Case example Modi \201 cation of scales It is clear that many scales that were developed and validated in one context have subsequently been used in other contexts. For example, the CHEOPS was o riginally developed for postoperative pain but has since been used in other painful procedu res. In some cases, use of a measure in another context requires modifi cation of the scale . Th is is particularly evident in studies using the CAMPIS Molly is a 7-year-old girl who is on the medical surgical ward of a tertiary care children \200\231s hospital following an emergency appen- dectomy. Molly had surgery yesterday and t oday her nurse, Tim, has noticed that she seems to be quiet and tearful. Molly has around the clock dosing of analgesics, but Tim suspects that she might still be h aving pain. Tim is aware that children in this age range can usually provide self-report of their SECTION 5 measurement of pain 388 validation of a rating scale for children \200\231s and adults \200\231 behaviors during pa inful medical procedures . J Pain Symptom Manage , 22 , 591 \200\223599. Blount , R. L. , Cohen , L. L. , Frank , N. C. , Bachanas , P. J. , Smith , A. J. , Manimala , M. R. , et al . ( 1997 ). Th e Child-Adult Medical Procedure Interaction Scale \200\224Revised: an asses sment of validity . J Pediatr Psychol . 22 , 77 \200\22388. Blount , R. L. , Corbin , S. M . , Sturges , J. W. , Wolfe , V. V. , Prater , J. M. , and James , L. D. ( 1989 ). Th e rel ationship between adults \200\231 behavior and child coping and distresss during BMA/LP pro cedures: a sequential analysis . Behav Th er , 20 , 585 \200\223601. pain, and uses a validated tool (the Faces Pain Scale \200\223Revised) to ask Molly to rate her pain. Molly does not talk or make eye contact with Tim when he is explaining the scale and reaches for her mother. Her mother encourages Molly to use the scale and Molly quickly points to the fi rst face (indicating no pain). Tim and Molly \200\231s mother explain the scale again and remind Molly to point to the face that matches how she feels. Molly again points to the fi rst face on the scale. Blount , R. L. , and Loiselle , K. A. ( 2009 ). Behavioral assessment of pediatric Outside the room, Molly \200\231s mother tells Tim that she believes Molly is having pain. She says that Molly doesn \200\231t like to take medicine and she wonders if Molly is ratin g her pain as very low to avoid taking medication. Tim agrees that this is possible and sug gests that they use some additional ways of assessing Molly \200\231s pain. Tim knows that he will be in Molly \200\231s room for a short period of time, so wants a scale that he can administer based on a short observation. He chooses the FLACC because this scale has been validated for children in Molly \200\231s age range and in postoperative pain. Using this s cale, Tim observes that Molly \200\231s face is grimaced and her jaw is clenched, her legs are tensed and restless and she is squirming in her bed, she is whimpering, but is consoled by her mother sitting in her bed with her. Using FLACC scoring, Molly scores a six out of ten. Tim takes this as additional evi- dence that Molly is experiencing pain. He pages the physician on call who recommends titrating Molly \200\231s medication on the basis of Tim \200\231s information. Tim discusses this plan with Molly and her mother and addresses Moll y \200\231s potential concerns about taking more medication (she was worried that she would need to get another needle). He also off ers to get a movie for Molly so she can be distra cted. About a half hour later, Tim again assesses Molly \200\231s pain using the FLACC. Her score has decreased to one out of ten. Molly appears generally relaxed, but shift s in her bed once while Tim is observing. Tim discusses this score with Molly and her mother and Ti m again asks Molly to rate her pain using the FPS \200\223R. Molly chooses the fi rst face of the FPS \200\223R and Molly \200\231s mother reports that she feels Molly \200\231s pain is now well managed. Tim remind Molly and her mother to call if they feel Molly \200\231s pain is increasing again and notes that he will be back to check on them in a few hours. pain . Pain Res Manag , 14 , 47 \200\22352. Blount , R. L. , Sturges , J. W. , and Powers , S. W. ( 1990 ). Analysis of child and adult behavioral variations by phase of medical procedure . Behav Th er , 21 , 33 \200\22348. Breau , L. M. , McGrath , P. J. , Camfi eld , C. , Rosmus , C. , and Finley , G. A. ( 2000 ). Preliminary validation of an observational pain checklist for persons with cognitive imp airments and inability to communicate verbally . Dev Med Child Neurol , 42 , 609 \200\2236 16. Breau , L. M. , McGrath , P. J. , Camfi eld , C. S. , and Finley , G. A. ( 2002 ) Psychomet ric properties of the non-communicating children \200\231s pain checklist-revised . Pain , 99 , 349 \200\223357. Breau , L. M. , McGrath , P. J. , Craig , K. D. , Santor , D. , Cassidy , K. , and Reid , G . J. ( 2001 ). Facial expression of children receiving immunizations: a principal component s Analysis of the Child Facial Coding System . Clin J Pain , 17 , 178 \200\223186. Caldwell-Andrews , A. A. , Blount , R. L. , Mayes , L. C. , and Kain , Z. N. ( 2005 ). Beha vioral interactions in the perioperative environment: a new conceptual framework and the de velopment of the perioperative child-adult medical procedure interaction scale . Anesthesio logy , 103 , 1130 \200\2231135. Cassidy , K. , Reid , G. J. , McGrath , P. J. , Finley , G. A. , Smith , D. J. , Morley , C . , et al . ( 2002 ). Watch needle, watch TV: audiovisual distraction in preschool immuniza tion . Pain Med , 3 , 108 \200\223118. Chambers , C. T. , Cassidy , K. L. , McGrath , P. J. , Gilbert , C. A. , and Craig , K. D. ( 1996 a). Child Facial Coding System manual. Halifax, Nova Scotia: Dalhousie University an d University of British Columbia. Unpublished manuscript. Chambers , C. T. , Reid , G. J. , McGrath , P. J. , and Finley , G. A. ( 1996 b). Developme nt and preliminary validation of a postoperative pain measure for parents . Pain , 68 , 397 \200\223413. Chorney , J. M. , Tan , E. T. , Martin , S. R. , Fortier , M. A. , and Kain , Z. N. ( 2012 ). Children \200\231s behavior in the postanesthesia care unit: the development of the Chil d Behavior Coding System-PACU (CBCS-P) . J Pediatr Psychol , 37 (3), 338 \200\223347. Cohen , L. L. , Blount , R. L. , Cohen , R. J. , Schaen , E. R. , and Zaff , J. F. 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Pedro , H. , Barros , L. , and Moleiro , C. ( 2010 ). Brief report: parents and nurses \200 \231 behaviors associated with child distress during routine immunization in a Portuguese p opulation . J Pediatr Psychol , 35 , 602 \200\223610. Johansson , M. , Carlberg , E. B. , and Jylli , L. ( 2010 ). Validity and reliability of a Swedish version of the Non-Communicating Children \200\231s Pain Checklist \200\224 Postope rative Version . Acta Paediatrica , 99 , 929 \200\223933. Reid , G. J. , Hebb , J. , McGrath , P. J. , Finley , G. A. , and Forward , S. P. ( 1995 ). Cues parents use to assess postoperative pain in their children . Clin J Pain , 11 , 229 \200\223235. Kanagasundaram , S. A. , Lane , L. J. , Cavalletto , B. P. , Keneally , J. P. , and Cooper , M. G. ( 2001 ). Effi cacy and safety of nitrous oxide in alleviating pain and anxiety dur ing painful procedures . Arch Dis Child , 84 , 492 \200\223495. Rosmus , C. , Johnston , C. C. , Chan-Yip , A. , and Yang , F. ( 2000 ). Pain response in C hinese and non-Chinese Canadian infants: is there a diff erence? Soc Sci Med , 51 , 175 \200\223184. Katz , E. G. Kellerman , J. , and Ellenberg , L. ( 1987 ). Hypnosis in the reduction of acu te pain and distress in children with cancer . J Pediatr Psychol , 12 , 379 \200\223394. Salmon , K. and Pereira , J. K. ( 2002 ). Predicting children \200\231s response to an inva sive medical investigation: the infl uence of eff ortful control and parent behavior . J Pe diatr Psychol , 27 , 227 \200\223233. Katz , E. R. , Kellerman , J. , and Siegel , S. E. ( 1980 ). Behavioral distress in childre n with cancer undergoing medical procedures: developmental considerations . J Consult Clin Psychol , 48 , 356 \200\223365. Schechter , N. L. , Bernstein , B. A. , Beck , A. , Hart , L. , and Scherzer , L. ( 1991 ). Individual diff erences in children \200\231s