Conclusion Collectively, information obtained from the clinical interview, ques- tionnaires , and observational measures allow for global evaluation of HRQOL and physical function in the child with pain. Due to the availability of numerous measures, the choice of instrument (s) needs to be guided by measurement quality of the instruments and the goals set by and t he clinician and/or the researcher. In examina- tion of the wide range of available instrum ents, we have identifi ed several research priorities: Case example \227\206 Validation of HRQOL and physical function measures for use in children with pain conditions requires further attention. At this time it is not clear whether currently avail able measures are appropriate in the context of acute pain or whether adaptations to existi ng measures or the development of new measures will be needed. Kristy is a 16-year-old female who began experiencing low back pain about 2 years ago. Prio r to pain onset, she participated in soft ball and volleyball at her school, but has now gi ven up these sports activities due to pain. Kristy has missed an increasing number of schoo l days in the past year, which she attributes to worsening pain from sitting for long perio ds. Her parents report that she is more sedentary than she used to be, spending much time l ying down at home. Th ey also note that she oft en refuses to do household chores that invo lve lift ing. Kristy has begun to avoid interactions with her friends because they oft en c hoose activities that involve walking long distances. Currently, Kristy reports that she ca n go on walks on days when her pain is less intense, but only walks for 20 to 30 min once o r twice a week. She also experiences increased pain when walking up and down stairs, and wh en her pain is severe she will sleep on the couch at night to avoid walking upstairs to her bedroom. Her night-time sleep has been disrupted for the past several months and she is of t en fatigued during the day. \227\206 To extend the clinical utility of measures, additional work is required to establ ish the clinical meaning of changes in scores for individuals. Th e development of cut-poin ts to indicate clinical severity of the limitation in HRQOL or physical function may be use ful for certain measures. For an example, see Kashikar-Zuck et al. ( 2011 ) concerning clin ical utility of the FDI. \227\206 Th ere is limited information on any objective or performance- based measure of p hysical function or activity in children with pain. Additional work is needed with performa nce-based tasks (e.g. timed walk), activity devices (e.g. actigraphy), and with physical fi tness measures (e.g. grip strength) to develop norma- tive data in pediatric pain populati ons and understand relative CHAPTER 41 measurement of health-related quality of life and physical function 423 Eccleston , C. , Jordan , A. , McCracken , L. M. , Sleed , M. , Connell , H. , and Clinch , J. ( 2005 ). Th e Bath Adolescent Pain Questionnaire (BAPQ): development and preliminary p sychometric evaluation of an instrument to assess the impact of chronic pain on adolescents . Pain , 118 , 263 \200\223270. Assessment that includes a combination of interview ques- tions, standardized measures of H RQOL and physical function in conjunction with performance measures may provide clini- call y relevant information. Th e clinical interview could be used to assess in detail Kristy \200\231s participation in physical and role activi- ties (e.g. doing family chores at home , attending school, doing things with friends). Specifi c interview probes could be used wi th Kristy and her parent(s) to understand Kristy \200\231s expectations for activity and ro le participation and what her individual values are around functional activities. A measure of overall HRQOL, such as the PedsQL 4.0, would provide information about perception of ov erall health impact, while a measure of pain-related activity limitations or disability suc h as the FDI or the CALI-21 would provide information about pain impact on functioning that may identify specifi c intervention targets or goals. Because Kristy reports trouble walki ng, and a timed 10- meter walk would estab- lish a baseline performance that could be used throughout treat- ment to assess progress. Additional measures of performance and fi tness might be chosen by a physical or occupational therapist. Eccleston , C. , Jordan , A. L. , and Crombez , G. ( 2006 ). Th e impact of chronic pain