Rehabilitation and self-management Th e primary treatment approach to the young person with chronic musculoskeletal pain is one of symptom management and psycho- social rehabilitatio n. Although it may be tempting to focus solely on the amelioration of the suff ering of the child, one of the most important aspects of rehabilitation is \200\230inclusion \200\231. A dedicated team that works consistently with the adolescent and family will facilitate co mmunication, ensure eff ective delivery of therapy, reduce iatro- genic infl uences and ena ble goals to be reached earlier (Christie and Wilson, 2005 ;Walco et al., 2010 ; see also B irnie et al., Chapter 12, this volume). Most approaches to rehabilitation share common fea- tures that include education, symptom control, behavioral science and physical therapy. Ho w these strands are delivered is debated. Certainly early recognition and intervention in a n outpatient or inpatient setting is key and, in most cases, leads to a more favor- able ou tcome (Anthony and Schanberg, 2007 ). Pharmacotherapy Many analgesics and diff erent interventions have been used for chil- dren with chronic musculoskeletal pain, but are not supported by well-controlled therapeutic tri als. It is becoming widely accepted, however, that any analgesic intervention should only b e used along- side multidisciplinary therapy (Eccleston et al., 2003 , 2009 ). Psychological therapies A Cochrane systematic review reported that psychological thera- pie s are eff ective for headache and may improve pain control in children with musculoskeletal pain (Eccleston et al., 2009 ). Small studies using cognitive-behavioral therapy (CBT) in juvenile fi bromyalgia (chronic widespread pain) show signifi cant improve- ment in the chi ld \200\231s confi dence with managing the pain, but disap- pointing eff ect on functional disability and depressive symptoms (Kashikar-Zuck, 2006 ; see also Logan et al., Chapter 50 , this vol- ume). For children who have signifi cant pain-associated disability (school abs ence, limited mobility, lost independence, extremely low mood, disturbed sleep) there are n o randomized controlled trials of multidisciplinary multicomponent CBT; however, there is e vidence that an interdisciplinary program has a positive impact for adolescents disabled wi th chronic pain (Eccleston et al., 2003 ). Th e role of the physician is oft en as an educa tor, to oversee analge- sic withdrawal and to support the overall message that it is safe t o increase activity despite pain and reduce reliance on medical sup- port (Clinch and Eccle ston, 2009 ). Th ere is no current evidence favoring a dedicated outpatient over inpatient service for mu sculoskeletal pain; however anecdo- tally it is reported that treating children away from b usy acute set- tings and keeping them in their local area, if possible, is benefi cial (Cli nch and Eccleston, 2009 ; Eccleston et al., 2003 ). Dedicated pain residential units are able to provide physical and psychological intense tre atment for children with signifi cant pain associated disability. Musculoskeletal pain comp rises approximately 60% of the presenting conditions in these units and over 80% of the chi ldren have related limb/back pain. Outcomes from these units show that pain does not signif i cantly change but function (includ- ing back to school), anxiety and coping is measurably improved (Eccleston et al., 2003 ). Recently the role of parents in pain behav- iour has b een evaluated (McCracken and Gauntlett-Gilbert, 2011 ), and parents are key in rehabilitati on plans. Specifi c parent pro- grammes in residential pain centers have been developed and show that changing parent behavior and responses to their child \200\231s pain, assists th e child moving on to more optimal outcomes (Gauntlett- Gilbert, 2013a ; McCracken and Gaunt lett-Gilbert, 2011 ). Physical therapies In conditions such as CRPS, early intensive physiotherapy (includ- ing d esensitization) with behavioral support can provide dra- matic reversal of the presenting s igns and symptoms for some patients (Littlejohn, 2004 ). Th e aim is accelerated mobilizati on (Lee et al., 2002 ), but this is hindered if the diagnosis is delayed and access to appr opriate physical and psychological rehabilita- tion is limited (Littlejohn, 2004 ). Many ca ses of diff use pain will require a gentle, paced approach. In all cases, the increase of a ctivity should be consistent despite the pain. With musculoskel- etal pains the more active the musculoskeletal system becomes the more likely the muscle spasms and tightening are to reduce. Education Although the evidence for education alone as a treatment for behav- iour change i s lacking, the provision of a rationale for