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Over the past two decades, there has been significant progress in the understanding of neuroanatomy, physiology, and the pharmacology of analgesics in children, which has led to considerable advancements in pediatric pain management. This chapter discusses developmental anatomy and neurochemistry, pain assessment, pharmacologic treatment of pain, and techniques for providing pain relief.


The Infants and fetuses in the last trimester are neurologically sophisticated in their ability to transmit pain signals and respond to stress.1 Cutaneous sensory nerve terminals are present in the perioral region at 7 weeks’ gestation and spread to all body areas by 20 weeks’ gestation. Nerve growth factors regulate the extension of peripheral nociceptive fibers into the dorsal spinal cord, with the larger A fibers entering prior to the C fibers at 8 to 12 weeks’ gestation. At birth, A and C fiber territories overlap in the developing substantia gelatinosa.2 Therefore, the neonatal response to a nonspecific sensory stimulus is low-threshold, nonspecific, and poorly organized, as are the well-defined neonatal motor reflexes.3,4 Noxious and non-noxious stimuli produce similar physiologic and behavioral infant responses, which complicate an accurate assessment of pain.5

In the central nervous system (CNS), the full complement of cortical neurons, approximately 1000 million, is present at 20 weeks’ gestation. Pain transmission pathways complete myelination in the spine and brain stem between 22 and 30 weeks’ gestation. Myelination extends to the thalamus by 30 weeks, and to the cortex by 37 weeks or term. Research using near-infrared spectroscopy (NIRS) shows activation of somatosensory cortex in preterm infants after noxious stimulation.5,6 Cortical descending inhibition develops post-term. Excitatory and inhibitory neurotransmitters and neuromodulators are present in the fetus, with the balance favoring excitation. Calcitonin gene-related peptide (CGRP), substance P, and the glutamate-NMDA systems are present at 8 to 10 weeks’ gestation. Enkephalins and vasoactive intestinal peptide (VIP) appear at 10 to 14 weeks’ gestation. Catecholamines are present in late gestation, and serotonin at 6 weeks’ postnatal. Of note, the receptors for excitatory neurotransmitters are numerous and widely distributed in the neonate, regressing toward an adult system in the postnatal months. As well, in the developing nervous system, inhibitory chemicals, such as γ-aminobutyric acid (GABA) and glycine, may act as excitatory transmitters. In an experimental murine model, the spinal cord concentration of N-methyl-D-aspartate (NMDA) receptors, and their ligand-affinity, is greater in neonates than in older animals. Neurokinin 1 (NK1) receptor density is also maximal in late fetal and early postnatal life; however, substance P levels are lower at birth than adult levels.7

In relation to stress responses, the functional neuroendocrine pathways between hypothalamus and pituitary are present at 21 weeks’ gestation. Corticotropin-releasing factor (CRF) may stimulate fetal adrenocorticotropic hormone (ACTH) and β-endorphin from that time period, and cortisol and β-endorphin increases have been assayed following ...

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