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. Beyond vaso-occlusion: other pain syndromes in SCD Other pain syndromes distinct from vaso- occlusive episodes are also common ( Table 25.1 ). Young children with acute splenic seques tra- tion, an oft en life-threatening trapping of sickled erythrocytes in the spleen, can e xperience acute left upper quadrant visceral pain from rapid enlargement of the splenic cap sule. Older children can simi- larly experience episodic right upper quadrant colicky abdom inal pain and jaundice from cholelithiasis, as chronic haemolysis results in bilirubin accu mulation in the gall bladder. Bone infarction lead- ing to avascular necrosis in the verteb ral column, shoulder, or hips, SECTION 4 pain in specific populations and diseases 250 Th e importance of including child report of pain is highlighted in sickle cell disease (Gr aumlich et al., 2001 ). Limited concordance between child and caregiver sickle pain reports has been noted, similar to other disorders. Parents and children \200\231s report of child SCD pain are only moderately consistent and are particularly diver- gent for interference with activities and pain descriptors (Barakat et al., 2008 b). Objective evaluations of sle ep (Law et al., 2012 ) or physical activity with actigraphy (Wilson and Palermo, 2012 ) may help clarify discrepant reports. Moreover, emerging technolo- gies have provided opportuni ties to facilitate daily patient report on pain. Electronic assessment was found to feasibl e for children and adolescents with SCD to monitor skills practice and daily pain using an electronic handheld device (McClellan et al., 2009 ). Data were complete when devices were accessed for daily pain diary data entry, and devices were accessed on 76% of pain diary da ys. Moreover, children, adolescents, and parents were highly satisfi ed with accessing devi ce to provide information on pain. Similar elec- tronic monitoring to guide analgesic medic ation usage has been recently described using cell phone technology, and appear partic- ula rly promising (Jacob et al., 2012 ) given the ubiquitous use of cell phones in the adolesce nt and young adult populations. functional disability (e.g. socioeconomic status; Barakat et al., 2007 ; Palermo et al., 20 08 ) and parenting stress as mediator of pain \200\231s association with reduced quality of life (Barakat et al., 2008 a), which underscores the need to develop family-focused interv en- tions to support communication around and management of SCD complications, in particula r pain, to minimize caregiver \200\231s distress in response to SCD-related events. Targets of these interventions are more broadly defi ned in terms of sickle cell knowledge, pain c oping and adherence, family functioning, and quality of life. A six-session family psychoed ucational intervention (Kaslow et al., 2000 ) produced improvements in knowledge of sickle cell disease that were maintained at a 6-month follow-up but had no eff ect on psychologica l adjustment, family functioning, and social func- tioning and support. Similarly, four-ses sion, family-based, cogni- tive-behavioral intervention for adolescents with SCD showed pro mise in terms of percentage of pain days, disease knowledge, and family cohesion (Barakat e t al., 2010 ); however, both groups reported improved psychosocial functioning, including a decrease in percentage of days with interference with daily activities at both time points , and decrease in pain-related hindrance of goals. More research is needed to evaluate components that may support maintenance of eff ects pas t the immediate post-intervention period and generalization of eff ects beyond pain to heal th care contacts, functional ability, and quality of life. In addition, evaluation of for- mat for delivery of the intervention (i.e. therapist-delivered versus self-administered, in dividual versus group format) and inclusion of family members or other supports is importan t. Psychological interventions described in the literature were developed for and implement ed with children and/or adolescents with SCD; however, no studies of psychological interven tions for young children with SCD were identifi ed. Given that parents experience uncertain ty about their ability to manage pain at home (Ievers-Landis et al., 2001 ), interventions that support development of parenting skills that address but do not reinforce pain are ess ential. Finally, there is a need to evaluate whether tailoring of pain interventions to bet - ter match African American values and systems, such as through inclusion of extended fami ly and integration of culturally sensitive content and components, improves the effi cacy o f psychological interventions for SCD pain (Schwartz et al., 2007 ). Importantly, related t o accessibility of interventions, preliminary data from an Internet-delivered intervention (Palermo et al., 2009 ) with chil- dren and adolescents with chronic pain using a family co gnitive- behavioral therapy approach showed signifi cant eff ects in terms of reduced pain and increased activities maintained