DEVELOPMENTAL CHANGES IN SPINAL CORD PAIN PROCESSING: IMPLICATIONS FOR MANAGEMENT
SA Pain Medicine Visitor’s Lecture
S.M. WALKER
UCL INSTITUTE OF CHILD HEALTH, LONDON, United Kingdom
Pain processing in early life cannot be simply considered as a more or less sensitive version of that seen in the adult. Age-related changes in signalling pathways, receptor expression and levels of neurotransmitters can alter the efficacy and side-effects of analgesic agents, and injury in the developing nervous system may result in changes that are not seen when the same insult occurs in the adult. Laboratory investigations of developmental changes are directed at: i) changes in baseline pain processing, ii) alterations in analgesic pharmacodynamics, and iii) responses to different forms of injury throughout the postnatal period. Understanding these developmental changes is essential for investigating the effects of pain and injury in early life, and will assist in the choice of developmentally appropriate analgesia and the design of clinical trials.
The spinal cord is an important site for modulation of pain transmission, but there are significant developmental changes in both the structure and function of nociceptive pathways1. There is an initial overlap between A-beta and C-fibres in the dorsal horn, which increases the response to peripheral stimuli and reduces the threshold for activation of withdrawal reflexes. C-fibre stimuli do not produce secondary hyperalgesia in early development, but central sensitisation can be mediated by A-fibre inputs. Changes in excitatory and inhibitory synaptic mechanisms tend to increase the level of excitability in the spinal cord2. NMDA receptors are more widely distributed, have a greater affinity for agonist, and allow greater calcium influx once activated. Local inhibitory signalling by glycine and GABA is initially immature, and effects of descending pathways on pain modulation change during development3.
Analgesic trials in paediatric patients present challenges due to ethical considerations of parental consent and use of placebos, difficulties with recruitment, and reliance on observer pain scales As a result, there is still a relative lack of well-designed clinical analgesic trials4 and both the quantity and quality of available evidence lags behind that available for adult practice. Clinical studies have provided important information on age-related pharmacokinetic changes of analgesics5. However, developmental changes in pharmacodynamic responses also have significant effects on efficacy and side-effects, and laboratory studies are required to investigate age-related changes in analgesic mechanisms of action. Opioid receptors are more widely distributed during early development and this contributes to increased functional sensitivity in early life6. Mechanisms underlying spinally mediated alpha2-adrenergic analgesia are functional from early development, but dose requirements for both analgesia and side-effects are reduced in early life 7. This information can be used to design more focussed clinical trials and direct analgesic therapy.
Advances in neonatal and paediatric medicine have resulted in treatment, which may include major surgery and/or prolonged intensive care management, at progressively earlier stages of development. As maturation of the developing nervous system is activity-dependent and exhibits marked plasticity8, understanding the relative effects of altered neural activity on normal development is crucial for balancing clinical therapy. Blocking sensory input into the spinal cord can prevent the normal maturation of nociceptive pathways, and the converse has also been postulated, i.e. can increased activity due to pain and injury in early life alter normal development? It is increasingly apparent from laboratory studies that there is no simple answer to this question, as long-term effects are critically dependent on the type and severity of initial injury. Severe inflammation during the neonatal period produces permanent structural changes in nociceptive pathways, but this is associated with persistent chronic inflammation and cannot be assumed to be due to the neonatal insult alone9. However, even relatively mild neonatal inflammation produces biphasic changes with baseline hypoalgesia, but an increased response to re-inflammation. These changes are developmentally specific as they are dependent on the initial insult occurring during the first postnatal week, and effects then persist into adulthood10. Peripheral nerve injury produces significant allodynia in the adult, but there are no significant changes in sensory thresholds if the lesion is produced during the first 3 postnatal weeks11. This is associated with age-related alterations in immune responses in the spinal cord and changes in gene expression in the dorsal horn and spinal cord that have implications for understanding neuropathic pain mechanisms in both children and adults. Long-term alterations in sensory function following early injury have been shown in clinical studies, but the degree and significance of these changes, and their ability to be prevented or modified by analgesia at the time of injury, requires further investigation.