on adolescents: a review of previously used measures . J Pediatr Psychol , 31 , 684 \200\223 697. Eccleston , C. , Malleson , P. N. , Clinch , J. , Connell , H. , and Sourbut , C. ( 2003 ). Chronic pain in adolescents: evaluation of a program of interdisciplinary cognitive behavi or therapy . Arch Dis Child , 88 , 881 \200\223885. Eiser , C. and Morse , R. ( 2001 ). Th e measurement of quality of life in children: past and future perspectives . J Dev Behav Pediatr , 22 , 248 \200\223256. Gold , J. I. , Mahrer , N. E. , Yee , J. , and Palermo , T. M. ( 2009 ). Pain, fatigue, and health-related quality of life in children and adolescents with chronic pain . Clin J Pain , 25 , 407 \200\223412. Halbig , M. and Horneff , G. ( 2009 ). Improvement of functional ability in children with j uvenile idiopathic arthritis by treatment with etanercept . Rheumatol Int , 30 , 229 \200 \223238. Harding , V. R. , Williams , A. C. , Richardson , P. H. , Nicholas , M. K. , Jackson , J. L . , Richardson , I. H. , et al . ( 1994 ). Th e development of a battery of measures for as sessing physical functioning of chronic pain patients . Pain , 58 , 367 \200\223375. Th ese measures can provide valuable information to assess Kristy on an individual basis, a nd to also compare the level of impairment secondary to pain in comparison to other adoles- cents with pain conditions. Furthermore, the measures can also allow the clinician to trac k Kristy \200\231s progress over time to objec- tively monitor her level of functioning and assess for changes in impairment if treatment is undertaken. Hermann , C. , Hohmeister , J. , Zohsel , K. , Tuttas , M. L. , and Flor , H. ( 2008 ). 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Cross-cultural adaptation and psychometric evaluation of the Childhood Health A ssessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries. Re view of the general methodology . Clin Exp Rheumatol , 19 , S1 \200\2239. Nodari , E. , Battistella , P. A. , Naccarella , C. , and Vidi , M. ( 2002 ). Quality of li fe in young Italian patients with primary headache . Headache 42 (4), 268 \200\223274. Selvaag , A. M. , Flato , B. Lien , G. Sorskaar , D. Vinje and Forre , O. ( 2003 ). Measuri ng health status in early juvenile idiopathic arthritis: determinants and responsiveness of the child health questionnaire . J Rheumatol , 30 , 1602 \200\2231610. O \200\231Sullivan , P. , Beales , D. Jensen , L. Murray , K. , and Myers , T. ( 2011 ). Ch aracteristics of chronic non-specifi c musculoskeletal pain in children and adolescents att ending a rheumatology outpatients clinic: a cross- sectional study . Pediatr Rheumatol Onli ne J , 9 , 3 . Sirard , J. 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W. , Limbers , C. A. , and Burwinkle , T. M. ( 2007 a). Impaired health- related quality of life in children and adolescents with chronic conditions: a comparative analysi s of 10 disease clusters and 33 disease categories/ severities utilizing the PedsQL 4.0 Gen eric Core Scales . Health Qual Life Outcomes 5 , 43 . Palermo , T.M. , Riley , C.A. , and Mitchell , B. A. ( 2008 c). Daily functioning and quali ty of life in children with sickle cell disease pain: relationship with family and neighbor hood socioeconomic distress . J Pain 9 (9), 833 \200\22340. Varni , J. W. , Limbers , C. A. , and Burwinkle , T. M. ( 2007 b). Parent proxy- report of their children \200\231s health-related quality of life: an analysis of 13,878 parents \200 \231 reliability and validity across age subgroups using the PedsQL 4.0 Generic Core Scales . Health Qual Life Outcomes , 5 , 2 . Palermo , T. M. , Schwartz , L. , Drotar , D. , AND McGowan , K. ( 2002 ). Parental report of health-related quality of life in children with sickle cell disease . J Behav Med 25 (3) , 269 \200\223283. Varni , J. W. , Limbers , C. A. , Burwinkle , T. M. , Bryant , W. P. , and Wilson , D. P. ( 2008 a). Th e ePedsQL in type 1 and type 2 diabetes: feasibility, reliability, and validit y of the Pediatric Quality of Life Inventory Internet administration . Diabetes Care , 31 , 672 \200\223677. Palermo , T. M. , Wilson , A. C. , Peters , M. Lewandowski , A. , and Somhegyi , H. ( 2009 ). Randomized controlled trial of an Internet-delivered family cognitive-behavioral therapy intervention for children and adolescents with chronic pain . Pain , 146 , 205 \200\22321 3. CHAPTER 41 measurement of health-related quality of life and physical function 425 Wilson , A. C. , and Palermo , T. M. ( 