- Assistant Professor of Evidence-based Practice, Department of Family and Community Health University of Pennsylvania School of Nursing, Director of Research and Evidence-based practice, Pennsylvania Hospital, USA
Correspondence Address:
Linda A. Hatfield
Assistant Professor of Evidence-based Practice, Department of Family and Community Health University of Pennsylvania School of Nursing, Director of Research and Evidence-based practice, Pennsylvania Hospital, USA
DOI:10.4103/2152-7806.144630
Copyright: © 2014 Hatfield LA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Hatfield LA. Neonatal pain: What's age got to do with it?. Surg Neurol Int 13-Nov-2014;5:
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Abstract
Background:The neurobiology of neonatal pain processing, especially in preterm infants, differs significantly from older infants, children, adolescence, and adults. Research suggests that strong painful procedures or repeated mild procedures may permanently modify individual pain processing. Acute injuries at critical developmental periods are risk factors for persistent altered neurodevelopment. The purpose of this narrative review is to present the seminal and current literature describing the unique physiological aspects of neonatal pain processing.
Methods:Articles describing the structures and physiological processes that influence neonatal pain were identified from electronic databases Medline, PubMed, and CINAHL.
Results:The representation of neonatal pain physiology is described in three processes: Local peripheral nervous system processes, referred to as transduction; spinal cord processing, referred to as transmission and modulation; and supraspinal processing and integration or perception of pain. The consequences of undermanaged pain in preterm infants and neonates are discussed.
Conclusion:Although the process and pain responses in neonates bear some similarity to processes and pain responses in older infants, children, adolescence, and adults; there are some pain processes and responses that are unique to neonates rendering them at risk for inadequate pain treatment. Moreover, exposure to repeated painful stimuli contributes to adverse long-term physiologic and behavioral sequelae. With the emergence of studies showing that painful experiences are capable of rewiring the adult brain, it is imperative that we treat neonatal pain effectively.
Keywords: Neonate, neurodevelopment, pain, preterm infant, pain processing
INTRODUCTION
Although it has been nearly 27 years since Anand and Hickey's[
EXPOSURE TO PAIN EARLY IN LIFE
Research suggests that strong painful procedures[
Extensive preclinical trials have established the physiological impact of early exposure to noxious stimuli on the developing nervous system.[
ELEMENTS OF PAIN PERCEPTION
Pain is a perception, not a sensation. It involves sensitivity to chemical changes in the tissues and interpretation that such changes are harmful. This perception is real, whether the harm has occurred in the past or is happening in the present. Cognition is involved in the formation of this perception. There are emotional consequences and behavioral responses to the cognitive, emotional and physiological aspects of pain.[
Pain is a linguistic description for an expansive variety of experiences and responses. It is an abstract representation of the information that is subsequently reexamined over long periods by the entire somesthetic system.[
Pain responses are integral components of an adaptive biologic system that enables a newborn to function in a dynamic, challenging, and potentially dangerous environment. These responses represent reactions, modulations, and integration by the peripheral nervous system (somatosensory, somatomotor, autonomic), spinal cord, and brain (brain stem, medulla, hypothalamus, thalamus, limbic system, cranial nerves, and the neocortex). Taken together, the responses are concurrent reactions of pain perception; an experience of emotions and autonomic, somatomotor and endocrine responses rather than sequential reactions.[
DEVELOPMENTAL NEUROBIOLOGY OF NEONATAL PAIN
Simply expressed, pain is a three-neuron relay that detects sensations in the periphery and conveys the sensations via second and third order neurons through the spinal cord, brainstem, and thalamic relay nuclei to the cerebral cortex.[
This representation of neonatal pain physiology is organized in three sections:
Local peripheral nervous system processes or transduction occurs when noxious stimuli are translated into neuronal action potential at the nociceptors, which are the sensory endings of the primary afferent neurons in the periphery Spinal cord processing, referred to as transmission and modulation, is the propagation of action potentials along ascending pathways from the site of transduction throughout the sensory nervous system to the spinal cord, then centrally to the brain; and activation of descending pathways that exert inhibitory effects on the synaptic transmission of noxious stimuli Supraspinal processing and integration of pain or perception of pain is the result of neural processing: Recognition, defining and responding to noxious stimuli in the brain.[
The discussion is presented sequentially for clarity; however, processes are interactive and occur concurrently.
