Seminars in Fetal & Neonatal Medicine (2006) 11, 260e267

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s i n y

Pain control: Opioid dosing, population kinetics and

side-effects
Sinno H.P. Simons a,b,*, K.J.S. Anand c,d

a
Department of Pediatric Surgery, Erasmus-MC/Sophia Children’s Hospital, Rotterdam, The Netherlands
b
Department of Neonatology, Campus Virchow Klinikum, Charité, Humboldt University Medical Center, Berlin, Germany
c
University of Arkansas for Medical Sciences, College of Medicine, Little Rock, Arkansas, USA
d
Pain Neurobiology Laboratory, Arkansas Children’s Hospital Research Institute, Arkansas Children’s Hospital,
Little Rock, USA

KEYWORDS Summary Neonates undergoing invasive procedures, postoperative pain or ventilatory sup-
Fentanyl; port commonly receive opioids for treating pain and stress. Randomized clinical trials have
Infant-newborn; examined the benefits and adverse effects of morphine or fentanyl for ventilated neonates
Morphine; and other indications. This paper summarizes the current evidence for opioid dosing in new-
Pain; borns, reviews their side-effects and explains the use of population kinetics and non-linear
Stress; mixed-effects modeling to analyze the data from clinical trials. Opioid use should be reserved
Surgery for severe pain postoperatively or during intensive care in neonates, using continuous infusions
rather than intermittent boluses. The safety and efficacy data from prolonged opioid use, par-
ticularly on the long-term outcomes of neonates, is still lacking. The pharmacodynamics and
pharmacogenetics of opioid use in infancy needs further investigation, using non-linear
mixed-effects models to drive individualized therapy. The current interest in opioid research
will reap rich dividends in providing pain relief for neonates and avoiding dangerous side effects.
ª 2006 Published by Elsevier Ltd.

Introduction distribution, metabolism and elimination, and variable

Opioids form the mainstay for treating moderate or severe
pain in preterm and term newborn infants. Opioid dosing
is complicated in this patient population because of
major differences in body composition, drug absorption,
* Corresponding author. Department of Pediatric Surgery,
Erasmus-MC/Sophia Children’s Hospital, Dr Molewaterplein 60,
3015 GJ, Rotterdam, The Netherlands. Tel.: C31 1 0244 9923/
C49 3 0447 14462; fax: C31 1 0463 6288.
E-mail address: sinnosimons@hotmail.com (S.H.P. Simons).
severity of illnesses, together with rapid changes in brain
development, receptor expression, opioid pharmacody-
namics, and pain mechanisms during the third trimester
of gestation and early infancy.
Research during the last two decades has focused on
opioid pharmacokinetics/pharmacodynamics (PK/PD) in
clinical trials and methods for pain assessment in the
newborn infant, but much greater evidence is needed to
develop a scientific rationale for the optimal use of
analgesic agents in neonates. Clinical analgesic trials in
newborns are limited by the lack of gold standards to assess
the different types of pain (injury-related, neuropathic,

1744-165X/$ - see front matter ª 2006 Published by Elsevier Ltd.