response to pain \200\224role of temperament and parental characteristics . Pediatrics , 87 , 171 \200\223177. Katz , E. R. , Sharp , B. , Kellerman , J. , Marston , A. R. , Hershman , J. M. , and Siege l , S. E. ( 1982 ). Beta-endorphin immunoreactivity and acute behavioral distress in childr en with leukemia . J Nervous Mental Dis , 170 , 72 \200\22377. Schiavenato , M. and Craig , K. D. ( 2010 ). Pain assessment as a social transaction beyond the gold standard . Clin J Pain , 26 , 667 \200\223676. Solodiuk , J. C. , Scott-Sutherland , J. , Meyers , M. , Myette , B. , Shusterman , C. , Ka rian , V. E. , et al . ( 2010 ). Validation of the Individualized Numeric Rating Scale (INR S): a pain assessment tool for nonverbal children with intellectual disability . Pain , 150 , 231 \200\223236. Kennedy , R. M. , Porter , F. L. , Miller , P. , and Jaff e , D. M. ( 1998 ). Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies . Pediatri cs , 102 , 956 \200\223963. King , S. , Chambers , C. T. , Huguet , A. , MacNevin , R. C. , McGrath , P. J. , Parker , L. , et al . ( 2011 ). Th e epidemiology of chronic pain in children and adolescents revisi ted: a systematic review . Pain , 152 , 2729 \200\2232738. LeBaron , S. and Zeltzer , L. ( 1984 ). Assessment of acute pain and anxiety in children and adolescents by self-reports, observer reports, and a behavior checklist . J Consult Clin Psychol , 52 , 729 \200\223738 . Tarnowski , K. J. , McGrath , M. L. , Calhoun , M. B. , and Drabman , R. S. ( 1987 ). Pedia tric burn injury \200\224self mediated versus therapist mediated debridement . J Pediatr Ps ychol , 12 , 567 \200\223579. Tucker , C. L. , Slifer , K. J. , and Dahlquist , L. M. ( 2001 ). Reliability and validity of the Brief Behavioral Distress Scale: a measure of children \200\231s distress during inv asive medical procedures . J Pediatr Psychol , 26 , 513 \200\223523. Voepel-Lewis , T. , Z anotti , J. , Dammeyer , J. A. , and Merkel , S. ( 2010 ). Reliability and validity of the face, legs, activity, cry, consolability behavioral tool in assessing acute pain in critica lly ill patients . Am J Crit Care , 19 , 55 \200\22361. Lewis , M. , Ramsay , D. S. , and Kawakami , K. ( 1993 ). Diff erences between Japanese inf ants and Caucasian American infants in behavioral and cortisol response to inoculation . Ch ild Dev , 64 , 1722 \200\2231731. Liossi , C. , White , P. , Franck , L. , and Hatira , P. ( 2007 ). Parental pain expectancy as a mediator between child expected and experienced procedure- related pain intensity dur ing painful medical procedures . Clin J Pain , 23 , 392 \200\223399. Voepel-Lewis , T. , Merkel , S. , Tait , A. R. , Trzcinka , A. , and Malviya , S. ( 2002 ). Th e reliability and validity of the face, legs, activity, cry, consolability observationa l tool as a measure of pain in children with cognitive impairment . Anesth Analg , 95 , 122 4 \200\2231229. Malviya , S. , Voepel-Lewis , T. , Burke , C. , Merkel , S. , and Tait , A. R. ( 2006 ). Th e revised FLACC observational pain tool: improved reliability and validity for pain assess ment in children with cognitive impairment . Ped Anesthesia , 16 , 258 \200\223265. von Baeyer , C. L. , Chambers , C. T. , and Eakins , D. M. ( 2011 ). Development of a 10-it em short form of the Parents \200\231 Postoperative Pain Measure: the PPPM-SF . J Pain , 12 , 401 \200\223406. Marmo , L. and Fowler , S. ( 2010 ). Pain assessment tool in the critically ill post- open heart surgery patient population . Pain Manage Nurs , 11 , 134 \200\223140. McGrath , P. J . ( 1998 ). Behavioral measures of pain . In G. A. Finley , and P. J. McGrath (eds) Measure ment of pain in infants and children , pp. 83 \200\223102. Seattle : IASP Press . von Baeyer , C. L. , and Spagrud , L. J. ( 2007 ). Systematic review of observational (beha vioral) measures of pain for children and adolescents aged 3 to 18 years . Pain , 127 , 140 \200\223150. Zabalia , M. , Breau , L. M. , Wood , C. , Leveque , C. , Hennequin , M. , Villeneuve , E. , et al . ( 2011 ). Validation of the French version of the non- communicating children \200\231s pain checklist-postoperative version . Can J Anaesth , 58 , 1016 \200\2231023. McGrath , P. J. , Johnston , G. , Goodman , J. T. , Dunn , J. , and Chapman , J. ( 1985 ). CHEOPS: a behavioral scale for rating postoperative pain in children . In SECTION 5 measurement of pain 390 Supplementary online materials Figure 37.1 Parents \200\231 postoperative pain measure (PPP M). Reproduced with permission from Chambers, C. T., Reid, G. J., McGrath, P. J., and Finle y, G. A., Development and preliminary validation of a postoperative pain measure for parent s, PAIN , Volume 68, pp. 307 \200\223313, Copyright 1996. Th is \201 gure has been re produced, with permission of the International Association for the Study of Pain (IASP). Th e \201 gure may NOT be reproduced for any other purpose without permission. Figure 37.3 Children \200\231s Hospital of Eastern Ontario Pain Scale (CHEOPS). Reproduced from McGrath P, Johnson G, Goodman J, Schillinger J, Dunn J, Chapman J, CHEOPS: A behaviora l scale for rating postoperative pain in children, in H. Fields, R. Dubner, F. Cervero (eds ) Advances in Pain Research and Th erapy, Volume 9, pp. 395 \200\223402, Copyright 1985, with permission of the author. Figure 37.4 NCCPCR (Non Communicating Children \200\231s Pain Scale). Reproduced from Breau , L. M., McGrath, P. J., Cam \201 eld. C. S., and Finley, G.A. Psychometric properties of the non-communicating children \200\231s pain checklist- revised, PAIN , Volume 99, Issue 1 \200\2232, pp. 349 \200\223357, Copyright 2002. Th is table/questionnaire has been rep roduced with permission of the International Association for the Study of Pain (IASP). Th e table may NOT be reproduced for any other purpose without permission Figure 37.2 Parents \200\231 postoperative pain measure short form (PPPM-SF). Reprinted fro m Th e Journal of Pain, Volume 12, Issue 3, Carl L. von Baeyer, Christine T. Chambers, and Darby M. Eakins, Development of a 10-Item Short Form of the Parents \200\231 Postoperative Pain Measure: Th e PPPM-SF, pp. 401 \200\223406, Copyright 2011 American Pain Society, p ublished by Elsevier Inc. All rights reserved, http://www. sciencedirect.com/science/journa l/15265900. CHAPTER 38 Biomarkers of pain: physiological indices of pain reactivity in infants and chil dren Susanne Brummelte , Tim F. Oberlander, and Kenneth D. Craig Summary Biomarkers are common in all areas of clinical work, health research, and are criti cal indicators of diseases and physiological states. Preferably, a biomarker should be non- invasively acces- sible, low in cost, highly specifi c, sensitive, and easy to interpret. D ue to the complexity of the pain system, no unidimensional reli- able biomarker for pain ha s been identifi ed to date. Developmental changes and delayed maturation of the involved ph ysiological sys- tems add another layer of complexity to the use of biomarkers in the pedia tric population. Nevertheless, readily available and reliable biomarkers of pain would grea tly enhance timely and appropriate treatment of pain, especially in infants and verbally or cognitively challenged children. Th is chapter examines currently available markers, their use, and limitations. birth, neonatal intensive care unit (NICU) care, pharmacological and non-pharmacological in terventions, and health and disease status (e.g. neurological injury). No single validated unidimensional physiological marker has emerged that satisfactorily ref l ects painful events in children. While the expectation that a sensitive and specifi c mar ker will be discov- ered drives research in this fi eld, research integrating the biologica l with the social-emotional nature of pain may ultimately become the most successful approa ch to understanding this universal but highly subjective human experience. De \201 ning biomarkers and pain reactivity Biomarkers have been defi ned as \200\230a ch aracteristic that is objec- tively measured and evaluated as an indicator of normal biologi c processes, pathogenic processes or pharmacological responses to a therapeutic interventio n \200\231 (Biomarkers Defi nitions Working Group, 2001, p. 91). Biomarkers typically can b e found in everyday clinical management of health and disease; however, as the pain experie nce is such a subjective, multidimensional