Maturation of local peripheral nervous system responses or transduction
The peripheral nervous system, part of the somatosensory system, consists of three primary afferent fibers, Aδ (thinly myelinated, mechanosensitive pain receptors), Aβ, and C-polymodal fibers (unmyelinated, mechanical, chemical, and thermal sensitive pain receptors)[
Table 1
Primary afferent fibers[
Tissue injury initiates a cascade of peripheral neuronal responses. Noxious stimuli are transduced to electrical activity at the peripheral terminals of Aδ and C polymodal fibers and are immediately conducted to the dorsal horn of the spinal cord. The cellular and blood vessel damage from the injury along with inflammatory and tumor cells, release biochemical mediators (bradykinin, calcium and potassium ions, substance P, and prostaglandins) that activate or sensitize Aδ and C polymodal afferent nociceptors that transmit pain impulses to the spinal cord and stimulate local inflammatory flare and wheal responses. Concurrently, substance P and prostaglandins increase the local tissue inflammation creating local primary hyperalgesia.[
In addition to hyperalgesia, tissue damage in early life causes profound and persistent dendritic sprouting in the local sensory nerve terminals. Compared with the older infant, sprouting is more prominent when tissue damage occurs at birth or shortly thereafter.[
In the past, lack of myelination was used to support the argument that the premature infant's nervous systems was immature[
Maturation of spinal cord processing or transmission and modulation
Early in life, the spinal cord of the neonate's immature nervous system functions as an independent unit. Because of the immature descending pathway, the neonatal cortex has little control over pain processes. Biobehavioral pain responses to noxious stimuli are a series of decorticate spinal reflexes. As the cortex assumes control, time, experience, and maturity integrate immature reflexes into sophisticated adult behavior patterns.[
The spinal cord level has three important nociceptive functions; (1) local responses, which are often reflexive protective; (2) ascending pain transmission, and (3) modulation of nociceptive impulses through descending pain pathways. A detailed description of the anatomy and physiology of the CNS is not provided. The reader is referred to standard neurobiology text for a detailed review.[
Local spinal cord responses
Within the spinal cord, glutamate and tachykinin stimulate N-methyl-D-aspartate (NMDA) and tachykinin receptors mediating nociceptive transmission. NMDA receptors are thought to be responsible for the central sensitization or “wind-up phenomenon” where sensory inputs to the CNS are amplified, resulting in an alteration of the CNS and increased pain.[
The NMDA receptor fields of dorsal horn cells in infants are larger than adult fields until 42 weeks gestation, then decline to adult size by 43-44 weeks gestation.[
In adults, γ-aminobutyric acid (GABA) inhibits the excitatory activity of glutamate, but in infants, GABA induces depolarization dependant, in part, on the intracellular concentration of chloride.[
These local spinal cord responses have a profound effect on a neonate's biobehavioral response to stimulation. Compared with full-term infants, children, adolescence, and adults, preterm infants have a lower threshold and a more pronounced reflex response to touch.[
The affinity of the NMDA receptor decreases with postnatal age. NMDA-evoked calcium influx in rat substantia gelatinosa neurons is very high in the first postnatal week then declines to adult levels by 6-8 weeks postnatally.[
Ascending transmission
There are a considerable number of seminal rigorously executed studies[
Research has established that facial expressions and body movements represent evidence-based acute pain behavioral variables in infants. Brow bulge, eye squeeze, and a deepening of the nasolabial furrow have been exhibited in infants as young as 26 weeks’ gestation in response to a heel lance procedures.[
Descending transmission, modulation of pain
Descending inhibitory controls are immature at birth.[
Neurotransmitters are essential components of adult and neonatal pain transmission. Adult and neonatal pain transmission is mediated at the level of the spinal cord by the neurotransmitters substance P, somatostatin, calcitonin gene-related peptide, vasoactive intestinal polypeptide, and glutamate. Modulation of pain transmission occurs through the local release of endogenous opioids, enkephalin or serotonin, norepinephrine, acetylcholine, neurotensin, and GABA, glycine, and dopamine from the PAG area.