doi:10.1016/j.siny.2006.02.008
Pain control 261

visceral, inflammatory) and their combinations in different

clinical settings (postoperative pain, burn pain, birth
trauma, critical illness). Objective methods for the assess-
ment of neonatal pain have focused on acute, tissue-injury
related pain, using constructs for only the intensity of pain.
Furthermore, ethical problems restrain the performance of
well-designed trials. For instance, the number of blood
samples that can be taken for opioid plasma level
measurement is limited, and these cannot always be taken
at predetermined times because of the different needs for
clinical blood sampling. To support clinical decision making
with reasonable costebenefit analyses for opioid use in
neonates, a clearer definition of unwanted opioid side
effects and adverse effects, together with their dose-
related incidence and their incidence in vulnerable
populations of neonates, is required. Some of these areas
are discussed in this paper, to better inform the clinician at
the bedside of a seriously ill newborn infant.
Opioid dosing
Opioid therapy is generally reserved for clinical situations
associated with severe pain. For neonatal patients, opioids
are mostly used during surgical and non-surgical proce-
dures, for postoperative pain and intensive care.1e3 Novel
study designs will be required to clarify the dosing sched-
ules for commonly used opioids, like morphine or fentanyl,
in different clinical situations.4
Fentanyl is a synthetic opioid with activity on m1- and
d-opioid receptors, used frequently in neonates because
of rapid analgesia,5 hemodynamic stability, blocking stress
responses,6,7 and preventing increases in pulmonary vascu-
lar resistance.8 Adult studies suggested that fentanyl is
80e100 times more potent than morphine but neonatal
studies have estimated a potency ratio of 13e20.9 Fentanyl
is highly lipophilic, crosses the blood brainebarrier rapidly,
accumulates in fatty tissues, and causes less histamine
release than morphine. Tolerance to fentanyl develops
more rapidly than to morphine,10 requiring the escalation
of doses during prolonged administration.11,12
Morphine produces analgesia via activity on m1- and m2-
opioid receptors, reduces behavioral and hormonal
responses,13,14 improves ventilator synchrony,15 alleviates
postoperative pain,13,16e18 sedates ventilated preterm
neonates,19,20 and alleviates acute pain caused by invasive
procedures21e23 (although with variable results24).
Postnatal intensive care
One of the most frequent applications of opioids in preterm
and term-born neonates is pain treatment during routine
intensive care. According to previous consensus statements
for neonatal pain therapy,25,26 opioids should be considered
for severely painful procedures (Table 1) or as continuous
infusions during mechanical ventilation. Continuous mor-
phine infusions can be considered for ongoing pain in the
newborn resulting from different etiologies.
The clinical effects of the administered opioids should be
monitored continuously for signs of respiratory or hemody-
namic compromise, or other side effects. The doses listed in
Table 2 are the initial doses recommended for opioid-naive
Table 1 When to consider using opioids in neonates
Painful procedures Ongoing or frequent
pain from
Peripheral arterial Mechanical ventilation
or venous cutdown and suctioning
Central venous Birth trauma
line placement
Peripherally inserted Indwelling chest
central catheter placement tubes or other catheters
Endotracheal intubationa Meningitis
Chest tube insertion Necrotizing enterocolitis
Circumcision Thermal or chemical burns
Other ongoing
severe pain states
a
In combination with atropine and non-depolarizing muscle
relaxant (pancuronium, vercuronium, rorcuronium).
patients. Adequate analgesic therapy requires clinically
driven titration towards the individual infant’s needs.
The optimal use of opioids for neonatal patients during
mechanical ventilation is still under discussion. Opioid
infusions seem more beneficial than intravenous midazolam
for sedation in ventilated neonates, as concluded in a re-
cently performed meta-analysis by the Pain Control Group of
the NICHD/FDA Newborn Drug Development Initiative.2 Lim-
ited evidence is available from studies comparing the bene-
ficial or side effects of fentanyl and morphine.9,10,27,28
Fentanyl has greater analgesic potency, a faster onset and
shorter duration of action than morphine. Fentanyl analgesia
might be preferred for short periods of time because toler-
ance develops more rapidly to fentanyl than to morphine,10
whereas morphine might be preferred for prolonged use.
Saarenmaa et al. compared both agents in a randomized trial
and showed less frequent gastrointestinal dysmotility in fen-
tanyl-treated newborns,9 although this study did not include
a placebo control group. Clinical trials comparing fentanyl
with placebo are limited but show reduced pain/stress in
ventilated newborns after a single dose of fentanyl,29 as
well as continuous fentanyl infusions.6,30
Morphine has been investigated more frequently and
thoroughly, although a large, placebo-controlled multicen-
ter trial comparing both morphine and fentanyl on impor-
tant outcome measures is not available. The neonatal pain
consensus statement advises neonatal intensive care units
(NICUs) to use only one opioid analgesic agent to ensure
familiarity with its use.25,26 Clinicians can switch from one
opioid agent to another after prolonged opioid use, or to
obtain better sedation, or to avoid specific side effects,
Table 2 Opioid dosing: starting dosage regimen
Opioid Bolus/ Continuous
intermittent doses infusion dose
Morphine 0.05e0.1 mg/kg iva 0.01e0.03 mg/kg per h
Fentanyl 0.5e2.0 mg/kg iv 0.5e2.0 mg/kg per h
a
Evidence for side-effects and worse outcomes were related
with additional morphine boluses given to neonates receiving
continuous infusions of morphine.
262 S.H.P. Simons, K.J.S. Anand