what are oft en counter-intuitive instructions in self-management is essen- tial. Additionally, one should never underestimate that the av erage understanding of musculoskeletal anatomy and physiology is oft en limited. A critical fi rst step in rehabilitation is to off er, reoff er, and reinforce an understanding of ho w one \200\231s body may be working to maintain pain. CHAPTER 24 non-inflammatory musculoskeletal pain 245 Proprioception improves (Lee et al., 2002 ; Low et al., 2007 ) and autonomic changes subsid e. Where possible the young person should work to devise his or her own \200\230fi tness p lan \200\231. Using a local gym rather than a hospital physiotherapy gym allows them to sta rt to return to a more normal environment (Eccleston et al., 2003 ). Working in this consis tent and paced manner can be extremely hard for the young person and their parents. Th e pa in invariably continues at the beginning (if not throughout) and motivation is poor. Parent al anxiety is high (Lee et al., 2002 ) and there is a fear that damage will be done. Psycho logical support during this time is important. Th e young person will need help setting goa ls, learn- ing how to communicate pain to peers and family, maintaining motivation on \200 \230bad days \200\231, managing low mood, dealing with anger and frustration, and overcomin g fears. Oft en they have not been at school for a long period of time and need help in pre paring again for this diffi cult environment. In some cases, there may be other mental heal th needs that can be identifi ed and appropriately treated. See also Holsti et al. (Chapter 57, this volume) and Tupper et al. (Chapter 56, this volume) for further details. \231 Evidence shows that early dedicated therapy can signifi cantly improve the outcome o f childhood chronic musculoskeletal pain. \231 Key areas for further research include evaluating the physiology of childhood muscul oskeletal pain, the role of parents, and eval- uating the effi cacy of pharmacological inte rventions. Case example Anna is a 12-year-old previously well girl, who develops pain in her left ankle following a fall during her gymnastics class. She attends the Accident and Emergency (A&E) department, no frac- ture is seen on X-ray, and her ankle is bandaged. She is advised to rest, take pa racetamol and ibuprofen for the pain, avoid weight bearing and use crutches until the pain settles. One week later, she returns to A&E as she still has severe pain. Repeat X-ray is n ormal, but her ankle is immobilized in a below-knee cast and she is referred for an orthope dic opinion at her local hospital. Four weeks later the cast is removed, her lower leg is n oted to be swol- len, red, warm, and slightly sweaty, and she is still unable to weight bea r due to pain. She is given codeine for analgesia, an MRI con- fi rms swelling but there is no localized infection or bony injury. Anna is referred for physiotherapy, but is unable t o perform most of the suggested exercises, as her leg is too painful. Over the next 2 month s, the pain extends to involve her whole lower limb, her leg is now cold and mottled, and s he can no longer wear shoes and socks as the skin is sensitive to touch. Anna can now only walk for short distances with crutches, is using a wheelchair to mobilize, cannot manage at school, and is sleeping poorly. Th ere are ongoing studies that show promise with visual coun- ter-stimulation, specifi cal ly in patients with CRPS. Mirror therapy, focusing on the hypothesis that incongruence betw een motor out- put and sensory input produces CRPS, is being evaluated in adults (McCabe et al., 2003 ) but there is no data for children. It is common for young people with musculoskeletal pain to have contact with complementary medicines (oft en sourced by their parents). While the evidence supporting many of these th erapies in children and adolescents is poor (Tsao and Zeltzer, 2005 ), some children report benefi t with topical treatments that are massaged into the painful area (e.g. back pain) (see also Weydert, Chapter 59; Zeltzer, Chapter 60, this volume). Both Anna and her parents are concerned that an important diagnosis has been missed, and re quest referral to another special- ist. A bone scan is performed which shows a generalized decrease uptake, and she is commenced on gabapentin for her pain. Despite increasing doses of gabapentin, and continued use of codeine and ibuprofen, Anna \200\231s pain does not imp rove. She is referred to a multi- disciplinary clinic. Anna reports continuing pain, she is unable to tolerate trousers on her left leg, and her leg feels weak. On exami- nation, she is sitting in a wheel chair and is reluctant to stand, her lower leg appears swollen, ligh t