GABA has a crucial role in preventing the spread of excitatory glutamatergic activity. In the adult spinal cord, GABA is an inhibitory amino acid transmitter that produces membrane hyperpolarization through the activation of postsynaptic GABAA and GABAB receptors and depresses transmitter release acting through presynaptic GABAB receptors. However in neonates, GABA is transiently overexpressed in the developing spinal cord. In 90% of embryonic dorsal horn neurons cultured for more than a week, both GABA and glycine induced an increased calcium and cellular depolarization.[
In the preterm infant, dopamine and norepinephrine are not available to modulate nociceptive activity before 36-40 weeks’ gestation. Moreover, the inhibitory fibers extending from the PAG area and other areas in the brainstem do not release serotonin until approximately 6-8 weeks after birth.[
The maturation of C fiber synaptic connections in the dorsal horn, interneuronal development in the substantia gelatinosa, and the functional development of descending inhibitory systems from the supraspinal centers occur postnatally in the rat. Modulatory mechanisms reach maturation later than the basic excitatory mechanism from low-threshold inputs; thus, a newborn infant can mount a response to painful stimuli. This response, however, may not always be predictable or well organized. Lack of inhibition contributes to exaggerated and generalized responses to all low and high thresholds of sensory inputs, whereas specific pain responses may require convergent afferent inputs building up over time to become clinically apparent.[
Supraspinal processes and integration
At 8 weeks gestation, the fetal neocortex begins to development and by 20 weeks, each cortex has a full complement of 109 neurons.[
Cortical cell migration from the germinal lining of the ventricles in which they originate to specific locations in the cortical plate is complete at approximately 24 weeks’ gestation.[
At 20 weeks gestation, intermittent nonspecific electroencephalographic bursts are seen in both cerebral hemispheres. They become sustained at 22 weeks and bilaterally synchronous at 26-27 weeks.[
CONSEQUENCE OF UNDERMANAGED PAIN
Multiple lines of evidence suggest that repeated and prolonged pain exposure early in life alters an infant's subsequent pain processing, long-term development, later pain sensitivity and may contribute to the transition from acute to chronic pain.[
Undermanaged pain in neonates leads to significant short- and long-term adverse consequences.[
Physical and psychological stress increases the opportunity for infection through generalized depression of the immune system.[
It is hypothesized that the long-term consequences of undermanaged pain in neonates are linked to the plasticity of the neonate's nervous system. Changes in the neonate's peripheral and CNS are innate and critical for normal fetal and neonatal development.[
Findings from cohort and crosssectional studies explain how repeated painful procedures are associated with long-term adverse events such as enhanced perceptual sensitization,[
A common feature of these studies is that the tissue injury occurred at a critical period of development and the adverse effects of the injury outlasted the injury itself. The long-term effects of the injury were adolescents and adults with altered pain sensitivity compared with controls. In addition, the area surrounding the injury retained the increased sensitivity to pain so that a new injury in that area resulted in enhance hyperalgesia, which is greater in magnitude and significantly more prolonged than controls. The altered sensory and pain sensitivity outcomes reflected in these studies demonstrate that early painful injuries result in long-term local and global alteration in sensory and pain processing.[
Epigenetic modifications
Epigenetic changes in the neonate's peripheral and CNS are innate and critical for normal fetal and neonatal development.[
In contrast to the genetic code, covalent modification of DNA by methylation is influenced by injury.[
CONCLUSION
Although pain responses in neonates bear some similarity to pain responses in older infants, children, adolescence, and adults; there are some pain responses that are unique to neonates rendering them at risk for inadequate pain treatment.[
Exposure to repeated painful stimuli contributes to adverse long-term physiologic and behavioral sequelae. The short-term consequences of undermanaged pain in neonates are behavioral and physiologic responses to noxious stimuli. The long-term consequences of repeated painful procedures vary with gestational age[
References
1. Abdulkader HM, Freer Y, Garry EM, Fleetwood-Walker SM, McIntosh N. Prematurity and neonatal noxious events exert lasting effects on infant pain behaviour. Early Hum Dev. 2008. 84: 351-5
2. Als H, Goldson E.editors. Reading the premature infant. Nurturing the Premature Infant: Developmental Interventions in the Neonatal Intensive Care Nursery. New York, NY: Oxford University Press; 1999. p. 18-85
3. Anand KJ, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky PM. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav. 1999. 66: 627-37
4. Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med. 1987. 317: 1321-9
5. Anand KJ, Anand K, McGrath P.editors. The applied physiology of pain. Pain in Neonates. Amsterdam, The Netherlands: Elsevier Science; 1993. p. 39-66
6. Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998. 73: 1-9
7. Anand KJ. Effects of perinatal pain and stress. Prog Brain Res. 2000. 122: 117-29
8. Anand KJ.editors. Immediate and long-term effects of pain on neonatal brain development. Developmental Interventions in Neonatal Care Contemporary Forums. Chicago, IL: 1995. p.