2012 ). Physical activity and function in adolescent s with chronic pain: a controlled study using actigraphy . J Pain , 13 , 121 \200\223130. Varni , J. W. , Limbers , C. A. , Neighbors , K. , Schulz , K. , Lieu , J. E. , Heff er , R . W. , et al . ( 2011 ). Th e PedsQL Infant Scales: feasibility, internal consistency relia bility, and validity in healthy and ill infants . Qual Life Res , 20 , 45 \200\22355. Young , N. L. , Varni , J. W. , Snider , L. , McCormick , A. , Sawatzky , B. , Scott , M. , et al . ( 2009 ). Th e Internet is valid and reliable for child- report: an example using the Activities Scale for Kids (ASK) and the Pediatric Quality of Life Inventory (PedsQL) . J Clin Epidemiol , 62 , 314 \200\223320. Varni , J. W. , Limbers , C. A. , Newman , D. A. , and Seid , M. ( 2008 b). Longitudinal fa ctorial invariance of the PedsQL 4.0 Generic Core Scales child self-report Version: one yea r prospective evidence from the California State Children \200\231s Health Insurance Progra m (SCHIP) . Qual Life Res , 17 , 1153 \200\2231162. Varni , J. W. , Seid , M. , Smith Knight , T. , Burwinkle , T. , Brown , J. , et al . ( 200 2 ). Th e PedsQL in pediatric rheumatology: reliability, validity, and responsiveness of th e Pediatric Quality of Life Inventory Generic Core Scales and Rheumatology Module . Arthrit is Rheum 46 (3), 714 \200\223725. Varni , J. W. , Seid , M. and Rode , C. A. ( 1999 ). Th e PedsQL: measurement model for the pediatric quality of life inventory . Med Care , 37 , 1 26 \200\223139. Online supplementary materials Table 41.4 Interview probes for assessing physical functioni ng. Reproduced from Tonya M. Palermo, Cognitive-Behavioral Th erapy for Chronic Pain in Chi ldren and Adolescents , Table 4.4, p.50, Oxford University Press, Inc., New York, USA, Copy right 2012, by permission of Oxford University Press. Table 41.5 Interview probes for assessing sleep problems. Reproduced from Tonya M. Palermo, Cognitive-Behavioral Th erapy for Chronic Pain in Children and Adolescents , Table 4.6, p. 52, Oxford University Press, Inc., New York, USA, Copyright 2012, by permission of Oxfor d University Press. 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This page intentionally left blank SECTION 6 Pharmacological interventions This page intentionally left blank CHAPTER 42 Principles of pain pharmacology in pediatrics Kim Chau and Gideon Koren Summary Changes during growth and development may profoundly alter the pharmacokinetic and pharmacodynamics profi le of medications in children of diff erent ages, and in comparison to adults. Genetic fac- tors can also infl uence the disposition and action of a drug, and con- tribute to interindividual diff erences in clinical response. Safe and eff ective phar macological management of pain in neonates, infants, and children requires a thorough under standing of the principles of analgesic pharmacology in pediatric patients. Analgesic dosin g regimens should take into account the severity of pain, the age or developmental state of the infant, and the therapeutic window of the drug. \227\206 Neonates and infants have higher percentage of body weight as water and smaller f at and muscle stores compared to adults; therefore, water-soluble drugs may have larger vol ume of distri- bution (Echeverria et al., 1975 ). \227\206 Th ey have an anatomically developed liver at birth; however, functional maturati on is delayed and as a result, neonates exhibit delayed maturation of hepatic drug metaboli zing enzymes com- pared to older children, until around 6 months of age (Tateishi et al., 1 997 ). \227\206 Th e kidney exhibits slower glomerular fi ltration rate and tubular secretion. \227\206 Plasma concentrations of albumin and alpha-1 acid glycoprotein are lower than in adults; for some drugs (e.g. sulphonamides) this may result in greater availability of unbo und active drugs and thereby, greater drug eff ect or increased risk of drug toxicity (Heim ann, 1980 ). Introduction Growth and development diff erences exist between children and adults and thes e may profoundly alter the pharmacokinetics and pharmacodynamics of medications in children (Anderson and Palmer, 2006 ; Kearns et al., 2003 ). In the past, formulaic approaches were used to determine pediatric drug doses, with some using dis- crete age points or principle s that assume that infant growth is a predictable and linear process. For example, using Yo ung \200\231s rule and Clark \200\231s rule, a child \200\231s dose is