Knelpunten in het management van acute pijn bij kinderen

18 nederlands tijdschrift voor anesthesiologie mei '10
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exposure and the working mechanism
of analgesics, tissue needs to be collected
for histological, molecular and
biochemical analysis. Obviously this
is not possible in human neonates. An
additional problem in clinical studies
is the correct comparison between
experimental and control groups, e.g.
the experimental group of preterm
born children can only be compared
to a healthy control group of children
with a different age, i.e. term born
children. Animal experimental studies
on the other hand, do allow the comparison
between a neonatal pain group
and a non-pain group of the same age.
Additionally, dose finding and safety
testing of analgesics can be more easily
carried out in an animal model. To this
end, the neonatal rat is used, which
developmental stage in the first week
of life corresponds to a human foetus
in the third pregnancy trimester or to
a preterm born child in the NICU.
Several clinically relevant animal models
for neonatal surgery, which show
long-term changes in pain sensitivity,
have been developed during the
past few decades. Incision of the hind
paw skin of a neonatal rat aged 3 days
old (P3) or P6, for instance, has been
shown to result in hyperalgesia following
repeated incision of the ipsilateral
paw, performed two weeks later [17].
Experimental modelling of repetitive
noxious routine interventions in the
NICU faced many difficulties or lacked
clinical relevance.
Figure 1. Experimental rat model to mimic repetitive pain exposure in preterm born children in
the NICU and its long-term consequences on pain sensitivity. Neonatal rat pups were noxiously
stimulated with a needle prick 4x/day during the first week of life (A). Control animals received a
fourfold daily tactile stimulus (B). When the rats reached the adult age of eight weeks, they were
injected with a noxious substance, causing painful inflammation, in the ipsilateral hind paw (C)
and 24h later, their pain sensitivity towards mechanical stimuli was tested with a set of calibrated
von Frey filaments with increasing stiffness (D).
Research conducted at the Pain Management and Research Centre (Maastricht, the Netherlands).
Noxious inflammatory substances,
such as complete Freund’s adjuvant
(CFA), an inflammatory booster, or
carrageenan (CAR), a polysaccharide,
were used via a single intraplantar injection
to induce pain in neonatal rats
of several days old (P0-P3) [18-22]. As
a consequence, these animals showed
long-term changes in pain sensitivity,
e.g. hypoalgesia to tactile and thermal
stimulation from the young adult age
of P34 up to at least P120 (adult) [9].
In contrast, when these adult rats received
an ipsilateral (neonatal CAR or
CFA exposed) re-inflammation of the
paw with CFA, they showed a higher
degree of mechanical allodynia and
thermal hyperalgesia [19, 20]. The findings
of the single-injection neonatal
inflammation models already showed
some similarity with the clinical situation
of long-term pain sensitivity
changes after neonatal pain exposure.
However, the nature of the neonatal
pain stimulus used, has a low clinical
relevance since injecting these inflammatory
substances does not occur in
neonates in the NICU. Moreover, a
single injection with a high dose of
CFA [18, 20, 21] results in chronic inflammation,
lasting for at least 8 weeks
after injection, and a low dose of CFA
or CAR [19, 22] results in a local inflammation
lasting for about 24 hours.
Next, researchers tried to develop
animal models which mimicked the
situation of neonatal pain exposure in
the NICU more closely. To this end,
neonatal rat pups were repetitively
(daily from P0-P14) injected with formalin,
a milder inflammatory agent,
into all four paws, resulting in longterm
increased pain sensitivity [23, 24].
The main limitation of using formalin
is the fact that it causes fixation of tissue,
since it is a derivative of the tissue
preservative formaldehyde. This could
change the morphology of peripheral
nerve endings.
The use of needle pricks as a neonatal
pain stimulus was considered as a good
model for repetitive pain stimulation
as it occurs in the NICU [25]. These
researchers only found minor effects
on long-term sensitivity to thermal
stimulation [25]. The nature of the
neonatal stimulus used here, is highly
clinically relevant since skin breaking
procedures are prevalent in the
NICU. Unfortunately the researchers