adults are reached within the first year
of life.
1000
800
..
"'.!
600
400
200
0
3
0;
In
In
>
o
2
Pallenl no.
Fig. 6. Sequential pharmacokinetic analysis of sufentanil elimination (terminal elimination half-life: tl;,~; clearance: CL; and volume of distribution at steady-state: V ss ) in 3 neonatal patients 1
and 3 to 4 weeks after birth.l 1361
Chronic renal failure does not affect the mean

values of clearance or tl/2 in adolescents, but interindividual differences appear to be more variable
in adolescents with renal failure.ll401
400
Olkkola et al.
10.2 Intranasal Pharmacokinetics
There is one report on the pharmacokinetics of

sufentanil after intranasal administration. 1152 ] Sufentanil 2 Ilg/kg was administered as nasal drops
from a tuberculin syringe to 15 children 10 minutes
before induction of anaesthesia. Venous samples
were drawn at 15,30,60,90 and 150 minutes after
the sufentanil was given. The C max for sufentanil
was reached after 15 minutes in 8 patients and after
30 minutes in the other 7 patients. The onset of
sedation was rapid and concentrations associated
with analgesia persisted into the postoperative period. The investigators concluded that it may be
inappropriate to administer sufentanil intranasally
for short diagnostic procedures, which are not associated with postoperative pain.l 152 ]
10.3.1 Anaesthesia
There is little information on the pharmacodynamics of sufentanil in children. Greeley et al. 1137 ]
have studied the pharmacokinetics and pharmacodynamics of sufentanil in paediatric cardiovascular
patients. Patients were divided into 4 groups on the
basis of age: (i) neonates 0 to 1 months; (ii) infants
1 to 24 months; (iii) children 2 to 12 years; (iv) and
adolescents 12 to 18 years. The plasma concentration of sufentanil at the time of additional anaesthetic supplementation to suppress haemodynamic
responses to surgical stimulation was 2.51 Ilg/L in
neonates, which was significantly higher than the
concentrations of 1.58, 1.53 and 1.56 Ilg/L observed in infants, children and adolescents, respectively. The investigators suggested that this was
due to either a decreased sensitivity to the anaesthetic effects of sufentanil in the neonates or to an
acute tolerance. 1137 ]
10.3.2 Ventilation
The effect of epidural sufentanil on ventilation

has been evaluated in 15 children undergoing surgery of the lower urinary tract. 1153 ] The children
ranged in age from 4 to 14 years. After induction
of anaesthesia, a 20-gauge epidural catheter was
inserted via the L3-L4 interspace. After surgery,
0.75 Ilg/kg of sufentanil in 2 ml of isotonic saline

solution was injected through the epidural catheter.
Plasma sufentanil concentrations were measured
for 240 minutes. C max values for sufentanil, mean
0.10 O.Olllg/L ( SD), were reached in the first
sample obtained 30 minutes after epidural administration of sufentanil. Although resting minute
ventilation did not decrease and end-tidal carbon
dioxide values did not increase, the slope of the
carbon dioxide ventilatory-response curve decreased significantly for approximately 2 hours
after administration of sufentanil. The investigators concluded that close monitoring of the patients
following epidural administration of sufentanil is
mandatory for more than 1 hour.l 153 ]
11. Conclusions
The pharmacokinetics and pharmacodynamics
of opioid analgesics have been studied intensively
in infants and children. For all the drugs studied,
elimination of the drug from the body is slower in
neonates than in adults. However, the rate of elimination usually reaches and even exceeds adult values within the first year of life. Maximal elimination is often reached during the latter part of the
first decade. The high rate of drug metabolism during the preschool and early school years even exceeds the rate of metabolism in adults, leading to
higher dosage requirements.
In regard to the pharmacodynamics of opioid
analgesics in infants and children, this age group
do not appear to be more sensitive to the effects of
opioids. Thus, except for the neonatal period, the
pharmacokinetics and pharmacodynamics of opioid analgesics are not markedly different from
those of adults, and the risk of using opioids in
infants and children is not higher for pharmacokinetic or pharmacodynamic reasons. The difficulty
of pain assessment in infants and children might
cause inadvertent overdosage.
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2. Radde Ie. Mechanisms of drug absorption and their development. In: Macleod SM, Radde IC, editors. Textbook of pedi-
atric clinical pharmacology. Littleton: PSG Publishing Company, 1985: 17-31