touch is painful but her left foot feels colder than the right, and she has reduced range of movement in both the ankle and knee. CRPS is diagnosed, and the nature of the condition and management are discussed with Anna and her parents. Her investigations are reviewed an d reassurance given that other diagnoses have been excluded and no further investigations a re required. Anna is referred for an intensive rehabilitation pro- gramme which includes ph ysiotherapy, psychological interventions, and education. Her parents are still concerned, a nd angry that it has taken so long for the diagnosis to be made, but agree to attend fam- i ly sessions during the program. Despite initial reluctance to do physiotherapy exercises wh ich exacerbated her pain, Anna is given a graded program, and her mobility gradually improv es. Th ree weeks later, she still has residual pain, but she is able to walk with- out aids , is weaning off her medications, and her sleep and mood have improved. Prior to discharge, Anna is given instructions about continuing management at home, including the need to deal with potential fl are-ups. On review 3 months later, Anna has returned to full-time school and although she had a relapse of pain and swell- ing in her leg 4 weeks previously, she w as able to manage this with increasing exercises and maintained weight bearing. Natural history and long-term outcomes Th e natural history of chronic musculoskeletal pain in children shows that, in many cases, functional and psychosocial outcomes are improved w hen compared with adults (Bursch et al., 1998 ; Gedalia et al., 2000 ). Early multidiscipli nary input (including CBT) has been associated with improved outcomes (Eccleston et al., 20 03 ). CRPS in children generally has a favorable prognosis if early physiotherapy is initia ted (with psychological support; Sherry et al., 1999 ; Stanton Hicks, 2010 ). Th is is impr oved if the parents are involved in the rehabilitation process (Gauntlett-Gilbert et al., 2 013b ). However, a prolonged time to treatment and the presence of marked autonomic changes are poor prognostic indicators in this condition. Summary points \231 Untreated complex pediatric pain is personally, socially, and fi nanc ially burdensome for individuals, families, and societies. \231 Ensure an early, thorough history and physical musculoskeletal examination to rule o ut new or suboptimally treated pathology in children with chronic musculoskeletal pain. \231 Evaluate the impact of the pain on the child and family (not just the level of pain) so that rehabilitation can be tailored \231 Involve a multidisciplinary team early (ideally in joint clinics) to facilitate cohe sive working and the introduction of psychological and physical therapies. SECTION 4 pain in specific populations and diseases 246 References Ahlqwist , A. , Hagman , M. , Kjellby-Wendt , G. , and Beckung , E. ( 2008 ). Ph ysical therapy treatment of back complaints on children and adolescents . Spine , 33 (20), E721 \200\223727. Eccleston , C. , Jordan , A. , McCracken , L. M. , Connell , H. , and Clinch , J. ( 2005 ). 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CHAPTER 25 Pain in sickle cell disease Carlton Dampier and Lamia Barakat Summary Sickle cell disease (SCD) presents a complex pain disorder to clinicians. Pain from vaso-occlusion of sickle erythrocytes can occur in multiple musculoskeletal locations, sev eral internal vis- cera such as the spleen, as well as the penis. Such pain is typically in termittent in childhood, shares features of acute pain with other pain disorders, and oft e n responds to non-steroidal anti-infl am- matory drugs (NSAIDs) and opioid analgesics. Adol escents with SCD oft en experience more frequent pain, and those with bone disease in spine , hips, or shoulders may experience chronic pain. Like other chronic pain disorders, this p ain oft en responds poorly to opioids, but there is limited current clinical or research da ta to support alternative medications. Many cognitive-behavioral strat- egies are helpful a s part of multidisciplinary pain management, particularly in adolescents, who may also bene fi t from psychologi- cal support to treat coexistent mood disorders, to increase coping sk ills, and to support appropriate school and family functioning. Future advances in pharmaco logical and psychological therapies are needed to ameliorate the substantial burden of pain in children and adolescents with SCD. estimated at over $ US450 000 per individual including home care, and annual charges have b een estimated at $ US350 million for ED visits and $ US1 to $ US2 billion for hospitalizati ons, depending on study methodology (Kauf et al., 2009 ). SCD pathophysiology Th e pathophysiology