phenomenon, identifi cation of biomarkers in thi s setting has been challenging (Marchi et al., 2009 ). To date, the focus has been on compl ex neurobiological sys- tem indicators that might provide reliable links between biology an d pain-related experience and behavior, such as variations in cardiac autonomic variability , immune function, brain blood fl ow, neuroimaging, and neuroendocrine stress hormone respo nses. Here, we focus on markers of particular promise, including those that have been studi ed suffi ciently in a pediatric population. Mainly, these are measures of autonomic nervous system (ANS) function, refl ected in measures of heart rate (HR) or heart rate variability (HRV), activity in the hypothalamic \200\223pituitary \200\223adrenal (HPA) axis (cortisol ), the endogenous opioid system, in particular Introduction Biomarkers of health or stress reactivity are widely used in all areas of pain medicine, typically adding meaning to self-report and non-verbal measures. Th ey are of cr itical importance when access to pain experience is diffi cult, such as in preverbal infant s and in children with developmental disabilities with limited com- munication and social e xpression. Th e neural substrate and related endocrine, immune, and genetic components of t he pain system off er a wide variety of potential biomarkers (Goldman and Koren, 2002 ; Obe rlander and Saul, 2002 ). However, physiological, contex- tual, and developmental factors, as well as methodological factors related to the acquisition and analysis of physiological signals or biomarkers, add challenges to the use of these biological responses in infants a nd children. Importantly, changes in biomarker levels must be considered in the context of an infant or child \200\231s neurobio- logical development and environmental contexts, such as preterm SECTION 5 measurement of pain 392 Biomarker characteristics Ideally, physiological markers would provide a meaningful biologi - cal signal with high sensitivity and specifi city ( Figure 38.1 ), such as low hemoglobin as an index of anemia. From this perspective, a perfect biomarker for pain would be reacti ve to the experience and able to distinguish pain from non-noxious stressful or non-stressf ul events. Other desirable characteristics include availability in a fast, easy, non-invasi ve, and inexpensive manner and empiric valid- ity. While HR or cortisol changes can be easi ly and inexpensively obtained, they are non-specifi c indices. Neuroimaging or genetic anal ysis typically are not available or even feasible and pose prob- lems for interpretability. beta endorphin, and genetic, infl ammatory, and neuroimaging sub- strates with potential as biomarkers. Th ese physiological measures are recognized here as indices of homeostatic changes that fo llow a painful event. Th e measures seek to be specifi c to the nociceptive system, but inv ariably engage all physiological systems reactive to pain and stress, thereby typically not serving as exclusive indicators of painful responses. Access to sensitive markers of pain is of great value to clinicians, even though specifi city remains an elusive objective. Th e properties and caveats of biomarkers need to be considered before examining in detail the multiple potential pain system markers. Th is perspective is off ered to encourage avoidan ce of thinking about these indices as \200\230meas- ures of pain \200\231. The pain system is multifaceted and typically engages a broad range of complex and interrel ated biological activities that are not easily quantified. The complexity of pain experi- e nce is also reflected in self-report (Melzack, 1975 ) and non- verbal expression (Craig et al., 2010 ) measurements. The highly diverse physiological systems subserving pain include central and peripheral neural components, genes, inflammatory and endocrine markers, all of which have been studied as indices of pain reactivity (Anand and Hickey, 1987 ; Borsook et al., 2011a ; Goldman and Koren, 2002 ; Peterson and Servinsky, 2007 ). Biomarkers reflect different levels/stages of the pain perception pathway ( Figure 38.2 ) and it is important to understand what the index indicates