Every baby, child and adolescent will experience pain at times throughout their life. Despite its ubiquity, pain is a major challenge for individuals, families, healthcare professionals, and societies. Pain is often hidden and can go undiscussed or ignored. Undertreated, unrecognised, or poorly managed pain in childhood leads to important and long-lasting negative consequences that continue into adulthood. This undertreatment should not continue. We have the tools, expertise, and evidence to provide better treatment for childhood pain.In this Commission we present four transformative goals that will, if achieved, transform the lives of children with pain and their families. These goals, taken at face value, may seem simple and obvious. However, if the goals were easy to achieve there would be few, if any, young people reporting poorly managed acute pain, pain after surgery or procedures, or ongoing chronic pain. Pain is multifactorial, and influenced by biological, psychological and social factors, making it complex and difficult to treat effectively, especially in infants, children and adolescents. This Commission focusses on children from birth through to 24 years of age in developed countries.The first transformative goal is to 'make pain matter'. Here we argue that pain has not mattered enough, as evidenced by common failings in clinical practice, low levels of training and investment, and a lack of concern for issues of equity and equality. Despite some good examples of knowledge translation, we highlight that investment in a strong social science research base for paediatric pain will catapult us into a new era in which we can address the social and cultural context of pain.The second is to 'make pain understood' at a fundamental biological and psychological level. There has been excellent progress in mechanistic understandings of nociception and pain perception for both acute and chronic pain states but gaps in knowledge remain. Advances in developmental biology, in genetics, in psychology, and in nosology and classification will all help speed up the discovery in these areas. There is also a need for greater investment in larger international birth cohort studies that incorporate comprehensive pain-related measurement incorporated.The third is to 'make pain visible'. Pain can and should be assessed. We need to help improve understanding of optimal methods for pain assessment at throughout childhood and in all clinical scenarios. While subjective pain report is the primary and desirable method when this is possible, many of the methods and measures that are in common use can and should be improved. There has been development in understanding the biological correlates of pain, and in broader patient reported outcome variables that can expand our horizons. Finally, we should be more focussed on assessing outcomes that are important to patients, rather than those that are central to researchers and clinicians.The fourth is to 'make pain better' by advancing our knowledge of multiple treatment options in all a...

Adult brain connectivity is shaped by the balance of sensory inputs in early life. In the case of pain pathways, it is less clear whether nociceptive inputs in infancy can have a lasting influence upon central pain processing and adult pain sensitivity. Here, we show that adult pain responses in the rat are 'primed' by tissue injury in the neonatal period. Rats that experience hind-paw incision injury at 3 days of age, display an increased magnitude and duration of hyperalgesia following incision in adulthood when compared with those with no early life pain experience. This priming of spinal reflex sensitivity was measured by both reductions in behavioural withdrawal thresholds and increased flexor muscle electromyographic responses to graded suprathreshold hind-paw stimuli in the 4 weeks following adult incision. Prior neonatal injury also 'primed' the spinal microglial response to adult injury, resulting in an increased intensity, spatial distribution and duration of ionized calcium-binding adaptor molecule-1-positive microglial reactivity in the dorsal horn. Intrathecal minocycline at the time of adult injury selectively prevented both the hyperalgesia and early microglial reactivity associated with prior neonatal injury. The enhanced neuroimmune response seen in neonatally primed animals could also be demonstrated in the absence of peripheral tissue injury by direct electrical stimulation of tibial nerve fibres, confirming that centrally mediated mechanisms contribute to these long-term effects. These data suggest that early life injury may predispose individuals to enhanced sensitivity to painful events.