such as those related to morphine-mediated histamine re-
lease.9,10,27,28 The evidence for opioid cross-tolerance is
lacking in neonates, although a limited role of methadone
therapy for treating opioid tolerance and withdrawal has
been proposed.31
A recent Cochrane meta-analysis of all high-quality
randomized controlled trials studying opioids during neo-
natal intensive care concluded that insufficient evidence
was available for routine opioid administration during
ventilatory support.32 This was mainly attributed to the
lack of overall benefits from morphine therapy on impor-
tant outcome measures such as death, intraventricular
hemorrhage, and periventricular leucomalacia. Further-
more, continuous morphine administration does not result
in clinically significant decreases of pain scores during
invasive procedures, such as heel-sticks24 or endotracheal
suctioning.33 Therefore, pre-emptive continuous opioid in-
fusions should not be given to newborns routinely during
postnatal intensive care. Results from two recently
performed placebo-controlled randomized trails are
summarized in Table 3.
Meta-analysis of the data from these two trials, expanded
with data from the NOPAIN pilot study, revealed that
morphine infusions reduce pain (although the clinical sig-
nificance of this decrease in pain can be questioned) but
increase the number of ventilated days.2 Results from the
NEOPAIN multicenter trial showed that intermittent
administration of morphine boluses were related to worse
pulmonary and neurological outcomes and increased hypo-
tension.34e36 Taken together, these data favor the use of