through a 3-month follow-up compared to a treatment as usual control group. Th is interactive, self-paced intervention involved eight online ses- sions and targeted improved knowledge, skills to address sleep, activity, and pain (relaxat ion, distraction, cognitive coping skills), parenting skills, and pain communication skills . Psychological therapies Cognitive-behavioral approaches, specifi cally deep breathing and p rogressive muscle relaxation, guided imagery, and calming self-talk, have been the most pro mising psychological therapies to address sickle cell-related and other pain among children and ado- lescents with SCD (Anie and Green, 2012 ; Chen et al., 2004 ). Chen and colleague s ( 2004 ), in their review of 22 interventional studies targeting pain and adherence, repo rted that cognitive-behavioral approaches were superior to educational interventions and pr ob- ably effi cacious in addressing both pain and health care contracts. In contrast, behav ioral and educational approaches alone are not suffi cient to modify adherence or pain. Fin dings regarding psy- chological interventions for SCD are consistent with the broader liter ature on effi cacious interventions for pediatric chronic pain in which a recent meta-analy sis indicated the superiority of cog- nitive-behavioral interventions (multicomponent, rela xation, and biofeedback approaches) to address pain across pediatric chronic pain condition s including SCD (Palermo et al., 2010 ). Initial eff orts to identify psychological interventions for children with SCD have been pr omising. Hypnosis delivered in group format and including caregivers over an 18-month perio d reduced sickle cell-related and other pain for children, adolescents, and adults with SCD (Dinges et al., 1997 ). In an eff ort to develop brief pain inter- ventions, Gil and colle agues (Gil et al., 1997 , 2001 ) reported on the results of an intervention for children an d adolescents with SCD that was initiated during a clinic visit, and supported through phon e calls and taped instructions. Th e intervention comprised deep breathing relaxation, plea sant imagery, and calming self-talk. Reduced labo- ratory task-based pain and less negative thinking were reported at the end of treatment. However, at follow-up, the treatment group endorsed more pain but also more active coping. When the children had pain and practiced c oping strategies, they had fewer health care contacts and missed fewer days of school. Also , the treatment group had less negative thinking on days with low levels of pain. A new approach to pain management, that may be eff ective for children and adolescents with SCD, is acceptance and commitment therapy (ACT). ACT emphasizes the promotion of daily fun ction- ing and quality of life while teaching a willingness to experience diffi cult and po ssibly unavoidable private events (e.g. pain, dis- comfort, fatigue, anxiety) without defen se when doing so serves valued ends. A recently published case study of a 16-year-old with SCD indicated improvements in pain, functional ability, and qual- ity of life at a 3-month follow-up assessment (Masuda et al., 2011 ). Further larger studies are in progress. More recent psychological intervention trials have been guided by reported associations of environmental factors with pain and CHAPTER 25 pain in sickle cell disease 251 Physical therapies Physical therapies, especially heat therapy, are commonly used to pro- v ide symptomatic relief at home (Dampier et al., 2004 a), but few such therapies have been s ubjected to rigorous evaluations. Massage ther- apy implemented for 20 min per day for 30 d ays by caregivers resulted in less pain, improved functional status, and lower levels of de pression and anxiety during intervention and at immediate post-intervention follow-up for c hildren and adolescents with SCD compared to an attention placebo control group (Lemanek et al., 2009 ). Unfortunately, caregivers in the massage therapy group had higher depression, sug- gesting that the demands of the intervention contributed to care provider stress. Tra nscutaneous electrical nerve stimulation (TENS) has also been studied in a small clinical t rial (Wang et al., 1988 ), and showed some modest clinical benefi t during vaso-occlusive p ain. and some extended family support as these episodes may last for several days and usually re quire around-the-clock medication for adequate management. Home management and appropriate emer- gency department utilization is also facilitated by access to trusted medical health professionals with experience in sickle cell disease and pain management who can help optim ize analgesic therapy. Families need to be reminded to provide these medications on an appr opriate time-contingent basis as most studies and anecdotal experience suggest that familie s administer these medications less frequently than recommended (Dampier et al., 2002 b). S ince com- plete pain relief is unlikely, families also need to be counseled on appropriate home therapy goals of maximizing comfort and func- tion while minimizing troublesome analge