based on a mathemati cal fractionation of the adult dose. To calculate an approximate child \200\231s dose, thes e formulas divide the child \200\231s weight (in pounds) by the assumed aver- age weight of an adult (150 lbs) and multiply the fractional result by the adult dose (Munzenberger and McKercher, 1980 ). With advances and integration of developmental pharmacology into clinica l practice, it is now recognized that neonates and infants are not merely \200\230small ad ults \200\231 and thus, they do not respond to pharma- cological therapy in a similar manne r to adults (Kearns et al., 2003 ). When approaching pharmacological decisions in managing pain in pediatric patients, there needs to be an appreciation of the interac- tion between pharmacokinetics and pharmacodynamics of thera- peutics. As a result, factors that must be considered when treating infants and children include: \227\206 Neonates have an immature blood \200\223brain barrier (BBB), which may allow incr eased passage of certain drugs, such as morphine and merperidine, into the brain (Bouwmeest er et al., 2003 ; Way et al., 1965 ). Unfortunately, there are still gaps in our understanding of the impact of maturational chan ges on the clinical pharmacology of most drugs; however, it is abundantly clear that the co ntinuous physiological development of neonates, infants, and children infl u- ences the dis position of most drugs (Holford, 1996 ; Kearns et al., 2003 ). Th erefore, to safely and ef f ectively manage pain in neonates, infants, and young children, a thorough understanding o f the prin- cipals of pain pharmacology in pediatric patients is essential. Developmental pediatric pharmacokinetics Th e use of pharmacological agents for the treatme nt of pain in pediatric patients should be guided by the general principles of developmenta l pharmacology. Accordingly, pediatric analgesic dosing regimens should take into account t he severity of pain and the age or developmental state of the infant (Helms and Barone, 200 8 ), as well as the therapeutic window of the drug, to avoid \227\206 Rate of drug absorption via oral route of administration is slower in neonates th an in infants and older children; thus, time to achieve maximal plasma levels is prolonged (Heimann, 1980 ). SECTION 6 pharmacological interventions 430 dose-dependent toxicities. Th e traditional empirical approach to determining pediatric dru g doses was based on the allometric size scaling principle, whereby pharmacokinetic paramet ers were based on relative body size and it was generally assumed there is a linear relatio nship between body mass and body surface area in infants, children, adolescents, and adults (Ritschel, 1980 ). However, infant growth and development are not always linear processes when growth and age-related changes in body composition and organ function are considered ( Kearns, 2000 ). Th erefore, simply scaling an adult dose for infants and children based on body weight or body surface area may result, at times, in either ineff ective pain manage- ment or severe, unexpected toxicity (Holford, 1996 ). As such, using a non-linear relations hip between weight and drug elimination capacity is more appropriate for determining drug d osing regimens of pain treatments in pediatric patients (Dawson, 1940 ). Of note, such guid elines are primarily applicable for initiating pain therapy, and long-term maintenance of p ain therapy must be individualized and requires consideration of developmental variations i n pharma- cokinetics and pharmacodynamics. Th us, to safely and eff ectively manage and tre at pain in pediatric patients, a fundamental under- standing of the interplay between growt h and development on the disposition and actions of drugs is necessary. the intestinal activity of cytochrome P450 (CYP) 1A1 (CYP1A1) is lower during infancy compa red to late childhood; however, it appears that the activity level increases with age (Stah lberg et al., 1988 ). At birth, glutathione-S-transferase (GST) activity is high compared t o older children, but decreases during infancy through early adolescence (Gibbs et al., 199 9 ). Relative to adults, the stratum corneum is thinner and the epi- dermis is also more hydrate d in neonates and throughout child- hood, which may result in an increase in percutaneous a bsorption during infancy (Fluhr et al., 2000 ). As infants and young children have a greate r total body surface area to body mass ratio than adults, topically applied drugs