Table 3 Comparison of the NEOPAIN and Dutch trial: studying continuous morphine in newborns receiving ventilatory support
Anand et al.34 Simons et al.33
Methods
Design RCT, placebo controlled, blinded, 16 RCT, placebo controlled, blinded, two centers
centers
Morphine doses Loading dose: 100 mg/kg morphine Loading dose: 100 mg/kg; morphine infusions
infusions 10e30 mg/kg (increasing with GA) 10 mg/kg/h
Additional ‘open label’ morphine permitted Additional ‘open label’ morphine permitted
if necessary if necessary
Primary outcome Composite outcome: neonatal death, Analgesia
severe IVH and PVL
Secondary outcome Analgesia, side-effects Composite outcome, (nor)adrenaline plasma
levels, side-effects
Patients
Inclusion Ventilated, within 72 h of birth Ventilated, within 72 h of birth
Number 898 150
Gestational age range 23e32 weeks 25e42 weeks
Results
Composite outcome Overall: no significant difference. Patients Overall: No significant difference. Significantly
without open label morphine: morphine group more IVH (all stages) in the placebo group
more composite outcome and severe IVH.
Placebo group with ‘open-label’
morphine: more composite outcome.
Morphine group with ‘open label’
morphine: more severe IVH
Analgesia Lower PIPP scores in morphine group No difference in pain scores (PIPP/NIPS/VAS/
after 24 h. No differences in DAN and Comfort score)
PIPP during heelsticks24
‘Open label’ morphine Fewer neonates in morphine group (45.3%) Non-significant difference between morphine
use than in placebo group (54.6%) group (27%) and placebo group (40%)
(Nor)adrenaline plasma e No difference in adrenaline and lower
levels noradrenaline in morphine group37
Side-effects
Hypotension Associated with pre-existing hypotension No overall effect of morphine on blood pressures.
and additional morphine doses35 More frequent hypotension by preemptive
morphine and by ‘open label’ use in
the placebo group38
Pulmonary outcome Morphine group longer ventilated, No differences in length of ventilation
no further differences36
DAN, Douleur Aigue Nouveau-ne; GA, gestational age; IVH, intraventricular haemorrhage; NEOPAIN, neurologic outcomes and pre-
emptive analgesia in neonates; NIPS, Neonatal Infant Pain Scale; PIPP, premature infant pain profile; PVL, periventricular leucomalacia;
VAS, visual analogue scale.
Pain control
continuous or slow morphine infusions above the use of re-
peated, intermittent boluses. Continuous opioid administra-
tion should not be used as the standard of care but started
only if required for specific clinical situations in individual
patients. After careful evaluation of the available evidence,
the NICHD/FDA Pain Control Group recently concluded that
there are limited data to guide clinical analgesic therapy
in neonates, and that much more research is needed.1e4
Opioids for surgery or postoperative analgesia
In the 1980s, studies by Anand and Aynsley-Green provided
evidence for the importance of analgesia during and after
neonatal surgery. It was shown that neonates mount a sub-
stantial stress response during surgery and that those who
received fentanyl during surgery had improved postopera-
tive outcome.7 These studies, only 20 years ago, were
a turning-point for many centers around the world to start
giving adequate analgesia and anesthesia for neonatal sur-
gery. Since then, many studies have been done to improve
neonatal analgesia during and after surgical procedures.
For postoperative analgesia, again morphine and fen-
tanyl are the best studied and most frequently used opioids,
although several other agents have been investigated.3,39
Many pharmacokinetic and some pharmacodynamic studies
with morphine have been performed. Clinical trials studying
morphine for postoperative analgesia have shown large in-
terindividual variability in morphine plasma levels and
a wide range of morphine requirements.40 Comparing inter-
mittent and continuous morphine dosing revealed no,17 or
limited,40 differences in pain relief or stress-hormone
levels.14 A meta-analysis calculated that an initial morphine
dose of 7 mg/kg/h is sufficient for postoperative analgesia in
term-born neonates.41 It has been suggested that neonates
need less morphine after cardiac surgery than after non-
cardiac surgery42 and pharmacokinetic studies showed
that morphine requirements increase with gestational and
postnatal age.13,43,44 The latter is probably mediated by
immature morphine metabolism, mainly hepatic glucuroni-
dation from morphine into morphine-3-glucuronide (M3G)
and the active metabolite morphine-6-glucuronide (M6G),
both of which are catalyzed by the enzyme UGT2B7.
In general, the doses as listed in Table 2 can also be used
for postoperative opioid analgesia. Perioperative pain con-
trol should, in most cases, begin with the anesthetic man-
agement during surgery. Again postoperatively, opioid
doses should be adapted towards the needs and clinical re-
sponses of the individual infant. The management of post-
operative pain was also complicated by the lack of
objective measurement tools for neonatal pain, a serious
limitation in assessing analgesic efficacy until recently.45e47
Population kinetics
Although a number of analgesic trials have been published
during the last few years, large gaps remain in the current
pharmacokinetic and pharmacodynamic knowledge of opi-
oid analgesics in the newborn infant. Prospective clinical
trials in newborn infants are difficult to perform, time
consuming, expensive and research methods are limited by
the special ethical considerations that must be taken into
263
account.4 An important ethical limitation is the number of
samples and amount of blood that can be obtained for phar-