9. Anand KJ, Brown MJ, Causon RC, Christofides ND, Bloom SR, Aynsley-Green A. Can the human neonate mount an endocrine and metabolic response to surgery?. J Pediatr Surg. 1985. 20: 41-8
10. Anand KJ, Carr D. The neuroanatomy, neurophysiology, and neurochemistry of pain, stress and analgesia in newborns and children. Pediatr Clin North Am. 1989. 36: 795-822
11. Anand KJ, Coskun V, Thrivikraman KV, Nemeroff CB, Poltsky PM. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav. 1999. 66: 627-37
12. Anand KJ, Grunau RE, Oberlander TF. Developmental character and long-term consequences of pain in infants and children. Child Adolesc Psychiatr Clin N Am. 1997. 6: 703-23
13. Anand KJ, Hall RW, Desai N, Shephard B, Bergqvist LL, Young TE. Effects of morphine analgesia in ventilated preterm neonates: Primary outcomes from the NEOPAIN randomised trial. Lancet. 2004. 363: 1673-82
14. Anand KJ, Hickey PR. Halothane-morphine compared with high dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med. 1992. 326: 1-9
15. Anand KJ, Scalzo FM. Can adverse neonatal experiences alter brain development and subsequent behavior?. Biol Neonate. 2000. 77: 69-82
16. Andreae MH, Andreae DA. Regional anaesthesia to prevent chronic pain after surgery: A Cochrane systematic review and meta-analysis. Br J Anaesth. 2013. 111: 711-20
17. Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: Sensitization, receptive fields and effects of contra lateral stimulation. Pain. 1994. 56: 95-101
18. Appelhans BM, Luecken LJ. Heart rate variability and pain: Associations of two interrelated homeostatic processes. Biol Psychol. 2008. 77: 174-82
19. Banasik J, Copstead LC, Banasik JL.editors. Pain. Pathophysiology: Biological and Behavioral Perspectives. Philadelphia, PA: W. B. Saunders; 2000. p. 1080-92
20. Basbaum A. Memories of pain. Sci Med. 1996. 3: 22-
21. Basbaum A, Jessell T, Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ.editors. Pain. Principles of Neural Science. New York, NY: McGraw-Hill Professional; 2012. p. 530-55
22. Basbaum AI, Fields HL. Endogenous pain control systems: Brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci. 1984. 7: 309-38
23. Beggs S, Currie G, Salter MW, Fitzgerald M, Walker SM. Priming of adult pain responses by neonatal pain experience: Maintenance by central neuroimmune activity. Brain. 2012. 135: 404-17
24. Bellu R, de Waal K, Zanini R. Opioids for neonates receiving mechanical ventilation: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2010. 95: F241-51
25. Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E. The GABA Excitatory/Inhibitory Shift in Brain Maturation and Neurological Disorders. Neuroscientist. 2012. 18: 467-86
26. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA, and AMDA receptors: A developmentally regulated ‘ménage a trois’. Trends Neurosci. 1997. 20: 523-9
27. Bicknell HR, Beal JA. Axonal and dendrite development of substantia gelatinosa neurons in the lumbosacral spinal cord of the rat. J Comp Neurol. 1984. 226: 508-22
28. Blankenship AG, Feller MB. Mechanisms underlying spontaneous patterned activity in developing neural circuits. Nat Rev Neurosci. 2010. 11: 18-29
29. Buchheit T, Van de Ven T, Shaw A. Epigenetics and the Transition from Acute to Chronic Pain. Pain Med. 2012. 13: 1474-90
30. Calvo M, Dawes JM, Bennett DL. The role of the immune system in the generation of neuropathic pain. Lancet Neurol. 2012. 11: 629-42
31. Carbajal R, Rousset A, Danan C, Coquery S, Nolent P, Ducrocq S. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA. 2008. 300: 60-70
32. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J. Bacteria activate sensory neurons that modulate pain and inflammation. Nature. 2013. 501: 52-7
33. Choonara I. Management of pain in newborn infants. Semin Perinatol. 1992. 16: 32-40
34. Colonnese MT, Kaminska A, Minlebaev M, Milh M, Bloem B, Lescure S. A conserved switch in sensory processing prepares developing neocortex for vision. Neuron. 2010. 67: 480-98
35. Coskun V, Anand KJ, Anand KJS, McGrath PJ.editors. Development of supraspinal pain processing. Pain in Neonates. Amsterdam, The Netherlands: Elsevier Science; 2000. p. 23-54
36. Craig K, Grunau RV, Anand KJ, Stevens BJ, McGrath PJ.editors. Neonatal pain perception and behavioral measurement. Pain in Neonates. Amsterdam, The Netherlands: Elsevier Science; 1993. p. 67-105
37. Craig K, Prkachin K, Grunau RV, Turk D.editors. The facial expression of pain. Handbook of Pain Assessment. New York, NY: Guilford Press; 1992. p.