of vaso-occlusion in SCD is quite complex and invo lves mechanisms beyond sickle polymer formation. One such mechanism demonstrated in in vitr o systems (Walmet et al., 2003 ) and in animal models (Embury et al., 2004 ) is the adhesio n of sickle erythrocytes, and perhaps other cellular elements including leuco- cytes and pl atelets (Turhan et al., 2002 ), to vascular endothelium. Th eir potential importance in vas o-occlusive pain in children has been demonstrated in biomarker studies (Dampier et al., 20 04 b), and specifi c anti-adhesive therapies are now being tested in pre- liminary effi cac y studies in both pediatric and adult populations. Cellular adhesion is further enhanced by the release of cytokines from ischaemic tissue injury resulting from vaso-occlusion, which act both by upregulating the surface expression of receptors (inter- leukin (IL)-1, IL-6, tumor necrosis factor (TNF)), or by increasing integrin avidity (IL-8) (Pathare et al., 200 3 ). Introduction Sickle cell disease (SCD) is a complex autosomal recessive disor- der of hemog lobin structure characterized by variable degrees of haemolytic anemia and intermittent epi sodes of vaso-occlusion that cause or contribute to a variety of acute and chronic compli- cations, and ultimately leads to the development of chronic organ damage. Th ese cumulative disease eff ects cause signifi cant morbid- ity, reduced quality of life, and shortened li fe expectancy. Studies from the former Comprehensive Sickle Cell Centers suggest that it is the occurrence of vaso-occlusive pain that has the strongest negative eff ect on child or adult-reported health-related quality of life compared to any other acute or chronic SCD-re lated compli- cations (Dampier et al., 2010 a, 2010 b). Healthcare utilization for pain man agement and their associated costs are substantial in this disorder. Yearly estimates of ho spitalization frequency in the US range from 70 000 to 90 000, and over 200 000 to 230 000 for emer- gency department (ED) visits based on data from the Nationwide Emergency Departme nt Sample, most of which ( > 80%) are for adults, with pain as the major indication (Lanzkr on et al., 2010 ). Th is ED utilization is three times higher than for congestive heart fai lure, HIV, or asthma. Lifetime costs for SCD care have been Th e tissue damage from ischaemia caused by sickle vaso-occlu- sion is an obvious source of an infl ammatory response, and anti- infl ammatory agents such as steroids and NSAIDs have clinical effi cacy in the treatment of pain in SCD patients Th e molecules involved in the infl ammatory response likely cause alterations in the properties of peripheral nerves lea ding to increased spontane- ous fi ring known as \200\230peripheral sensitization \200\231 , and the enhanced excitability of nociceptors leads to the development of primary hyperalg esia (see Walker and Baccei, Chapter 6, this volume, for additional details). Th ese conseq uences of the pro-infl ammatory component of vaso-occlusion likely contribute to the challe nge in treating pain associated with SCD. Epidemiology of pain in SCD Pain is the most common symptom of SCD, but remains poorly char acterized, and can begin early in the fi rst year of life as levels of fetal hemoglobin dec line in susceptible individuals. In a pro- spective longitudinal study of 103 infants with SCD from birth to 7 years of age (Dampier et al., 2010 a), the total frequency of days that children had pain was 1.6%. Th is represented distinct episodes of pain typically lasting several days (3 2.9 days, range 1 \200\22323 days), CHAPTER 25 pain in sickle cell disease 249 Table 25.1 Other pain syndromes in sickle cell disease of which only 14% required hospitalizations. Over 80% of the chil- dren reported to have pa in in the 0- to 12-month age interval had pain locations (hands/feet) and signs/symptoms (s welling or ten- derness) consistent with dactylitis, which became progressively less preval ent in older age intervals reaching a level of about 10% by age 48 to 60 months. Th e preva lence of sickle pain occurrence is consistently higher and its duration longer in the child ren with the typically more severe type of SCD, SS or SB0 thalassaemia, compared to those w ith the milder SCD type, SC or SB+ thalas- saemia, at all age groups. Th e time to fi rst r eported occurrence of pain is also infl uenced by sickle genotype, and is signifi cantly sh orter in children with SS with a mean of 18.5 2.5 months, com- pared to 39.0 4.9 mont hs for those with SC, 24.4 3.8 months in SB+ thalassaemia, and 37.9 11.7 months in SB 0 thalassaemia (p = 0.003, log rank test). Similar genotype diff erences are noted for time to the second reported pain event (SS 21.3 2.3 