Knelpunten in het management van acute pijn bij kinderen

mei '10 nederlands tijdschrift voor anesthesiologie 17
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1. Neonatal pain exposure and
its long-term consequences
Newborns are often exposed to noxious
stimuli in the neonatal intensive
care unit (NICU). The impact of this
pain exposure is increasing due to high
preterm birth rates and medical advances
which decrease the gestational
age at which preterm born neonates
survive. Besides major surgery, neonates
undergo many noxious stimuli
for monitoring of their health status in
the NICU for which analgesia is often
inadequately administered. In a Dutch
NICU, neonates received up to 14 daily
repetitive noxious routine procedures,
such as heel pricks, injections and intubations
[1].
It has been suggested that neonatal
pain exposure has a long-term impact
on pain sensitivity later in life.
Sensory neuronal circuits within the
CNS are still undergoing development
after birth and this development is
activity-dependent, i.e. the formation
and extension of the pain network is
based on the amount of nociceptive
stimuli neonates receive [2]. Excessive
noxious stimulation of the pain
network via either major surgery or
repetitive pain exposure in the NICU
may result in different pain response
later in life. For instance, children who
had experienced neonatal surgery,
showed an increased need of intra- and
post-operative analgesia following
surgery in the same dermatome later
in life[3]. Also, neonatal circumcision
increased the pain response to a future
pain stimulus, i.e. routine vaccination,
three months later [4]. Not only
neonatal surgery, but also a history of
NICU-stay has been linked with longterm
changes in pain sensitivity. Preterm
and full-term school-aged (9-11
years) children previously exposed to
painful NICU procedures were found
to be less sensitive to acute heat stimulation
than children which were not
exposed to NICU interventions, which
reflects a decreased baseline pain sensitivity
[5]. In contrast, when exposed to
a prolonged noxious thermal stimulus,
the ex-NICU children showed lower
pain thresholds than control children
[5]. In conclusion, clinical evidence is
accumulating on the impact of early
life pain exposure and its long-term
consequences on pain sensitivity.
2. Analgesia in newborns
and infants: An evidence
based approach
Pain and anxiety have been recognized
as significant problems in hospitalized
children. Especially in the very young
and under specific conditions (postoperative;
critically ill children), there
is a lack of evidence-based selection
and dosing of analgesics, while longterm
consequences of prolonged use
of these drugs are unknown. Eighty
percent of drugs are used off-label
and/or unlicensed. This has raised
public awareness in both the USA
and EU (Best Pharmaceuticals for
Children Act in 2002, NIH/FDA meeting
2004, European law dedicated
to Medicines and Children, 2007).
The European Medicines Agency
(EMEA) has identified a number of
analgesics and sedatives as research
focus for pain and anxiety in line with
the recently released Medicines for
Children Research Network (MCRN)
and the ERA-NET PRIOMEDCHILD
(2008). These priorities include
morphine and paracetamol in the
newborn, peri-operative paracetamol
and midazolam. The EPIPAIN study
(Epidemiology of Procedural Pain in
neonates) revealed that each neonate
was found to experience a median of
115 procedures during a study period
of 14 days while the majority (79,2%)
of these procedures was not accompanied
by analgesia [6]. It is thought
that adequate analgesic therapy for
neonates receiving intensive care may
be beneficial with respect to shortterm
and perhaps long-term outcomes
[7-9]. However, two studies on shortterm
effects of opioids in premature
neonates showed minimal to no effects
on the behavioural pain scores and
slightly reduced stress hormone levels
following continuous morphine treatment
in ventilated newborns [10, 11].
None of the studies provided enough
evidence to recommend continuous
morphine as a standard of care for
preterm ventilated newborns. A recent
Cochrane review [12] came to the same
conclusion. Nowadays paracetamol is
the most common used analgesic and
antipyretic drug in children and even
prescribed in neonates to treat mild
to moderate pain or combined with
opioids. Paracetamol is less potent
than opioids and with probably less
side effects, although hepatotoxicity is
described [13-16]. Limited studies are
published on the use of intravenous
paracetamol in preterm neonates,
especially those under the gestational
age of 28 weeks. To provide evidence
for the most effective and safe drug
for newborns and infants, studies are
needed on the effects and safety of
paracetamol and morphine in young
infants. As evidence for morphine in
neonates is subject to debate, studies
on (opioid saving properties of )
paracetamol are needed. In particular,
in post-operative conditions and after
prolonged use in critically ill children.
Within these studies, emphasis should
be put upon the characterization
of the optimal dose based on body
weight, post-menstrual and post-natal
age. Therefore the influence of age
on the pharmacokinetic (PK) and
pharmacodynamic (PD) parameters
of these drugs should be investigated.
Advanced statistical techniques such
as non-linear mixed effects modelling
are applied. Using these modelling
techniques, infrequently obtained
samples and observations in the real
life clinical situation can be utilized to
analyze population PK (drug concentrations)
and PD (efficacy and safety
endpoints) as well as determinants
of variability in drug response. Ultimately
this results in rational individualized
dosing regimens for neonates
and infants.
3. The development of
experimental neonatal
pain animal models
Three important research questions
arise from the abovementioned clinical
evidence for long-term changes
in pain sensitivity after early-life pain
exposure in the NICU and use of analgesia
in neonates and infants:
1. What are the underlying mechanisms
of long-term consequences of
repetitive neonatal pain exposure?
2. Which analgesic drugs are effective
for pain management in neonates
and infants and can they affect the
long-term pain sensitivity changes?
3. PK and PD parameter characteristics
of analgesic drugs in neonates
and infants?
Due to several important limitations
in clinical research, experimental
neonatal pain models have been developed.
To study the underlying mechanisms
of the long-term changes in pain
sensitivity following neonatal pain