sic side eff ects. Low-potency analgesics, such as acetaminophen or ibuprofen, are typically chosen as initial therapy by most families and are oft en adequate for less intense pain, particularly in yo unger children. Th ese analgesics are oft en chosen out of concern for the adverse conseque nces of opioid analgesics and have the advantage of little sedation and subsequent disrupti on of age-appropriate distracting activities. Pharmacological therapies Pharmacology of opioid analgesics in SCD A unique feature of SCD pain treatment is the impact of chronic anemia on analgesic pharmacokinetics. One of the no rmal com- pensatory mechanisms to chronic anemia is increased cardiac output with resultant increase in hepatic blood fl ow, as well as increased renal blood fl ow and glomerular fi ltration rate. Many analgesics, such as morphine, that have a component of their meta- boli c pathway dependent on hepatic or renal clearance will have accelerated plasma clearance in individuals with SCD. Plasma mor- phine clearances in pediatric subjects aged 6 to 19 year s ranged from 6.2 to 59.1 ml/min/kg (mean, 35.5 12.4) during steady- state infusions com pared to 20 to 25 ml/min/kg in children with cancer or postoperative pain (Dampier et al., 1995 ). Over the age range studied clearance values were negatively correlated with age. Ph armacokinetic modeling suggested a two-compartment model with a short initial distribution phase (mean half-life = 4.5 min) and a rapid terminal elimination half-life (77.6 19.2 m in). Similarly, in a study of 20 adult SCD patients in steady state (Darbari et al., 2011 ) , a mean morphine clearance of 68 ml/min/kg (4.1 1.1 L/h/kg) was observed, which is also over twice that typical in adult individuals without SCD. Th e pharmacokinetics of other a nalgesics or analge- sic adjuvants have not been determined in patients with SCD, but those dependent exclusively or renal clearance, such as gabapentin or pregabalin (Bockbrader et al., 2010 ) will likely be cleared more quickly so conventional drug dosing recommendations may result in subtherapeutic drug levels in many SCD individuals. Th ese con- siderations underscore the need to conduct formal pharmacoki- netic studies of commonly used analgesic medications and novel investigational agents in this population. A substantial variety of oral opioid analgesics of varying potency are available in liquid and tablet formulations for management of more intense pain in children with SCD. However, comparative effi cacy or potency data is not available in the SCD population so opioid sele ction is generally individualized based on patient-spe- cifi c effi cacy and side eff ect p rofi les. While labeled dosing and fre- quency are usually recommended, the enhanced hepati c and renal clearance of morphine in this population (Dampier et al., 1995 ), the potential impact of prevalent genotypes impacting morphine metabolism (Joly et al., 2012 ), and the potential occurrence of opioid tolerance suggests that dose and frequency of oral opioids m ay need to be individualized. Th ere is little published literature or clinical trial exper ience with the use of newer buccal or intranasal opioid preparations in the SCD population, but these medications may have a more potential useful role for rapid pain relief in the E D setting rather than at home. Th ere have been few comparative studies of adjunctive non-opi- oid analgesic medications i n this population. Th e combination of potent opioids and ibuprofen likely provides the mos t pain relief in the home setting compared to weaker opioid combinations, particularly for older children with more intense pain (Dampier et al., 2002 b). An observational study usin g drugstore claims data suggested that pharmacological treatments for sickle pain con- sist ed mainly of NSAIDs and weak opioids (Jerrell et al., 2011 ). Signifi cantly more SCD patie nts with more than three yearly in- patient or ER visits for pain management were prescribe d stronger opioids, antidepressants, and anticonvulsants. Prescriptions of both stronger op ioids and antidepressants or anticonvulsants were sig- nifi cantly associated with lower cu mulative rates of acute sickle pain visits over time in this cohort. Further clinical trial data is needed to support these clinical fi ndings and establish comparative effi cacy and safety data for various analgesic and anticonvulsant or antidepressant combinations, parti cularly as many of these classes of medications are not currently labeled for use in pediat ric age groups. Home management Most families prefer to manage their child \200\231s vaso-occlusive pain at home, as the home setting is likely to be more comfortable for children and less disruptiv e to the family. Many families have also experienced negative attitudes towards patients wi th sickle cell dis- ease by health care providers in the ED setting, oft en based on a prof ound fear of catering to opioid addiction, that can compromise analgesic therapy (Zempsky, 2009 ). Successful home management optimally requires the presence of a caregiver relativel y skilled