months, SC 43.5 4.3 months, SB+ thala ssaemia 30.3 3.9 months, also p = 0.003). Longitudinal modeling of pain trajectories ove r this early childhood period suggests about 70% of SCD infants and young children remain r elatively asymptomatic while about 10% to 15% have relatively frequent pain over this perio d and a similar number develop frequent pain aft er age 2 to 3 years of age. Syndrome Body site Characteristics Acute bone infarction Ribs, long bones Acute necrosis of bone marrow Acute cholelithiasis Gall bladder Acute visceral pain from pigment gallstone irritation or common bile duct obstruction Acute splenic sequestration Spleen Acute visceral pain related to stretch of splenic capsule from rapid splenic enlargement Avascular necrosis Hips, shoulders, vertebrae Progressive collapse of bone cortex related to persistent vascular compromise of cortex and marrow Headache Head Headache pain with or without migrainous characteristics Leg ulcers Ankles, feet Acute and chronic pain from ischaemic damage to skin and underlying soft tissue Osteomyelitis Any bone Bacterial infection of bone cortex or marrow, often related to chronic ischaemia Almost all children with SCD experience increasing pain as they progress through childhood into adolescence and young adulthood, but studies suggest that the large majority of these painful episodes continue to be managed at home (Dampier et al., 2002 a, 2002 b). However, a small minority of children transition, oft en in their early adolescent years, from spora dic episodic acute pain to frequent recurrent acute pain, and these individuals represent t he majority of pediatric patients hospitalized for acute pain (Platt et al., 1991 ). Splenic infarction Spleen Acute visceral pain from splenic infarction involving splenic tissue extending to splenic c apsule can be a source of acute pain as well as chronic pain in adolescent and young adult patient s. Physical therapy is oft en helpful for ini- tial symptom management of hip pain, but som e patients will have progressive collapse, particularly in the head of the femur, that will ultimately require joint replacement for relief of chronic pain or to improve physical fun ctioning. While uncommon in the pediatric age group, leg ulcers, typically over the medial malleolus of either or both ankles, can be a source of considerable pain and disability (Mi nniti et al., 2010 ). Headaches, as an isolated pain syndrome, or as part of a vaso-occlusi ve event, are relatively common, but not well characterized (Niebanck et al., 2007 ). Some have features char- acteristic of migraine headaches, others may be more typical of tension -type headaches, while a small number of individuals satisfy current diagnostic criteria fo r chronic daily headache. Headaches may be somewhat more frequent in children with a histor y of sickle cell-related cerebrovascular events. Th ere are no studies in pediatric SCD describing the prevalence of chronic pain, but daily opioid usage has been suggested as a sur- rogate for chronic pain. Data on the self-report ed usage of daily oral opioids was obtained from the patient registry (Dampier et al., 2010 b) of the 10 SCD programs of former Comprehensive Sickle Cell Centers Clinical Trial Conso rtium. Usage was relatively infre- quent prior to adolescence, particularly in the SC/SB+ c ohort, and widespread throughout the adult age range. Th e incidence of new onset daily opi oid usage was 3% per year, and once initiated was not oft en discontinued in the subsequent 2 years (<30%). Pain is a more complex experience in adults with SCD, with features of both acute recurrent and chronic pain. A study of a cohort of adults using daily pain diaries documented that p ain was reported on 56% of days and exacerbations of pain (crises) on 13% of days, with alm ost 30% of patients reporting pain in greater than 95% of diary days (Smith et al., 2008 ). Assessment Multidimensional assessment of chronic and acute sickle cell and other pain acro ss settings (home, school, and hospital) is the foundation of eff ective pain management. A ge-appropriate pain intensity measures used for other acute pain disorders or for post- ope rative pain (McGrath et al., 2008 ) also have been validated in SCD. Inclusion of measures with body diagrams is particularly useful given that multiple sites of pain are oft en pres ent (Walco and Dampier, 1990 ). Measures of pain interference with physical functioning, su ch as the Child Activity Limitation Interview, CALI (Palermo et al., 2004 ), or the Pediatr ic PROMIS (Patient Reported Outcome Measurement Information System) pain interference scale (Varni et al., 2010 ), also may provide additional important information useful in assessi ng treatment responses.