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AHRQ Comparative Eff ectiveness Reviews. Rockville, MD : Agency for Healthcare Research and Quality (US) . Singh-Grewal , D. , Wright , V. , Bar-Or , O. , and Feldman , B. M. ( 2006 ). Pilot study o f fi tness training and exercise testing in polyarticular childhood arthritis . Arthritis R heum , 55 (3), 364 \200\223372. Slater , M.-E. , De Lima , J. , Campbell , K. , Lane , L. , and Collins , J. ( 2010 ). Opio ids for the management of severe chronic nonmalignant pain in children: a retrospective 1-y ear practice survey in a children \200\231s hospital . Pain Med , 11 (2), 207 \200\223214. Wood , P. ( 1978 ). Special meeting on: nomenclature and classifi cation of arthritis in ch ildren . In E. Munthe , (ed.) Th e Care of Rheumatic Children , pp. 47 \200\22350. Basel : EULAR . Steans , A. , Manners , P. J. , and Robinson , I. G. ( 1990 ). A multicentre, long- term ev aluation of the safety and effi cacy of ibuprofen syrup in children with juvenile chronic a rthritis . Br J Clin Pract , 44 (5), 172 \200\223175. Woolf , C. J. , and Salter , M. W. ( 2000 ). Neuronal plasticity: increasing the gain in pain . Science , 288 (5472), 1765 \200\2231769. Zeltzer , L. , Bursch , B. , and Walco , G. ( 1997 ). Pain responsiveness and chronic pain: a psychobiological perspective . J Dev Behav Pediatr , 18 (6), 413 \200\223422. Stinson , J. N. , Connelly , M. , Jibb , L. A. , Schanberg , L. E. , Walco , G. , Spiegel , L. R. , et al . ( 2012 ). Developing a standardized approach to the assessment of pain in children and youth presenting to pediatric rheumatology CHAPTER 23 Chronic pain syndromes in childhood: one trunk, many branches Neil L. Schechter Summary Although this volume is replete with detailed discussions about specifi c pain prob lems, the focus of this chapter is on a discus- sion of the commonalities in etiology, asso ciated symptoms, and treatment of many of the frequent chronic pain problems. We will explo re in brief the data that demonstrates the co-occurrence of many of the common chronic pain problems in children and the epidemiological similarities that exist between aff ected ind ividuals. Th en we will review the concept of central sensitization and the physiological e vidence that supports its presence in many of the functional pain problems. We will briefl y review some of the symp- toms associated with these entities (orthostatic intolerance, sl eep disturbance, depression, anxiety, hypermobility, family distress). Finally, we will dis cuss briefl y a general approach to these problems emphasizing the collection of specifi c information in the history and physical examination, the critically important presentation of the formulation to the family, and the treatment modalities that appear to be eff ective for many of these conditions. In-depth dis- cussion of each of these pain problems is avai lable in chapters spe- cifi cally designated to review them in detail. entities together and the importance of their simultanous evalu- ation and treatment. Such an approach will hopefully reduce the burden of unnecessary investigation and treatment in these chil- dren who are oft en already overwhelmed by the collective eff orts of the medic al community. Epidemiology of chronic pain in children Th ere has been long-standing recognition that chi ldren and ado- lescents experience chronic pain and that it is a relatively common experien ce for them. In a large community sample, Perquin et al. ( 2000 ) reported an incidence of chronic pain (defi ned as recurrent or continuous pain for more than 3 months) of 25% with headache, abdominal pain, and limb pain the most common presentations. Th ere have been mul tiple other large-scale surveys which report a similar incidence. Additionally, the co-occurrence of chronic pain problems has been recognized for many years in the adult literature. Table 23.1 presents selected data adapted from a comprehensive re view of this subject by Yunus ( 2007a ). He summarizes the data which demon- strates the li kelihood of having a second chronic pain syndrome in individuals who have at least one. For example, he reports that the prevalence of irritable bowel syndrome is 45% in individu- al s with fi bromyalgia (with a range of 32 \200\22370% depending on the study). Yunus identif i ed the co-occurrence of fi bromyalgia, chronic fatigue syndrome, irritable bowel syndrome , tension and migraine headaches, temporomandibular disorders, primary dysmenor- rhoeal pai n, post-traumatic stress disorder, and multiple chemical sensitivities. As is evident from this chart of studies on adults, there is frequent overlap among these entities which Yunus calls central sensitivity syndromes based on his hypothesis of their etiology. Introduction In this chapter, we will highlight relevant issues around the fre- quent co-oc currence of common chronic pains. Th is overlap may easily escape the notice of busy specia lists who tend to focus on the specifi c symptoms most relevant to their discipline. For ex am- ple, it would not be unusual for a child who is being evaluated for persistent abdomina l pain by a gastroenterologist to simultane- ously be experiencing headache or widespread m usculoskeletal pain. Because these symptoms are not the focus or expertise of the gastroent erologist, he or she may ignore these additional symp- toms assuming that they will be addr essed by others. As a result, the frequency with which these pains co-occur and the similar ities in their etiology