in pain assessment with access to appropriate analgesic medication, Families naturally use both medical and psychological interven- tions to address symptomati c treatment of pain. Several studies of caregivers of children with SCD have found that a l arge percent- age of families use complementary approaches of prayer, spiritual SECTION 4 pain in specific populations and diseases 252 healing, massage, and relaxation in addition to medication to manage their child \200\231s pain at home (Dampier et al., 2004 a; Yoon and Black, 2006 ). In both studies, complementar y approaches were used more frequently with higher levels of pain or medica- tion use. depression may enhance the risk for pulmonary complications such as acute chest syndrome. C ommon GI-related opioid adverse eff ects may be signifi cantly ameliorated by peripherally acting opi- oid antagonists, such as methylnaltrexone (Gatti and Sabato, 2012 ) and similar agents, but they have not been studied in SCD, and are not yet labeled for pediatric patie nts. Th e concurrent use parenteral NSAIDs, usually ketorolac, is a widespread clinical practice in the ED and in-patient setting as an additional analgesic, and may have additional benef i t as an anti-in- fl ammatory agent given the increase evidence for the role of infl am- m ation in sickle cell disease pathophysiology (Dworkis et al., 2011 ), but large scale effi cacy studies are lacking and caution advised in those children with SCD and impaired renal function. Evidence of effi cacy of other adjuvant analgesics for acute sickle pain, as have been proposed for postoperative pain (Wu and Raja, 2011 ) have not been subjected to clini cal trials. Benefi t from concurrent low- dose ketamine has been described in a small case series (Zempsky et al., 2010 ), and there is anecdotal experience with the use of oral or t ransdermal clonidine, an 2-adrenergic agonist, to enhance analgesia and to reduce sympto ms of opioid withdrawal following prolonged periods of opioid PCA. Management of chronic/persistent pain In contrast to acute pain management in SCD, the mana gement of chronic pain has not been described, particularly in adolescents and young adults , and management strategies are oft en extrapo- lated from adult literature. Currently, suc h management in SCD has largely relied on use of long-acting opioid preparations, either in oral or transdermal formulations, but there is an increasing reali- zation in the general US adult population that such daily opioid usage is more frequent in individuals with comor bid psychological and psychiatric disorders (Edlund et al., 2010 ), and has substantial lon g-term adverse eff ects, especially in large doses, including a risk for opioid-induced hyp eralgesia, addiction, tolerance, constipation, nausea, somnolence, and immune suppression ( Hutchinson et al., 2011 ; Kalso et al., 2004 ). Studies are needed in pediatric SCD to furt her characterize appropriate patient selection and dosing for chronic daily opioids, the ro le of alternative non-opioid analgesics, antidepressants, anticonvulsants, and their long-t erm health out- comes. Adolescents and young adults with SCD started on daily opioids shoul d also receive concurrent psychosocial and psychiat- ric support given the role that emotio nal, social, and psychiatric issues negatively contribute to the pain experience (Sullivan and Ballantyne, 2012 ). Emerging and future directions in sickle pain Prevention of sickle pain Fundamentally the b est way to prevent pain in sickle cell disease is to prevent vaso-occlusion. Current therap y with hydroxyurea is oft en not able to produce a high enough fetal hemoglobin response to prevent sickling and subsequent vaso-occlusion in some patients, particularly those with r elatively low baseline fetal hemoglobin levels. Alternative fetal hemoglobin inducers are b eing developed based on other mechanisms of action including histone deacety- lase inhibito rs, and novel thalidomide analogs (Akinsheye et al., 2011 ; Sankaran, 2011 ), both of which have entered clinical trials. Rather than reducing sickle polymer formation by decreasing the intracellular sickle hemoglobin content, other approaches to pre- vent sickling attempt to directly modify the properties of the sickle hemoglobin molecule. A naturally occurring aromatic aldehyde, 5-hydroxymethyl-2-furfural (5HMF) has been shown to form a high-affi ni ty Schiff -base adduct with sickle hemoglobin and inhibits red cell sickling by allosterica lly shift ing oxygen equilib- rium curves towards the left (Abdulmalik et al., 2005 ). Th i s com- pound has begun phase I/II clinical trials. In-patient/ED pain management Authoritative guidelines are available for the management of severe SCD pain in the acute care setting (Benjamin, 1999 ; Rees et al., 2003 ), but are so mewhat outdated. However, more contemporary single site pain management practices from a nu mber of paediat- ric hospitals have been published (Morrissey et al., 2009 ; Zempsky et al. , 2008 ). A recent \200\230snapshot \200\231 of clinical analgesic practice, across a larg e number of