Alterations in neural activity due to pain and injury in early development may produce long-term effects on sensory processing and future responses to pain. To investigate persistent alterations in sensory perception, we performed quantitative sensory testing (QST) in extremely preterm (EP) children (n=43) recruited from the UK EPICure cohort (born less than 26 weeks gestation in 1995) and in age and sex matched term-born controls (TC; n=44). EP children had a generalized decreased sensitivity to all thermal modalities, but no difference in mechanical sensitivity at the thenar eminence. EP children who also required neonatal surgery had more marked thermal hypoalgesia, but did not differ from non-surgical EP children in the measures of neonatal brain injury or current cognitive ability. Adjacent to neonatal thoracotomy scars there was a localized decrease in both thermal and mechanical sensitivity that differed from EP children with scars relating to less invasive procedural interventions or from those without scars. No relationship was found between sensory perception thresholds and current pain experience or pain coping styles in EP or TC children. Neonatal care and surgery in EP children are associated with persistent modality-specific changes in sensory processing. Decreases in mechanical and thermal sensitivity adjacent to scars may be related to localized tissue injury, whereas generalized decreases in thermal sensitivity but not in mechanical sensitivity suggest centrally mediated alterations in the modulation of C-fibre nociceptor pathways, which may impact on responses to future pain or surgery.

Infant pain is a clinical reality. Effective pain management in infants requires a specialist approach--analgesic protocols that have been designed for older children cannot simply be scaled down for CNS pain pathways and analgesic targets that are in a state of developmental transition. Here, we discuss the particular challenges that are presented by an immature CNS for the detection and treatment of pain. We show how the application of neurophysiological and neuropharmacological approaches can help to overcome the problems inherent in measuring and treating pain in infants, and how research data in these areas can be used to devise age-appropriate methods of assessing pain as well as strategies for pain relief. The evidence that untreated pain in infancy results in long-term adverse consequences is presented, thereby emphasizing the need for a longer term view of infant pain management.

Pain in early life can enhance the response to subsequent injury, but effects are influenced by both the nature and timing of neonatal injury. Using plantar hindpaw incision, we investigated how postnatal age influences the response to repeat surgical injury two weeks later. The degree and time course of behavioural changes in mechanical withdrawal threshold were measured, and injury-related hyperalgesia was further quantified by flexion reflex electromyographic responses to suprathreshold mechanical stimuli 24 h following incision. Plantar hindpaw incision produces acute mechanical hyperalgesia in neonatal and adult rats, but incision in neonatal pups has an additional effect on the response to subsequent injury. With initial incision at postnatal day (P) 3 or 6, the degree of hyperalgesia following repeat incision 2 weeks later was greater than in animals having a single incision at the same age. At older ages (initial incision at P10, P21 or P40) responses did not differ in repeat and single incision groups. To test the role of primary afferent activity, levobupivacaine sciatic block was performed prior to P6 plantar incision, and controls received saline or subcutaneous levobupivacaine. Repeat peri-operative, but not a single pre-operative sciatic block, prevented the enhanced response to repeat incision two weeks later. Our results show that the first postnatal week represents a critical period when incision increases hyperalgesia following repeat surgery two weeks later, and effects are initiated by peripheral afferent activity. This has potential therapeutic implications for the type and duration of peri-operative analgesia used for neonatal surgery.

BackgroundSurgery or multiple procedural interventions in extremely preterm neonates influence neurodevelopmental outcome and may be associated with long-term changes in somatosensory function or pain response.MethodsThis observational study recruited extremely preterm (EP, <26 weeks' gestation; n=102, 60% female) and term-born controls (TC; n=48) aged 18–20 yr from the UK EPICure cohort. Thirty EP but no TC participants had neonatal surgery. Evaluation included: quantitative sensory testing (thenar eminence, chest wall); clinical pain history; questionnaires (intelligence quotient; pain catastrophising; anxiety); and structural brain imaging.ResultsReduced thermal threshold sensitivity in EP vs TC participants persisted at age 18–20 yr. Sex-dependent effects varied with stimulus intensity and were enhanced by neonatal surgery, with reduced threshold sensitivity in EP surgery males but increased sensitivity to prolonged noxious cold in EP surgery females (P<0.01). Sex-dependent differences in thermal sensitivity correlated with smaller amygdala volume (P<0.05) but not current intelligence quotient. While generalised decreased sensitivity encompassed mechanical and thermal modalities in EP surgery males, a mixed pattern of sensory loss and sensory gain persisted adjacent to neonatal scars in males and females. More EP participants reported moderate–severe recurrent pain (22/101 vs 4/48; χ2=0.04) and increased pain intensity correlated with higher anxiety and pain catastrophising.ConclusionsAfter preterm birth and neonatal surgery, different patterns of generalised and local scar-related alterations in somatosensory function persist into early adulthood. Sex-dependent changes in generalised sensitivity may reflect central modulation by affective circuits. Early life experience and sex/gender should be considered when evaluating somatosensory function, pain experience, or future chronic pain risk.