and treatment may not be fully appreciated. By the end of this chap ter, we hope that the reader will appreciate the importance of recognizing the common eleme nts that bind these Th e overlap of these syndromes in the pediatric population is a more recent discovery. Alt hough Zuckerman et al. ( 1987 ) noted the frequent coexistence (22%) of headache and stomac h aches in pre- school children in England when surveying the community for the incidence o f these pain problems, the signifi cance of this overlap in children was not a focus of res earch in the pediatric literature until 1997, when Krstjansdottir ( 1997 ) studied this phe nomenon CHAPTER 23 chronic pain syndromes in childhood: one trunk, many branches 229 Table 23.1 Associations among central sensitivity syndromes (CSS) Condition Mean prevalence (%) of another CSS in patients with this condition (range of %) Total no. of studies Total no. patients FMS CFS 39 (22 \200\22374) 6 214 IBS 45 (32 \200\22370) 17 1776 Migraine 38 (22 \200\22349) 3 183 UHA 50 (35 \200\22356) 5 558 TTH 42 (22 \200\22360) 5 889 CFS FMS 48 (16 \200\22380) 2 57 IBS 36 1 25 IBS FMS 36 (28 \200\22365) 5 179 CFS 14 1 200 UHA 42 (31 \200\22350) 3 297 Migraine CFS 51 1 63 FMS = \201 bromyalgia syndrome; IBS = irritable bowel syndrome; TTH = tension headache; U HA = unspeci \201 ed headache. Adapted from Seminars in Arthritis and Rheumatism , Volume 36, Issue 6, Muhammad B. Yunus, Fibromyalgia and overlapping disorders: the unifying concep t of central sensitivity syndromes, pp. 339 \200\223356, Copyright 2007, with permission from Elsevier, http://ww w.sciencedirect.com/science/journal/00490172. Evidence for shared biological mechanisms Although the data is still emerging, it appears f rom multiple streams of evidence that many of the functional pain syndromes are asso- ciate d with abnormalities of nociceptive processing which may account for the fact that individu als with these conditions oft en experience severe pain without evidence of structural path ology or other physiological derangement. Th is may result from, depending on the condition and situation, enhanced neurotransmission stem- ming from hyperarousal of central neurons (central sensitization) (Geisser et al., 2008 ; Giesecke et al., 2004 ; Woolff , 2001), aut onomic nervous system dysfunction (Janig, 2009 ), hypothalamic \200\223pitu- itary \200\223 adrenal axis dysfunction (Chang et al., 2009 ), and/or from dysfunction of descending pain modulatory abilities (Johannesson et al., 2007 ; Lautenbacher and Rollman, 1997 ). Even tho ugh the mechanistic details require more research and may vary from indi- vidual to individ ual, there is a robust literature which suggests that individuals with functional pain synd romes oft en have an altered response to clinical and experimental pain exemplifi ed by inc reased spontaneous fi ring, decreased threshold, increased response ampli- tude, expanded r eceptive fi eld. Th is is evident on both oral reports of increased pain in clinical situat ions and on laboratory induced pain as well as on functional magnetic resonance imaging eva lu- ations which suggest an altered pain response in individuals with chronic pain as compa red to controls. directly. She reported that over a 3-month period, 21% of children who had one pain had at least one other. Subsequently, other inves- tigators found a co-occurrence rate that ranged from a low of 5% (Larsson and Sund, 2007 ) to a high of 50% (Kroner-Herwig et al., 2011 ) depending on defi nitions of chronic pain. Fichtel and Larsson ( 2002 ) found that almost 1 5% of their Scandinavian sample of chil- dren with chronic pain had four or more pain sites . Shared biological and clinical features Th e recognition that multiple pain sites are commo n in individ- uals who have chronic pain has prompted a more in-depth look for similarities between these entities. Th e fact of their frequent co-occurrence has signifi cant researc h implications as it requires an explanatory model that is broader than focus on a specifi c end organ (stomach, back, head, etc.). It is not only the frequency of overlap of these e ntities that is noteworthy, however, but also the co-occurrence of many other associated fe atures. Th ese include female predominance, association with psychological disorders, schoo l and sleep disruption, frequent fatigue and loss of mental clarity. Additionally, many of the same centrally acting non-specifi c treatments (exercise, stress reduction, acupuncture , neuromodulat- ing drugs such as antidepressants and anticonvulsants) are eff ective for t hese all of these syndromes. Th ese shared characteristics pro- vide further support for th e linkage of these entities and add to the critical importance of a multidisciplinary appro ach which allows the insights of researchers who had been narrowly exploring one type of pa in to infl uence the thinking of those exploring other pain problems. In this section, we w ill review the evidence that supports the existence of the numerous commonalities among the se entities. Because much of the work stems from adult research, we will use the schema dev ised by Mayer and Bushnell ( 2009 ) in the fi nal sec- tion of their seminal volume on func tional pain syndromes where they attempt to synthesize what we have learned about the inter -re- lationship of these common problems in adults and add pediatric data where it is avail able. Th is recognition has led a number of investigators to conclude that at their core, many of these entities have