38. Cui JG, Meyerson BA, Lindeoth B. Opposite effects of spinal cord stimulation in different phases of carrageenan-induced hyperalgesia. Eur J Pain. 1999. 3: 365-74
39. Davis DA, Luecken LJ, Zautra AJ. Are reports of childhood abuse related to the experience of chronic pain in adulthood?: A meta-analytic review of the literature. Clin J Pain. 2005. 21: 398-405
40. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human central nervous system: What is happening when?. Early Hum Dev. 2006. 82: 257-66
41. de Graaf J, van Lingen RA, Simons SH, Anand KJ, Duivenvoorden HJ, Weisglas-Kuperus N. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: Five-year follow-up of a randomized controlled trial. Pain. 2011. 152: 1391-7
42. Denk F, McMahon SB, Tracey I. Pain vulnerability: A neurobiological perspective. Nat Neurosci. 2014. 17: 192-200
43. Fabrizi L, Slater R, Worley A, Meek J, Boyd S, Olhede S. A shift in sensory processing that enables the developing human brain to discriminate touch from pain. Curr Biol. 2011. 21: 1552-8
44. Feldman DE, Knudsen EI. Experience-department plasticity and the maturation of glutamatergic synapses. Neuron. 1998. 20: 1067-71
45. Fitzgerald M, Hanson M.editors. The development of descending brainstem control of spinal cord sensory processing. Foetal and Neonatal Brainstem: Development and Clinical Issues. Cambridge, England: Cambridge University Press; 1991. p. 127-36
46. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci. 2005. 6: 507-20
47. Fitzgerald M. Development of pain mechanisms. Br Med Bull. 1991. 47: 667-75
48. Fitzgerald M, Anand KJ, McGrath PI.editors. Development of pain pathways and mechanisms. Pain in Neonates. New York, NY: Elsevier; 1993. p. 19-37
49. Fitzgerald M, Anand KJ, Stevens BJ, McGrath PI.editors. Development of the peripheral and spinal pain system. Pain in Neonates. Amsterdam, The Netherlands: Elsevier; 2000. p. 9-22
50. Fitzgerald M, Wall PD, Melzack R.editors. Developmental neurobiology of pain. Textbook of Pain. Edinburgh, Scotland: Churchill Livingstone; 1999. p. 235-52
51. Fitzgerald M. Pain and analgesia in neonates. Trends Neurosci. 1987. 10: 344-6
52. Fitzgerald M. The sprouting of saphenous nerve terminals in the spinal cord following early postnatal sciatic nerve section in the rat. J Comp Neurol. 1985. 240: 407-13
53. Fitzgerald M, Jennings E. The postnatal development of spinal sensory processing. Proc Natl Acad Sci U S A. 1999. 96: 7719-22
54. Fitzgerald M, Koltzenburg M. The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Res Dev Brain Res. 1986. 24: 261-70
55. Fitzgerald M, Millard C, MacIntosh N. Hyperalgesia in premature infants. Lancet. 1988. 6: 292-
56. Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain. 1989. 39: 31-6
57. Fitzgerald M, Shaw A, McIntosh N. Postnatal development of the cutaneous flexor reflex: Comparative study of preterm infants and newborn rat pups. Dev Med Child Neurol. 1988. 30: 520-6
58. Fitzgerald M, Shortland P. The effect of neonatal peripheral nerve section on the somatodendritic growth of sensory projection cells in the rat spinal cord. Brain Res. 1988. 470: 129-36
59. Fitzgerald M, Walker SM. Infant pain management: A developmental neurobiological approach. Nat Clin Pract Neurol. 2009. 5: 35-50
60. Flechsig PE.editors. Gerhirn und Seele. Leipzig: Veit; 1897. p.
61. Flechsig PE. Ueber die entwickelungsgeschichtliche (myelogenetische) Flachengliederung der grosshirnrinde des menschen. Arch Ital Biol. 1901. 36: 30-9
62. Flint AC, Maisch US, Weishaupt JH, Kriegstein AR, Monyer H. NR2A subunit expression shortens NMDFA receptor synaptic currents in developing neocortex. J Neurosci. 1997. 17: 2469-76
63. Gibbins S, Stevens B. The influence of gestational age on the efficacy and short-term safety of sucrose for procedural pain relief. Adv Neonatal Care. 2003. 3: 241-9
64. Gibbins S, Stevens B, McGrath PJ, Yamada J, Beyene J, Breau L. Comparison of pain responses in infants of different gestational ages. Neonatology. 2008. 93: 10-8
65. Gilles F, Shankle W, Dooling E, Gilles F, Leviton A, Dooling E.editors. Myelinated tracts: Growth patterns. The Developing Human Brain: Growth and Epidemiologic Neuropathology. Boston: John Wright; 1983. p. 117-83
66. Gliess J, Stuttgen G, Stave U.editors. Morphologic and functional development of the skin. Physiology of the Perinatal Period: Functional and Biochemical Development in Mammals. New York: Appleton-Century-Crofts; 1970. p. 889-906
67. Green PG, Chen X, Alvarez P, Ferrari LF, Levine JD. Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat. Pain. 2011. 152: 2549-56
68. Grunau RE. Neonatal pain in very preterm infants: Long-term effects on brain, neurodevelopment and pain reactivity. Rambam Maimonides Med J. 2013. 4: e0025-
69. Grunau RE, Whitfield MF, Petrie-Thomas J, Synnes AR, Cepeda IL, Keidar A. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain. 2009. 143: 138-46
70. Grunau RV, Holsti L, Haley DW, Oberlander T, Weinberg J, Solimano A. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain. 2005. 113: 293-300
71. Grunau RV, Holsti L, Whitfield MF, Ling E. Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?. Clin J Pain. 2000. 16: 37-45
72. Grunau RV, Johnston CC, Craig KD. Neonatal facial and cry responses to invasive and non-invasive procedures. Pain. 1990. 42: 295-305
73. Grunau RV, Whitfield MF, Petrie JH.editors. Extremely low birth weight (ELBW) toddlers are relatively unresponsive to pain at 18 months corrected age compared to larger birth weight children. Proceedings of the Neonatal Society Meeting. Clare, Ireland: Shannon, Co; 1994. p.