for the pain experience of an individual. It may ind icate features of afferent nociceptive input, but fail to account for affective and cogniti ve features of pain experience. Further, biomarkers considered to be related to a painful c on- dition, may not necessarily indicate the presence of pain. For example, cystatin C can be elevated during labor pain (Mannes et al., 2003 ), but also during pain-controlled Cesar ean sec- tions (Eisenach et al., 2004 ), suggesting that this marker may disclose tissue da mage rather than pain per se. Importantly, non-noxious processes such as general arousal, s tress or tissue damage may all contribute to changes in potential biomarkers. In addition, markers may differ for different sources of pain, as preclinical studies suggest that infla mmatory and neuropathic pain, for instance, have distinct markers (for review, see Marchi e t al., 2009 ). Thus, pain biomarkers can be characterized as cel- lular, molecular, and phy siological indices of processes involved in pain and pain-related generalized stress respon ses, but while pain is invariably stressful, not all stress is painful. Setting the scene In the fi rst instance, having readily available and reliable non-inva- s ive biomarkers would greatly facilitate timely recognition of pain in infants and children. While the sensitivity and specifi city of a response may be questioned, physiological resp onses may be con- sidered evidence of pain reactivity and should not be discounted as a \200\230surrogate measure \200\231 of pain in infants, regardless of the physiolog- ical re pertoire available (Anand and Craig, 1996 ). Th e question of whether the response is speci fi c to pain oft en requires clarifi cation, with context (e.g. injury or invasive procedur e) typically provid- ing the necessary confi rmation. Th e reactions also are important bec ause they verify the individual \200\231s capacity to mount and regu- late a response in th e face of a painful stimulus. \200\230Pain biomarkers \200\231 should be regarded as an in dex of a physiological process of \200\230reac- tivity \200\231 that refl ects how one or more systems \200\230behave \200\231 or respond to a painful event and a capacity for reco very and not a direct measure of pain per se. Th ese markers directly refl ect features of systems that respond to stressors, and increases or decreases in the magnitude or rates of change indicate disease processes. Secondly, biomarkers are used as outcome measures to quantify the eff ect of pharmacologica l or psychological interventions. HR, stress hormones, or catecholamine responses may be bl unted by interventions, such as the use of analgesics (Anand and Hickey, 1992 ) or local an esthetics (Lindh et al., 2000 ). Diminished reac- tivity presumably refl ects less biologic al distress, thereby suggesting treatment eff ectiveness. However, an analgesia-induced dec rease in a biomarker does not by itself indicate that pain is reduced and this needs to be verifi ed through an association with reduced subjective distress. Th irdly, biomarker responses are used as predictors of health and developmental outcome. F or instance, higher baseline vagal or par- asympathetic modulation in full-term infants pre dicts greater cor- tisol response to a heel stick at 6 months of age (Gunnar et al., 1995 ) and in former low birth weight infants, low biobehavioural pain reactivity at 32 weeks pre dicts poorer motor function at 8 months (Grunau et al., 2006 ). Further, more neonatal proc edural pain in preterm infants in the NICU is associated with reduced white and subcortical gray matter maturation (Brummelte et al., 2012b ). In this sense, features of pain exposur e itself provide biomarkers that predict later development. In line with this, it is import ant to note that repeated exposure to painful procedures may also infl uence the response o f a biomarker as children may transform to the repeated or continuous exposure with altered pain sensitivity (see Grunau, Chapter 4, this volume). Conceptual Model of a Pain Biomarker OUTCOME \200\234Biomarker Behavior \200\235 System Disturbance Painful Event Figure 38.1 Ideal concept of a biomarker. Physiological markers