display g reater systemic exposure in infants, which may result in toxic eff ects if the dose adminis tered is not age-appropriately adjusted (Fluhr et al., 2000 ; West et al., 1981 ). Rectal administration of drugs is increasingly being used in infants and young children, bu t may have greater bioavailability in neonates due to the delayed developmental maturity of hepatic drug-metabolizing enzymes. Conversely, neonates and infants may absorb less drug f ollowing rectal administration compared to adults (van Lingen et al., 1999 ) due to a great er number of high-amplitude pulsatile contractions resulting in greater expulsion of drugs (Di Lorenzo et al., 1995 ). As absorption and bioavailability of acetami- nophen suppositor ies are unpredictable, and delayed peak plasma concentration is observed compared to oral a dministration, rectal administration may result in subtherapeutic plasma concentrations (Au tret et al., 1993 ; Goldstein et al., 2008 ; Rumore and Blaiklock, 1992 ; see also Anderson , Chapter 43 , this volume). Absorption of drugs Th e absorption of drugs administered to neonates and infants is signif i cantly infl uenced by developmental changes in absorptive surfaces, such as the gastroint estinal tract, pulmonary bronchioles, and skin; these sites of absorption determine the rat e and extent of the bioavailability of a drug (Kearns, 2000 ). Furthermore, the rela- tive amount of drug available for absorption is aff ected by the intra- luminal pH. For example, gastric pH is higher (greater than 4) in neonates compared to older children, aff ecting t he stability and the degree of ionization of a drug, and thus infl uencing the amount of dr ug that can be absorbed (Agunod et al., 1969 ). Th erefore, strong acidic drugs, such as pe nicillin, administered orally have a greater bioavailability in neonates than in older chil dren; whereas, for neonates to achieve therapeutic plasma levels of orally adminis- tered d rugs that are weak acids, such as phenobarbital, larger doses may be required due to the hi gher intraluminal pH (Kearns et al., 2003 ; Koren et al., 1993 ). Distribution of drugs Developmental changes in body composition are primarily respon- sible for the age-associated diff erences in drug distribution. As neonates and infants have rel atively larger extracellular and total- body water, coupled with smaller fat and muscle sto res compared to adults, when water-soluble drugs are administered, plasma lev- els in these compartments may be lower (i.e. larger volume of dis- tribution; Echeverria et al., 1975 ; Siber et al., 1975 ). Additionally, neonates and young infants have lower amounts of total circulat- ing plasma proteins, such as albumin and 1 -acid glycoprotein, resulting in a n increase in the free fraction of drugs, which infl u- ences the availability of the activ e moiety of drugs (Ehrnebo et al., 1971 ). Th e free fraction of highly protein-bound drugs is higher in neonates compared to older children and adults, as fetal albumin has lower bi nding affi nity for weak acids, and there is an increase in endogenous substances (e.g. fre e fatty acids) with a high affi nity for displacing drugs from albumin binding sites (Ehrne bo et al., 1971 ; Windorfer et al., 1974 ). Other age-related physiological changes, such a s diff erences in organ perfusion, regional blood fl ow, and permeability of cell membranes , can also dramatically infl uence drug binding and distribution. Following birth, neonates experience a marked increase in gas- tric emptying due to the imp rovement of the coordination of antral contractions (Gupta and Brans, 1978 ; Ittmann et al. , 1992 ). Th is is clinically signifi cant as the rate of drug exposure along the mucosal s urface of the small intestine is determined by the transit time of the drug within the gast rointestinal tract. As a result of increased gastric emptying in neonates, orally administe red drugs are less well absorbed and more time is required to achieve therapeutic plasma le vels of drugs in neonates compared to older children and adults (Heimann, 1980 ). Although few bioavailability studies have examined the absorption of drugs in infants and older chil dren, it has been suggested that both passive and active transportation are fully mature in infants by approximately 4 months of age (Anderson and Holford, 2008 ; Heimann, 1980 ). Drug metabolism Compared to older children and adults, neonates and infants exhibit distinc t developmental immaturity of many phase I (oxida- tion; Hines and McCarver, 2002 ) and pha se II (conjugation) drug- metabolizing enzymes (McCarver and Hines, 2002 ; Tateishi et al., 1997 ), which can contribute to observed drug toxicities in this age group (Weiss et al., 1960 ). During postnatal development, distinct patterns of change are observed in the isofo rm-specifi c expression Delayed maturation or developmental diff erences in the activity of intestinal drug-metabol izing enzymes in neonates and infants may aff ect the bioavailability of drugs (Hines and M cCarver, 2002 ), and can alter the systemic absorption of therapeutically active metabolite s of certain drugs, such as theophylline. For example, CHAPTER 42 principles of pain pharmacology in pediatrics 431 and activity of phase I enzymes, such as the cytochrome P450 fam- ily of drug-metabolizing enzymes: in children under 6 years of age even when acetaminophen plasma levels are within the range that is toxic at older ages (Rumore and Blaiklock, 1992 ). \231 Th e activity of CYP2E1 surges within hours aft er birth (Vieira et al., 1996 ). Elimination of drugs Beginning at 9 weeks of age, there is a developmental increase in the glomerular fi ltration rate, a process that is dependent on nor- mal nephrogenesis but is c omplete by 36 weeks of gestation, and then infl uenced by postnatal changes in renal and in trarenal blood fl ow (Robillard et al., 1988 ). During the fi rst 2 weeks of life, there is a rapid and marked increase in the glomerular fi ltration rate, which reaches its peak adu lt values by 8 to 12 months of age (Arant, 1978 ; van den Anker et al., 1995 ). Correspondi ngly, delayed maturation of tubular secretion is observed following birth; however, it reac hes adult capacity by the fi rst year of life (Arant, 1978 ). \231 Th is is immediately followed by the detection of CYP2D6 (Treluyer et al., 1991 ). \231 By the fi rst week of life, the expression of CYP3A4 (Lacroix et al., 1997 ) and CYP 2C (CYP2C9 and CYP2C19; Treluyer et al., 1997 ) become detectable. \231 By 1 to 3 months of life, CYP1A2 begins to appear (Sonnier and Cresteil, 1998 ). Th e cytochrome P450 superfamily of enzymes catalyzes the oxi- dation of opioids, convertin g the parent opioid to a more polar metabolite to facilitate its excretion. Of importance i n opioid metabolism are CYP3A4 and CYP2D6. Relatively low levels of P450s are expressed in the fetal liver; the level of CYP2D6 expres- sion reaches only 3% to 5% of adult expression in the third trimes- ter (Ladona et al., 1991 ). However, expression and activity level of CYP2D6 approaches 95% of adult capacity by 2 weeks of life (Blake et al., 2007 ). In compa rison, the expression of CYP3A4/5 begins to increase at 1 week of life reaching 30% of adul t levels by the age of 1 month. As developmental diff erences in the maturation of renal function can signifi cantly infl u ence the plasma clearance of drugs extensively eliminated by the kidneys (e.g. ceft azidime and famotidine; James et al., 1998 ), consideration of the ontogeny of renal function and age-appropriate dosing regimens for infants is necessary to avoid potential toxicity. Developmental pediatric pharmacodynamics It is well-established that physiological developm ent plays an important role in the mechanism of action of, and the response to, a drug. How ever, the eff ect of ontogeny on the interactions between a drug within the human body and the consequence of these inter- actions are still incompletely understood. Certain drugs, s uch as cyclosporine (Marshall and Kearns, 1999 ) and warfarin (Takahashi et al., 2000 ), de monstrate developmental diff erences in the interac- tion between a drug and the targeted r eceptor. Whereas, drugs such as midazolam show a clearer relationship between plasma level and the pharmacological eff ect of the drug (e.g. sedative eff ect; Marshall et al., 2000 ) . Although the ontogeny of phase II drug-metabolizing enzymes is less well established than p hase I drug-metabolizing enzymes, available data suggests that specifi c isoforms of uridin e diphosphate (UDP)-glucuronosyltransferase (UGT) display distinct patterns of maturation, which can markedly aff ect the pharmacokinetics of drugs (Barrett et al., 1996 ): \231 Th e expression and activity of the isoforms UGT1A6 and UGT1A9, are lower in neonate s and infants, and the glucuro- nidation of acetaminophen by UGT1A6 and, to a lesser extent , UGT1A9, is markedly decreased relative to adolescents and adults (Miller et al., 1976 )