74. Grunau RV, Whitfield MF, Petrie JH. Pain sensitivity and temperament in extremely low-birth-weight premature toddlers and preterm and full-term controls. Pain. 1994. 58: 341-6
75. Grunau RV, Whitfield MF, Petrie JH. Pain sensitivity in toddlers of birthweight<1000 grams compared with heavier preterm and full birth weight toddlers. Pediatr Res. 1991. 29: 256A-
76. Grunau RV, Whitfield MF, Petrie JH, Fryer EL. Early pain experience, child and family factors, as precursors of somatization: A prospective study of extremely premature and fullterm children. Pain. 1994. 56: 353-9
77. Hammer P, Banck MS, Amberg R, Wang C, Petznick G, Luo S. mRNA-seq with agnostic splice site discovery for nervous system transcriptomics tested in chronic pain. Genome Res. 2010. 20: 847-60
78. Hatfield LA, Ely EA. Measurement of acute pain in infants: A review of behavioral and physiological variables. Biol Res Nurs. 2014. p.
79. Hatfield LA, Meyers MA, Messing TM. A systematic review of the effects of repeated painful procedures in infants: Is there a potential to mitigate future pain responsivity?. J Nurs Educ Pract. 2013. 3: 99-112
80. Hermann C, Hohmeister J, Demirakça S, Zohsel K, Flor H. Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain. 2006. 125: 278-85
81. Holsti L, Grunau RE, Oberlander TF, Whitfield MF. Prior pain induces heightened motor responses during clustered care in preterm infants in the NICU. Early Hum Dev. 2005. 81: 293-302
82. Holsti LP, Grunau RE, Whifield MF, Oberlander TF, Lindh VP. Behavioral responses to pain are heightened after clustered care in preterm infants born between 30 and 32 weeks gestational age. Clin J Pain. 2006. 22: 757-64
83. Horii Y, Kandda K. Developmental alterations in NMDA receptor-mediated [Ca+]i elevation in substantia gelatinous neurons of neonatal rat spinal cord. Brain Res Dev Brain Res. 1994. 80: 141-8
84. Humphrey T. Some correlations between the appearance of human fetal reflexes and the development of the nervous system. Prog Brain Res. 1964. 4: 93-135
85. Janig W. The sympathetic nervous system in pain. Eur J Anaesthesiol. 1995. 12: 53-60
86. Johnston CC, Fernandes AM, Campbell-Yeo M. Pain in neonates is different. Pain. 2011. 152: S65-73
87. Johnston CC, Stevens BJ. Experience in a neonatal care unit affects pain response. Pediatrics. 1996. 98: 925-30
88. Johnston CC, Stevens BJ, Horton L. Changes in physiological responses to heel stick in premature infants. Neonatal Netw. 1992. 11: 67-
89. Johnston CC, Stevens BJ, Yang F, Horton R. Developmental changes in response to heel stick in preterm infants: A prospective cohort study. Dev Med Child Neurol. 1996. 38: 435-45
90. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: Risk factors and prevention. Lancet. 2006. 367: 1618-25
91. Kim H, Dionne RA. Individualized pain medicine. Drug Discov Today Ther Strateg. 2009. 6: 83-7
92. Kim J, Foy M, Thompson R. Behavioral Stress modifies hippocampal plasticity through NMDA receptor activation. Proc Natl Acad Sci U S A. 1996. 93: 4750-3
93. Koga K, Furue H, Rashid H, Takaki A, Katafuchi T, Yoshimura M. Selective activation of primary afferent fibers evaluated by sine-wave electrical stimulation. Mol Pain. 2005. 1: 13-
94. Kwok CH, Devonshire IM, Bennett AJ, Hathway GJ. Postnatal maturation of endogenous opioid systems within the periaqueductal grey and spinal dorsal horn of the rat. Pain. 2014. 155: 168-78
95. Lee YS, Kim H, Wu TX, Wang XM, Dionne RA. Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin Pharmacol Ther. 2006. 79: 407-18
96. Leon AC, Davis LL, Kraemer HC. The role and interpretation of pilot studies in clinical research. J Psychiatr Res. 2011. 45: 626-9