ideally provide a meaningfu l biological signal with high sensitivity and speci \201 city. Image courtesy of Tim Oberl ander. CHAPTER 38 biomarkers of pain: physiological indices of pain reactivity in infants and chil dren 393 Biomarker response patterns Decoding complex and variable patterns of potential biomarker a ctivity into measurable and identifi able components is frequently challenging. Th e respon se patterns refl ect processes which main- tain the function of homeostatic physiological s ystems within a relatively narrow range. Deconstructing the complexity is typically accomplished as follows. First, key features are identifi ed that refl ect both the amount of change from baseline, or reactivity ( intensity ), and return to baseline, the regulatio n phase ( recovery ) ( Figure 38.3 ). Quantifi cation is typically represented by a mean of multiple meas- ures of change scores (simple time 1 minus time 2), along with the standard deviation. Th e capacity to upregulate or downregulate the response can be represented by the slope of the change from base- line to maximal stress or stress to recovery (Linden et al., 1997 ), calculated using regression coeffi cients. An area under the curve (AUC) measu re has gained attention as a meaningful cumulative measure of reactivity and recovery, as, for instance, for the cortisol awakening response (Pruessner et al., 2003 ). More organized pat- terns of rhythmic physiological signals, such as HR, signal a greater capacity to res pond to environmental demands. Rather than sig- nalling pain, measures of changes in autono mic and central nerv- ous system activity may refl ect the neural capacity to mount a pain response and an appropriate physiological reaction to a painful stimulus. Nociception (A \200erent inputs) Biomarkers of activity of the nociceptive pathway Perception* (Pain experience) Treatment Biomarkers of Pain or e \200ective treatment in children with limited pain expression beha viors (e.g. non-verbal, autistic etc.) Comparisons of responses between two or more groups require consideration of baseline level s. Th e Law of Initial Values asserts that the size of a psychophysiological response is de pendent on the initial baseline level of the measure (Berntson et al., 1994 ; Wilder, 1962 ). Diff erences between groups in responses to pain- ful events may refl ect diff ering bas elines rather than a variable impact of the noxious event itself. For example, ceiling eff ects have been observed; infants already in an aroused state at the onset of a noxious even t may demonstrate a smaller increase in sympathetic arousal and a smaller decrease in paras ympathetic withdrawal (Grunau et al., 2001 ). Expression* (Pain behavior) In \202uenced by expectation, experience, fear, emotion, attention, belief etc. Figure 38.2 Biomarkers along the pain pathway. Pathway from pain perception to pain express ion in humans and potential for biomarkers of pain at each level. Adapted from Eija Kalso, Biomarkers for pain, PAIN , Volume 107, Issue 3, pp. 199 \200\223201, Copyright 2004. Th is \201 gure has been reproduced with permission of the International Association for the Study of Pain (IASP). Th e \201 gure may not be reproduced for any other purpose wi thout permission. Regulation: Change Score from pain to recovery Intensity: Means SD (How much is enough?) 30 25 Reactivity: Change score from baseline (Law of Initial Value) 20 15 10 5 0 Figure 38.3 Quantifying components of the patterns of response to a painful event. Hypothet ical reactivity patterns comparing responses in Group A vs. Group B. Patterns include measu res of: Intensity (magnitude), Reactivity, Regulation, Direction, and Slope . Image courtes y of Tim Oberlander. Baseline lance recovery \200\2235 Slope (regression coe \203cient): re \202ects tendency to upregulate or downregulate resp onses Direction: is an increase the same as a decrease? SECTION 5 measurement of pain 394 Other limits on biomarkers have been reported. A static or slow responding system or one th at has a limited range of responses is less likely to provide satisfactory biomarkers than a dynamic one. Systems with inherent rhythms, such as the HPA diurnal pattern, may bias aga inst observing an acute response to a painful event if one samples during a morning cortiso l peak period. A predictable response pattern is easier to observe when the signal returns to a baseline compared with a response pattern that remains elevated (continuous response) or has an unpredictable or paroxysmal pat- tern following a stressful event (see Figure 38. 