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.

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.