97. Low LA, Fitzgerald M. Acute pain and a motivational pathway in adult rats: Influence of early life pain experience. PLos One. 2012. 7: e34316-
98. Low LA, Schweinhardt P. Early life adversity as a risk factor for fibromyalgia in later life. Pain Res Treat. 2012. 2012: 140832-
99. Marin-Padilla M. Structural organization of the human cerebral cortex prior to the appearance of the cortical plate. Anat Embryol (Berl). 1983. 168: 21-40
100. Marti E, Gibson SJ, Polak JM, Facer P, Springall DR, Van Aswegen G. Ontogeny of peptid-and amine-containing neurones in motor, sensory, and autonomic regions of the rat and human spinal cord, dorsal root ganglia, and rat skin. J Comp Neurol. 1987. 266: 332-59
101. McGrath P.editors. Pain in Children. New York, NY: Guilford Press; 1993. p.
102. Melzack R. Gate control theory: On the evolution of pain concepts. Pain Forum. 1996. 5: 128-38
103. Melzack R. Recent concepts of pain. J Med. 1982. 13: 147-60
104. Melzack R, Wall PD. Pain mechanisms: A new theory. Science. 1965. 699: 971-81
105. Melzack R, Wall PD. Pain mechanisms: A new theory: A gate control system modulates sensory input from the skin before it evokes pain perception and response Pain Forum. 1996. 5: 3-11
106. Melzack R, Wall PD. Psychophysiology of pain. Int Anesthesiol Clin. 1970. 8: 3-34
107. Miranda A. Early life stress and pain: An important link to functional bowel disorders. Pediatr Ann. 2009. 38: 279-82
108. Peters JW, Schouw R, Anand KJ, van Dijk M, Duivenvoorden HJ, Tibboel D. Does neonatal surgery lead to increased pain sensitivity in later childhood?. Pain. 2005. 114: 444-54
109. Porter FL, Grunau RE, Anand KJ. Long-term effects of pain in infants. J Dev Behav Pediatr. 1999. 20: 253-61
110. Prechtl HF. The behavioural states of the newborn infant (a review). Brain Res. 1974. 76: 185-212
111. Rabinowicz T, de Courten-Meyers GM, Petetot JM. Human cortex development: Estimates of neuronal numbers indicate major loss during late during gestation. J Neuropathol Exp Neurol. 1996. 155: 320-8
112. Raja SN, Meyer RA, Ringkamp M, Wall P D, Melzack R.editors. Peripheral neural mechanisms of nociception. Textbook of Pain. Edinburgh, Scotland: Churchill Livingstone; 1999. p. 11-58
113. Rakic P, Goldman-Rakic PS. Development and modifiability of the cerebral cortex: Early developmental effects: Cell lineages, acquisition of neuronal positions, and areal and larninar development. Neurosci Res Program Bull. 1982. 20: 433-51
114. Ranger M, Johnston CC, Anand KJ. Current controversies regarding pain assessment in neonates. Semin Perinatol. 2007. 31: 283-8
115. Rawlings DJ, Miller PA, Engle RR. The effect of circumcision on transcutaneous P02 in term infants. Am J Dis Child. 1980. 134: 676-8
116. Reddi D, Curran N. Chronic pain after surgery: Pathophysiology, risk factors and prevention. Postgrad Med J. 2014. 90: 222-7
117. Reichling DB, Kyrozis A, Wang J, Mcdermott A. Mechanisms of GABA and glycine depolarization induced calcium transients in rat dorsal horn neurons. J Physiol. 1994. 476: 411-21
118. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010. 16: 1267-76
119. Reynolds ML, Fitzgerald M. Long-term sensory hyperinnervation following neonatal skin wounds. J Comp Neurol. 1995. 358: 487-98
120. Rodrigues AC, Guinsburg R. Pain evaluation after a non-nociceptive stimulus in preterm infants during the first 28 days of life. Early Hum Dev. 2013. 89: 75-9
121. Sandkühler J. Models and Mechanisms of Hyperalgesia and Allodynia. Physiol Rev. 2009. 89: 707-58
122. Schechter NL. The undertreatment of pain in children: An overview. Pediatr Clin North Am. 1989. 36: 781-94