4 ). Th us, consid- eration must be given to a biomarker \200\231s typical response pattern and contextual infl uences to appreciate its behavior in a painful context. function are closely linked to systems that modulate pain reactivity (Randich and Maixner, 1984 ) and activation of vagal aff erents can both facilitate and inhibit nociception (Lovi ck, 1993 ). Developmental maturation of the ANS has to be taken into account when investigating HR and HRV. Typically, mean basilar HR among term-born infants increases to a maximum in the fi rs t 2 months of life and then decreases through infancy (Doussard- Roosevelt et al., 1997 ). In contrast, HRV undergoes opposite changes, and aft er the fi rst 2 months of life is gene rally positively correlated with age (Finley and Nugent, 1995 ; Massin and von Bernuth, 199 7 ). HR typically shows an immediate increase follow- ing the noxious event (Craig et al., 1993 ; Oberlander and Saul, 2002 ) and a decline during recovery. However, in infants a sho rt decrease in HR has been described 3 to 5 sec aft er a vaccine, followed by the character istic increase (Johnston and Strada, 1986 ). Heart rate and heart rate variability Th e ANS plays a key part in the homeostatic response to internal demands and external challenges (stress). Th us, measures of ANS function such as HR or HRV are well suited as biomarkers as these are biological signals that refl ect c omponents of the stress and/or pain response systems. HRV refl ects variation in the time b etween heart beats and is a natural occurring physiological phenomenon. ANS function can be easily studied via non-invasive methods and displays a fast (within seconds) response and recovery pattern that can be quantifi ed to yield measures of magnitude, variability, and d irection of the signal (see Figures 38.3 and 38.4 ). Eff ects are mediated via two branches , parasympathetic and sympathetic, and responses can be quantifi ed to yield discrete conti nuous and bi-di- rectional indexes of relationships between both branches (Berntson et al., 1997 ; Grossman, 1992 ). Further, critical measurement and contextual caveats need to be considered in using HRV mea sures. HRV varies with the length of the HR epoch assessed and proximity to the noxious eve nt. HRV increases as the length of the record increases (McIntosh et al., 1993 ; Oberlander et al., 2000 ; Saul et al., 1988 ). See Voss et al. ( 2009 ) for a review of methodologica l considerations in the use of HRV. Cortisol measures Cortisol is the predominant glucocorticoid in humans and it regu- lates h omeostatic stress responses by mobilizing energy to meet the body \200\231s needs, such as elevating blood glucose levels. In response to a stressor, the HPA axis releases cortisol f rom the adrenal cor- tex, thus off ering a key stress biomarker refl ecting both central an d peripheral reactivity. HR, particularly variations linked to respiratory patterns (vagal tone), provides commonly used autonomic biomarkers (Porges, 1992 ). Systems that control autonomic aspects of cardio vascular Salivary cortisol can be non-invasively obtained and has been more widely studied as a biom arker of aff ective and behavioral responses to stress than pain per se (for review, see Di ckerson Homeostasis: balancing demands Disequilibrium Reestablishing homeostasis Continuous response External demands Figure 38.4 Phases and patterns of biomarker reactivity. Hypothetical characteristic behavi ors of a stress/pain biomarkers extending from an undisturbed baseline condition to acute r esponse phase (reactivity) to recovery (regulation of response) period. Image courtesy of T im Oberlander. Paradoxical response Stressor Regulated response Internal demands Recovery CHAPTER 38 biomarkers of pain: physiological indices of pain reactivity in infants and chil dren 395