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10. THE PAEDIATRIC PATIENT
10.1 DEVELOPMENTAL NEUROBIOLOGY OF PAIN
Following birth, the neural pathways required for nociception are functional and cortical
responses to noxious stimuli such as blood tests can be demonstrated in even the most
premature neonate (Slater et al, 2006). However, as significant functional and structural
changes occur in nociceptive pathways during the postnatal period, pain does not evoke the
same pattern of activity in the infant and adult central nervous system (Fitzgerald & Walker,
2009). The expression of a number of molecules and channels involved in nociception are
developmentally regulated, there are changes in the distribution and density of many
important receptors, and the levels and effects of several neurotransmitters alter significantly
during early life (Fitzgerald, 2005).
Although C‐fibre polymodal nociceptors are mature in their pattern of firing at birth and are
capable of being activated in the periphery by exogenous stimuli, their central synaptic
connections in the dorsal horn are initially immature. However, ‘wind up’ can be produced by
relatively low intensity A‐fibre (rather than C‐fibre) stimulation, as A‐beta fibres initially extend
up into laminae I and II and only withdraw once C fibres have matured. This overlap means
there is less discrimination between noxious and non‐noxious stimuli, and as the receptive
fields of dorsal horn neurones are large, peripheral stimuli can excite a greater number of
central neurones. In addition, descending inhibitory pathways and inhibitory networks in the
dorsal horn are not fully mature in early development. Therefore, rather than neonates being
less sensitive to painful stimuli as was once thought, the relative excess of excitatory
mechanisms and delayed maturation of inhibitory mechanisms produce more generalised and
exaggerated reflex responses to lower intensity stimuli during early development (Fitzgerald,
2005). Although the underlying mechanisms may differ, nociceptive pathways can be sensitised
by painful stimuli in early life, as demonstrated by a reduction in reflex thresholds in neonates
following repeated heel lance (Fitzgerald et al, 1988 Level IV) and infants following abdominal
surgery (Andrews & Fitzgerald, 2002 Level IV).
Factors affecting the pharmacokinetic profile of analgesic drugs (body water and fat
composition, plasma protein binding, hepatic metabolism and renal function) change rapidly
during the first weeks of life. Postnatal changes in the pharmacokinetic profile of a number of
analgesic drugs (eg morphine and paracetamol [acetaminophen]) resulted in significant age‐ CHAPTER 10
related changes in dose requirements during infancy and childhood (Bouwmeester et al, 2004;
Palmer et al, 2008; Prins et al, 2008). In addition, changes in nociceptive processing may have
significant effects on the pharmacodynamic response to analgesics in early life (Walker, 2008).
Therefore, developmental age and not just weight should be considered when calculating
analgesic dosing. Laboratory studies have demonstrated postnatal changes in the mechanism
of action, analgesic efficacy, and side‐effect profile of analgesics that can inform subsequent
clinical trials (Nandi & Fitzgerald, 2005; Walker, 2008; Fitzgerald & Walker, 2009). In addition,
prolonged reductions in synaptic activity by general anaesthetics and analgesics can produce
unexpected neurotoxic effects, such as apoptosis, in the developing nervous system (Mellon et
al, 2007), although the clinical significance of these findings requires further research.
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