Abnormal or excessive activity related to pain and injury in early life may alter normal synaptic development and lead to changes in somatosensory processing. The aim of the current study was to define the critical factors that determine long-term plasticity in spinal cord afferent terminals following neonatal inflammation. Hindpaw inflammation was produced in neonatal rat pups with 5 or 25 microl 2% carrageenan, and 5 or 25 microl complete Freund's adjuvant (CFA). All groups displayed a clear inflammatory response that recovered in 2 weeks in all but the 25 microl CFA group, who had persistent chronic inflammation confirmed by histological examination of the paw at 8 weeks. The 25 microl CFA group was also the only group that displayed a significant expansion of the sciatic and saphenous nerve terminal field in lamina II of the dorsal horn at 8 weeks, using wheat-germ agglutinin-horse radish peroxidase transganglionic labelling. This effect was not accompanied by changes in dorsal root ganglion (DRG) cell number, expression of activating transcription factor 3 (ATF3), or alterations in calcitonin gene related peptide (CGRP) or isolectin B4 binding; and was not mimicked by partial nerve damage. No long-term change in mechanical or thermal behavioural sensory thresholds was seen in any group. Lower dose CFA caused an acute, reversible expansion of terminal fields in lamina II in neonatal animals, while CFA did not produce this effect in adults. The duration and effect of neonatal inflammation is therefore dependent on the type and volume of inflammatory agent used. The expansion of afferent terminals in lamina II following neonatal CFA inflammation is maintained into adulthood if the inflammation is also maintained, as seen following 25 microl CFA. This effect is not seen in adult animals, emphasising the plasticity of the nervous system early in development.

SummaryBackground and Objectives: Perioperative pain in children can be effectively managed with systemic opioids, but addition of paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce opioid requirements and potentially improve analgesia and/or reduce adverse effects. Methods: A systematic literature search was conducted to identify trials evaluating postoperative opioid requirements in children and comparing NSAID and/or paracetamol with placebo. Studies were stratified according to design: continuous availability of intravenous opioid (PCA/NCA) vs intermittent 'as needed' bolus; and single vs multiple dose paracetamol/NSAIDs. Primary outcome data were extracted, and the percentage decrease in mean opioid consumption was calculated for statistically significant reductions compared with placebo. Secondary outcomes included differences in pain intensity, adverse effects (sedation, respiratory depression, postoperative nausea and vomiting, pruritus, urinary retention, bleeding), and patient/parent satisfaction. Results: Thirty-one randomized controlled studies, with 48 active treatment arms compared with placebo, were included. Significant opioid sparing was reported in 38 of 48 active treatment arms, across 21 of the 31 studies. Benefit was most consistently reported when multiple doses of study drug were administered, and 24 h PCA or NCA opioid requirements were assessed. The proportion of positive studies was less with paracetamol, but was influenced by dose and route of administration. Despite availability of opioid for titration, a reduction in pain intensity by NSAIDs and/or paracetamol was reported in 16 of 29 studies. Evidence for clinically significant reductions in opioid-related adverse effects was less robust. Conclusion: This systematic review supports addition of NSAIDs and/or paracetamol to systemic opioid for perioperative pain management in children.