3. Welling PG. Interactions affecting drug absorption. Clin Pharmacokinet 1984; 9: 404-34
4. Celander O. Studies of the peripheral circulation. In: Cassels D,
editor. The heart and circulation in the newborn. New York:
Grune and Stratton, 1966: 98-11 0
5. Friis-Hansen B. Body water compartments in children: changes
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6. Brook CDG. Cellular growth: adipose tissue. In: Falkner F,
Tanner 1M, editors. Human growth: postnatal growth. 2nd ed.
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7. Radde Ie. Drugs and protein binding. In: Macleod SM, Radde
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8. Pelkonen 0, Kaltiala EH, Larmi TKI , et al. Comparison of activities of drug metabolizing enzymes in human fetal and
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9. Pokela M-L, Olkkola KT, SeppaHi T, et al. Age-related morphine kinetics in infants. Dev Pharm Ther 1993; 20: 26-34
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II. Neims AH. Renal elimination of drugs at various ages. In:
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Clinical Pharmacokinetics and Pharmacodynamics of Opioid Analgesics in Infants and Children

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Clinical Pharmacokinetics and Pharmacodynamics of Opioid Analgesics in Infants and Children

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CLINICAL PHARMACOKINETICS IN SPECIAL POPULATIONS

Clin . Phorm ocokinet. 28 (5): 385-404, 1995

Clinical Pharmacokinetics and

kinetics and pharmacodynamics of opioid analgesics in infants and children have

Pain in childhood has not always been managed

1. General Aspects of Pharmacokinetics

drugs is difficult to measure, and therefore there is

Opioid Analgesics in Infants and Children

Physiological changes in renal function mean that

Morphine has low lipid solubility and a pKa

Although morphine is generally administered

Clin. Pharmacokinet. 28 (5) 1995

Opioid Analgesics in Infants and Children

2.3 Oral Pharmacokinetics

There appears to be only one report on the oral

of morphine in cerebrospinal fluid was 220 150

Compared with adults, infants have been

Plasma concentration (J.lg/L)

Fig. 2. Relationship between plasma morphine concentration

Pethidine has a lipid solubility higher than that

Opioid Analgesics in Infants and Children

pethidine to 25% and alkalinisation decreases it to

tributing to the pharmacological effect of pethidine

After intramuscular injection of pethidine in

tremely steep. Plasma pethidine concentrations of

ues appeared relatively late: 147 44 minutes (

In adults the minimum analgesic concentration

Opioid Analgesics in Infants and Children

comparable to that of morphine, but it tends to cause

clear if the ceiling effect exists for both analgesic

of its higher plasma clearance, the t1;2 of methadone

Limited. All rights reserved.

of its higher clearance, the t1;2 values for oxycodone

Opioid Analgesics in Infants and Children

Fentanyl has a pKa value of 8.4 and less than

Adis International Limited. All rights reserved.

Clin. Pharmacokinet. 28 (5) 1995

Alfentanil is a tertiary amine with a lower lipid

Opioid Analgesics in Infants and Children

Fig. 4. The number of episodes of fentyl-induced apnoea per

of 6.5 and less than 10% of alfentanil is ionised at

adults.[124-126.128,134,135] Interestingly, in preterm

There appears to be no information on the analgesic concentrations of alfentanil in infants and

One study has evaluated the ventilatory effects

insufficient anaesthesia during surgery, additional

Sufentanil is a tertiary amine with a better lipid

Opioid Analgesics in Infants and Children

10. 1.2 Elimination

Animal and human studies have suggested that

Chronic renal failure does not affect the mean

10.2 Intranasal Pharmacokinetics

There is one report on the pharmacokinetics of

The effect of epidural sufentanil on ventilation

0.75 Ilg/kg of sufentanil in 2 ml of isotonic saline

Clin. Pharmacokinet. 28 (5) 1995

Opioid Analgesics in Infants and Children

atric clinical pharmacology. Littleton: PSG Publishing Company, 1985: 17-31

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