a similar etiology \200\224 a hypersensitivity to noxious and non-nox ious stimuli typically known as central sensitization (Woolf, 2011 ) which is multifacto- r ial in origin. In fact, Yunus ( 2007a , 2008 ) has recently clustered a number of these ent ities together under the rubric of \200\230central sensitivity disorders \200\231 implying the centrality of central sensitiza- tion in their etiology. He identifi ed research that demonstrated an altered response to pressure, heat, cold, and auditory sensations in adults with migraine, fi bromyalgia, and irritable bowel syndrome. Similarly, Von Baeyer and Cham pion ( 2011 ) conclude that these SECTION 4 pain in specific populations and diseases 230 Family history Th ere is strong evidence that chronic pain problems tend to run in families . Th is is most likely due to a number of factors including the genetics of nociception, ge netic inheritance of painful conditions, and parental modeling of pain behavior. problems are all manifestations of an underlying pain vulnerability which stems from multip le sources but yields similar outcomes. Th e origins for this increased susceptibility to pain are quite com- plex and not fully un derstood and likely vary from individual to individual. Mayer and Bushnell ( 2009 ) and Yun us ( 2007b ) have sug- gested that this alteration may emerge from multiple mechanisms, bot h biological and social. Th ese may include genetic predisposi- tion, anxiety or depression , increased psychosocial stressors, early life adversity, infections, and/or infl ammation. Microtrauma such as that stemming from hypermobility or overuse may also play a role. Th e se factors may impact on the central nervous system and cause the hyperexcitability that is called central sensitization which they feel is the core biological link and fi nal common pathway to the creation of functional pain disorders. Other models suggest while acknowled ging the centrality of central sensitization that psychological factors exert their infl ue nce independently and not necessarily through a hyperexcited central neurons. Studies have attempted to evaluate the relative contributions of genetics to variations in pain sensitivity, in both animals and humans (Foulkes and Wood, 2008 ). For example, Mogil and col- leagues compared the pain thresholds within and between 11 inbred laboratory mouse strains using multiple laboratory-induced pain modalities and identifi ed signifi cant gen etic contributions to nociception and a variety of candidate genes (Mogil et al., 1999 ). In addition to experimentally induced pain, several studies have investigated the genetic c ontribution to diff erences in severity of and susceptibility to certain chronic pain condi tions. A recent study by Kato and colleagues which included 15,950 pairs of twins, found a genetic contribution of about 50% to the likelihood of developing fi bromyalgia (Kato et al ., 2006 ). Th e inheritance of other chronic pain problems has been studied. Migraines (wit h and without aura) all have a substantial risk of familial recurrence. Concordance rates f or migraine are consistently higher among monozygotic than dizy- gotic twins (Montagna, 200 8 ). Th irty-three per cent of individu- als with irritable bowel syndrome have a family hi story (Whorwell et al., 1986 ). Th ere is similar data for other central sensitivity syndro mes. As should be evident from the preceding discussion, if one assumes that functional pain dis orders emerge from a composite of biological vulnerabilities and psychosocial factors which jointly create abnormalities of pain processing or the misperception of those signals, the n the notion that pain can be categorized as strictly physical or psychological is highly o utdated and in fact destructive. Unfortunately, however, many families may become frustrate d by the traditional approach to unexplained pain \200\224extensive laboratory investigatio n and imaging which if negative results in referral to a mental health professional. It is essential that the child and family understand that declaring the pain syndrome to be funct ional does not at all imply psychogenesis. Th e pain itself is the disease. Additionally, a number of environmental characteristics may play an important role. Parenta l modeling of pain behavior has been demonstrated to increase pain behavior in their childr en. Parents with pain are more likely to have children with pain and children are more like ly to have pain sites that are similar to their parents (Evans et al., 2007 ). Parents \200 \231 interactions with their chil- dren may have a role in infl uencing the likelihood that the pain will aff ect the child \200\231s functioning (Goodman and McGrath, 2003 ). Th e r elative contribution of genetics, modeling, and parental response to the pain experience pr obably varies from child to child but it is clear that chronic pain aggregates in families. Schanberg and col- leagues ( 2001 ) reviewed the family history of 100 patients seen in a pediatric rheumatology clinic and found that 90% of parents reported at least one chronic p ain condition, typically lower back pain, shoulder/neck pain, and migraine headache. On ave rage, par- ents reported a history of 3.5 chronic pain conditions. Ninety-three per cent of parents reported at least one relative with chronic pain in their immediate family. It is critical therefore that a detailed fam- ily history be obtained to further our understandin g of the factors contributing to the child \200\231s chronic pain.