Several aspects of early pain processing have led to significant debate. “Pain” and “nociception” cannot be used interchangeably when discussing clinical practice in neonates and pre-verbal infants, or in the foetus. Foetal responses to noxious stimuli cannot be extrapolated from data in a prematurely born neonate at the same postconceptional age, due to effects of the changing environment and level of sensory input, and the effect of endogenous neuro-inhibitors from the placenta12. Preverbal children and neonates can not directly tell us about their “pain” experience but recent studies have shown cortical activation, specifically in response to painful stimuli, even in very premature neonates (Slater et al, in press). Surrogate measures such as changes in stress hormones are not direct correlates of the degree of “pain”, and the increased excitability of reflex responses cannot be directly equated with increased “pain”. However, it is clear that reducing behavioural and hormonal responses to noxious inputs improve short-term and possibly long-term outcomes in neonates and infants. Collaborative studies between scientists and clinicians will further improve our understanding of the impact of developmental age on acute and long-term responses to early pain and injury, and continue to identify the most appropriate type and route of administration of analgesic agents.
Time of Presentation
Sunday 14 May 2006 - 0830-1000
References
1. Fitzgerald M: The development of nociceptive circuits. Nat Rev Neurosci 2005; 6: 507-20
2. Pattinson D, Fitzgerald M: The neurobiology of infant pain: development of excitatory and inhibitory neurotransmission in the spinal dorsal horn. Reg Anesth Pain Med 2004; 29: 36-44
3. Hathway G, Harrop E, Baccei M, Walker S, Moss A, Fitzgerald M: A postnatal switch in GABAergic control of spinal cutaneous reflexes. Eur J Neurosci 2006; 23: 112-8
4. Berde CB, Jaksic T, Lynn AM, Maxwell LG, Soriano SG, Tibboel D: Anesthesia and analgesia during and after surgery in neonates. Clin Ther 2005; 27: 900-21
5. Walker S, Howard R: Neonatal Pain. Pain Reviews 2004; 9: 69-79
6. Nandi R, Beacham D, Middleton J, Koltzenburg M, Howard RF, Fitzgerald M: The functional expression of mu opioid receptors on sensory neurons is developmentally regulated; morphine analgesia is less selective in the neonate. Pain 2004; 111: 38-50
7. Walker SM, Howard RF, Keay KA, Fitzgerald M: Developmental Age Influences the Effect of Epidural Dexmedetomidine on Inflammatory Hyperalgesia in Rat Pups. Anesthesiology 2005; 102: 1226-1234
8. Fitzgerald M, Walker S: The role of activity in developing pain pathways., Proceedings of the 10th World Congress on Pain. Progress in Pain Research and Management, Vol. 24. Edited by Dostrovsky J, Carr D, Koltzenburg M. Seattle, IASP Press, 2003, pp 185-196
9. Walker SM, Meredith-Middleton J, Cooke-Yarborough C, Fitzgerald M: Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn. Pain 2003; 105: 185-95
10. Ren K, Anseloni V, Zou SP, Wade EB, Novikova SI, Ennis M, Traub RJ, Gold MS, Dubner R, Lidow MS: Characterization of basal and re-inflammation-associated long-term alteration in pain responsivity following short-lasting neonatal local inflammatory insult. Pain 2004; 110: 588-96
11. Howard RF, Walker SM, Michael Mota P, Fitzgerald M: The ontogeny of neuropathic pain: Postnatal onset of mechanical allodynia in rat spared nerve injury (SNI) and chronic constriction injury (CCI) models. Pain 2005; 115: 382-9
12. Mellor DJ, Diesch TJ, Gunn AJ, Bennet L: The importance of 'awareness' for understanding fetal pain. Brain Res Brain Res Rev 2005; 49: 455-71