macokinetic analyses of a drug. Also, blood samples cannot
always be taken at predetermined times because of clinical
constraints. The heterogeneity of the studied population
adds to this, with widely variable gestational ages, post-
natal ages, bodyweights, variability in severity of illness,
kidney and liver function, amongst other factors.
A modern analysis technique to deal with these compli-
cated issues is to analyze data using non-linear mixed-
effects modeling (NONMEM) methods. NONMEM is an
analysis technique that is used in adults to analyze the
kinetics of pharmacological agents. It can be used to provide
estimates of pharmacokinetic parameters and the explora-
tion of covariate relationships (so-called fixed effects).
Furthermore, population parameter variability, within and
between subjects, and residual variability (random effects)
can be easily incorporated into the model, features that
beleaguered the analysis of classical pharmacokinetic
models. Although originally used for pharmacokinetic anal-
yses, NONMEM can also be used to study the pharmacody-
namics of a drug. Next to plasma levels of opioids and their
metabolites, the pain scores or stress hormone levels can
also be included into the model. All available PK/PD studies
of neonatal morphine use were unable to correlate plasma
levels with pain scores until now.13,40,44 NONMEM provides
promising opportunities to further analyze the relationships
between opioid plasma levels and pain scores in newborn
infants. NONMEM has already been used to study
pharmacokinetics in newborns for caffeine, midazolam,
acetaminophen (paracetamol), antibiotics (such as genta-
micin and vancomycin), and other drugs used in the neo-
nate. Only few trials have used NONMEM to analyze
opioids in newborn infants. Bouwmeester and colleagues
analyzed morphine and its metabolites M3G and M6G in new-
borns and young infants after surgery.48 A mathematical
model was created in which a certain dose of morphine
given results in a plasma morphine concentration with a
certain volume of distribution (Fig. 1).
Morphine is metabolized in the liver to M6G and M3G and
consequently ‘cleared’ into these two metabolites (CL2M6G
and CL2M3G). Another part of morphine is excreted un-
metabolized, mainly in the urine (CLEX). The liver-produced
metabolites result in certain M3G and M6G plasma levels in
their specific volumes of distribution (V6M and V3M), and are
excreted mainly in the urine, defined as elimination clear-
ance (CLM6G and CLM3G). The mathematical formulae
underlying this pharmacokinetic model enabled Bouw-
meester et al to analyze the effects of age and other factors
on morphine and metabolite pharmacokinetics. A second
study plotted Bouwmeester’s data with plasma levels from
neonates receiving various doses of morphine for analgesia
and sedation during extracorporeal membrane oxygenation
(ECMO).49 Interpretation of the morphine plasma levels
from ECMO-treated infants is complicated because of the
large ranges in morphine dosing between individuals,
many alterations in dosing for each patient, interactions
with several co-medications, and unknown effects of
the ECMO membranes. Despite this complexity, using
population pharmacokinetics, the clearances of morphine
and its metabolites could be calculated and compared
with data from non-ECMO treated newborns (Fig. 2).
264
Figure 1 Pharmacokinetic model of morphine (from ref.,48
with permission). CL2M3G/CL2M6G, formation clearance to
metabolites; CLEX, unaccounted clearance; CLM3G/CLM6G,
elimination clearance of metabolites; CM3G/CM6G, serum me-
tabolite concentration; CS, morphine serum concentration;
Dose, dose given; V, volume of distribution for morphine;
V3M/V6M, volume of distribution of metabolites.
This study illustrates the usefulness of NONMEM methods
for studying the pharmacokinetics of opioids, to calculate
clearances and half-lives, and to develop recommendations
for opioid doses that should be used under specific circum-
stances, such as interactions with comedications or ECMO
systems. The modeling of plasma levels can provide data for
mean pharmacokinetic parameters in a specific population
of newborn patients, which, in turn, can be used to
calculate mean effective analgesic plasma concentrations
and to design a dosing regimen. The interindividual vari-
ability between patients, however, results in the limited
usefulness of population pharmacokinetics to predict the
amount of analgesia required by an individual patient. If
more data become available about DNA polymorphisms
explaining the interindividual variability in opioid plasma
levels between subjects, future studies will incorporate this
genetic variability into their PK/PD models.
Figure 2 Individual predicted morphine clearance values,
standardized to a 70-kg person, from the NONMEM post hoc
step, are plotted against age. The solid line demonstrates
a non-linear relationship between clearance and age for post-
operative children (open diamonds) (from ref., 4 9 with
permission).
S.H.P. Simons, K.J.S. Anand
Side effects
The ideal opioid drug would have a rapid onset of action,
a short duration of action, proven efficacy against acute
and chronic pain, and minimal side effects such as hypo-
tension, respiratory depression, chest-wall rigidity, urinary
retention, nausea/vomiting, constipation, increased risk of
necrotizing enterocolitis, and others (Table 4). Long-acting
drugs such as morphine and methadone might not be useful
when immediate analgesia is required, whereas short-
acting drugs like fentanyl, alfentanil and remifentanil can
cause significant hypotension, chest-wall rigidity, and toler-