123. Scholz J, Woolf CJ. Can we conquer pain?. Nat Neurosci. 2002. 5: 1062-7
124. Schug SA, Chong C. Pain management after ambulatory surgery. Curr Opin Anaesthesiol. 2009. 22: 738-43
125. Schulte F, Linneweh F.editors. Gestation, wachsturn und hirnentwicklung. Fortscritte der Paedologie. Berlin: Springer-Verlag; 1968. p. 46-64
126. Schwaller F, Fitzgerald M. The consequences of pain in early life: Injury-induced plasticity in developing pain pathways. Eur J Neurosci. 2014. 39: 344-52
127. Seo S, Grzenda A, Lomberk G, Ou XM, Cruciani RA, Urrutia R. Epigenetics: A promising paradigm for better understanding and managing pain. J Pain. 2013. 14: 549-57
128. Shipton EA. The transition from acute to chronic post surgical pain. Anaesth Intensive Care. 2011. 39: 824-36
129. Simons SH, van Dijk M, Anand KJ, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med. 2003. 157: 1058-64
130. Sivilotti LG, Gerber G, Rawat B, Woolf CJ. Morphine selectively depresses the slowest, NMDA-independent component of C-fiber-evoked synaptic activity in the rat spinal cord in vitro. Eur J Neurosci. 1995. 7: 12-8
131. Spehlmann R.editors. EEG primer. New York: Elsevier/North-Holland; 1981. p.
132. Spehlmann R.editors. EEG Primer. New York, NY: Elsevier/North Holland; 1981. p.
133. Sredl D. Myths and facts about pain in neonates. Neonatal Netw. 2003. 22: 69-71
134. Stein C, Machelska H. Modulation of peripheral sensory neurons by the immune system: Implications for pain therapy. Pharmacol Rev. 2011. 63: 860-81
135. Stevens BJ, Johnston CC. Premature infant's response to pain: A pilot study. Nurs Que. 1991. 11: 90-5
136. Stone LS, Szyf M. The emerging field of pain epigenetics. Pain. 2013. 154: 1-2
137. Teng CJ, Abbott FV. The formalin test: A dose-response analysis at three developmental stages. Pain. 1998. 76: 337-47
138. Terman GW, Bonica JJ, Loeser J, Butler S, Chapman C, Turk D.editors. Spinal mechanisms and their modulation. Bonica's Management of pain. Philadelphia, PA: Lippincott Williams and Wilkins; 2001. p. 73-152
139. Tilney F, Rosett J. The value of brain lipoids as an index of brain development. Bull Neurol Inst. NY. 1931. 1: 28-71
140. Van Cleve L, Johnson L, Andrews S, Hawkins S, Newbold J. Pain responses of hospitalized neonates to venipuncture. Neonatal Network. 1995. 14: 31-5
141. Van Pragg H, Frenk H. The development of stimulation-induced analgesia (SPA) in the rat. Brain Res Dev Brain Res. 1991. 64: 71-6
142. Vinall J, Grunau RE. Impact of repeated procedural pain-related stress in infants born very preterm. Pediatr Res. 2014. 75: 584-7
143. Volpe JJ, Fletcher J.editors. Intracranial hemorrhage: Subdural, primary subarchnoid, intracerebellar, intraventricular (term infant) and miscellaneous. Neurology of the Newborn. Philadelphia, PA: Saunders; 2000. p. 397-428
144. Voscopoulos C, Lema M. When does acute pain become chronic?. Br J Anaesth. 2010. 105: i69-85
145. Walden M, Penticuff JH, Stevens B, Lotas M, Kozinetz CA, Clark A. Maturational changes in physiologic and behavioral responses of preterm neonates in pain. Adv Neonatal Care. 2001. 1: 94-106
146. Walker SM, Tochiki KK, Fitzgerald M. Hindpaw incision in early life increases the hyperalgesic response to repeat surgical injury: Critical period and dependence on initial afferent activity. Pain. 2009. 147: 99-106
147. Wang J, Reichling DB, Kyrozis A, Mcdermott AB. Developmental loss of GABA and glycine induced depolarization and Ca2+transients in embryonic rat dorsal horn neurons in culture. Eur J Neurosci. 1994. 6: 1275-80
148. Williamson PS, Williamson ML. Physiological stress reduction by local anaesthetic during newborn circumcision. Pediatrics. 1983. 71: 36-40