ance. In addition, very little is known about the side effects
of repeated opioid administration, or specific safety issues
related to critically ill, neurologically impaired, congeni-
tally malformed, or other special populations of neonates.
One of the main arguments against the treatment of
neonatal pain with opioids is the uncertainty about their
side effects.50 Research groups studying neuronal apoptosis
in rodent models concluded that anesthetic agents are
harmful for the neonatal rat brain,51e54 and that these
data might be translated to the human developing
brain.53,55 However, repeated administration of high doses
was used in these rodent studies56,57 and their translation
to the human newborn has been questioned.58,59 Neverthe-
less, these data continue to support some clinicians in their
fear of using these anesthetic agents.
Limited data are currently available about the long-term
effects of morphine and fentanyl in newborn rats,60e64
whereas the limited evidence available from human trials
concerning opioid use in the neonatal period generally sug-
gest beneficial long-term effects.65e67 Large, randomized
controlled trials studying the effects of opioids in human neo-
natal clinical practice are not able to show negative effects of
this treatment.33,34 The expected side effects of morphine,
such as hypotension35,38 and effects on pulmonary out-
come,36 were found to be limited to specific subgroups, and
therefore can be avoided. The primary outcomes of the trials
suggest a possible effect of morphine on the development of
intraventricular hemorrhages, which might be a protective
effect of routinely administrated morphine,33 or caused by
the intermittent administration of additional morphine
doses.34 Overall intermittent boluses of morphine seem to
be related with worse outcome and side effects.34e36
Table 4 The side-effects of morphine and fentanyl in
newborns
Opioid Side-effect References
Morphine Respiratory depression 41,68e72
Decreased gastrointestinal 9
motility
Hypotension 16,73,74
Urinary retention 75
Risk of necrotizing enterocolitis 76
Fentanyl Respiratory depression 6,77
Hypotension 78
Muscle rigidity 79e83
Hypothermia 7,84
Adapted from ref.26
Pain control
Side effects from neonatal opioid use on long-term
outcomes remain largely unknown. The follow-up of ran-
domized controlled trials that studied effects of morphine
use in the neonatal period did not find any differences in
the cognitive, behavioral and neuromotor outcomes of
morphine-treated children compared to the control
group.67 This study was flawed by its small sample size
and the use of pancuronium for some neonates in the
control group. A non-randomized, retrospective cohort
study found that, following birth asphyxia, MRI scans of
the neonates who received morphine or fentanyl for post-
natal intensive care demonstrated significantly less brain
injury in all regions studied, and these infants had better
long-term neurologic outcomes.66 The neonates who re-
ceived opioids had also experienced hypoxic/ischemic
insults of greater magnitude (with higher plasma lactate
levels and lower 5-min Apgar scores), suggesting that use
of opioids after perinatal asphyxia might have no significant
long-term detrimental effects and might increase the
brain’s resistance to hypoxic-ischemic damage.66 More
data is required, however, from the follow-up of infants
that have participated in randomized controlled trials of
opioids during the neonatal period.50,85
No large, multicenter, placebo-controlled, randomized
trial investigating fentanyl in newborns has been per-
formed. Data from relatively small trials show no serious
side effects on the short time perspective with fentanyl in
newborns.6,30,86 apart from respiratory depression and pro-
longed ventilation. Another randomized trial comparing
morphine with fentanyl suggests even fewer side effects
from fentanyl than from morphine.9
Conclusions
Clinical trials, mainly including morphine and fentanyl, have
shown that opioids can be safely used for neonates during
postnatal intensive care and postoperative care. For severe
pain, continuous morphine infusions appear to be the first
choice. During mechanical ventilation and neonatal inten-
sive care treatment, morphine should not be routinely given
to all ventilated preterm newborns but can be started for
the individual infant with significant pain from chest tubes
or other devices, based on pain scores. Continuous low-dose
infusions are preferred, particularly for preterm neonates,
because intermittent boluses might be related to worse
neurological outcomes. The long-term effects of opioids
received during the neonatal period remain unknown.
Practice points
 Morphine and fentanyl are reserved for postopera-
tive pain or severe pain during intensive care
treatment in newborns.
 During mechanical ventilation, evidence of opioid
use is still lacking and should therefore be consid-
ered individually for each patient; doses should be
adapted to the infant’s needs.
265
Research agenda
 Despite the information that has become available
from recently performed trials, the safety and
efficacy of short-term and long-term opioid ther-
apy for newborn patients needs to be evaluated
in additional well-designed trials.
 Pharmacokinetic, dynamic and genetic data
obtained in from these trials should be analyzed
using non-linear mixed-effects-modeling (NONMEM).
 Greater understanding of the genetic, epigenetic,
environmental, and clinical factors that determine
opioid dosing will allow greater predictability of
clinical effects and side effects for individual
patients.
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