pediatric hospitals participating in an obser- vational study of the developmen t of acute chest syndrome aft er hospitalization for sickle pain management, suggested the use of opioid-based patient-controlled analgesia (PCA) was the most common analgesic practi ce (Miller et al., 2012 ). Opioid doses var- ied widely, but appeared to be somewhat higher for those individu- als receiving PCA compared to time-contingent opioids, and for those r eceiving hydromorphone compared to morphine. Th e rela- tionship between opioid dosing and prior daily opioid usage was not described in this cohort, but adult chronic pain patients with chronic opioid use have been shown to report higher postoperative pain scores aft er s urgery and have a slower rate of pain resolution (Chapman et al., 2011 ), and a similar pat tern is likely in sickle cell disease. An improved understanding of the pathogenesis of vaso-occlu- sion has led to the targeting of several pathways contributing to vaso-occlusion. Hypoxia from ischaemia leads to alterat ions in many factors and metabolites which may contribute to the patho- genesis of pain and enhance further vaso-occlusion. Drug dis- covery approaches have identifi ed that increase d adenosine levels promoted sickling, haemolysis and damage to multiple tissues in SCD tran sgenic mice and promoted sickling of human erythrocytes mediated through adenosine A(2B) re ceptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metab olite that decreases the oxygen binding affi nity of haemo- globin (Zhang et al., 2011 ). A ntagonists of the adenosine A(2B) receptor are being developed and tested in early phase cl inical trials for amelioration of sickle pain. Nausea, pruritus, and constipation are common opioid-related adverse eff ects during such t reatment (Dampier et al., 2011 b), and require symptomatic management. Th e use of concurre nt low-dose opioid antagonist (naloxone) has been shown in several small cohorts (Koch et a l., 2008 ; Monitto et al., 2011 ) to ameliorate many CNS opioid-related symptoms without co mpromising anal- gesia, and may have particular benefi t in SCD where respiratory CHAPTER 25 pain in sickle cell disease 253 baseline health (n = 55) and race-matched controls (n = 57), SCD patients when compared to controls had signifi cantly lower cold pain thresholds and heat pain thresholds, but not me chanical pain thresholds (Brandow et al., 2011 ). Older age was associated with lower cold pain thresholds, lower heat pain thresholds, and lower mechanical pain thresholds. Further studies will be neces- sary to characterize the risk factors and time course for these chan ges in processing of nociceptive signaling in both children and young adults with SCD, and to determine their implications for analgesic management. Similarly, a number of cell surface receptors on sickle eryth- rocytes or endothelial cells participate in promoting the adher- ence of blood cells during vaso-occlusion (Kaul et al. , 2009 ). Polymorphonuclear neutrophils (PMNs) also can capture circulat- ing sickle red bl ood cells in infl amed venules, leading to critical reduction in blood fl ow and vaso-occlu sion suggesting a role for the selectin family of cell adhesion molecules. P-selectin-speci fi c inhibitors (aptamers; Gutsaeva et al., 2011 ) and pan-selectin inhibitors (Chang et al ., 2010 ) have shown effi cacy in animal mod- els of vaso-occlusion, and are also in early phase clinical trials for sickle cell crises. Conclusion SCD is a complex pain disorder that remains poorly understood with limited evide nce base for analgesic therapies. Pain from vaso-occlusion of sickle erythrocytes can occur in multiple mus- culoskeletal locations, several internal viscera such as the spleen, as w ell as the penis. Such pain is typically intermittent in child- hood, and oft en responds t o NSAIDs and opioid analgesics sim- ilarly to acute pain in many other pain disorders. Adol escents with SCD oft en experience more frequent pain, and those with bone disease in spine , hips, or shoulders may experience chronic pain, which may show limited responses to opioi ds as in other chronic pain disorder. Many cognitive-behavioral strategies are helpful as p art of multidisciplinary pain management, par- ticularly in adolescents, who may also benef i t from psychological support for coexistent mood disorders, to increase coping skills, an d to support appropriate school and family functioning. Future advances are needed to furth er the evidence base for effi cacious pharmacological and psychological therapies to amelio rate the substantial burden of pain in children and adolescents with SCD. Ultimately preven tive therapies for vaso-occlusion, infl amma- tory and ischaemic tissue damage, and develop ment of hyperal- gesia will fi nally change the face of this common genetic disorder ( Figu re 25.1 ). Sickle pain pathophysiology Several studies in mouse models of SCD have described sen- sory changes consistent with altered nociceptor function. Paw withdrawal threshold and withdraw al latency (to mechanical and thermal stimuli, respectively) and grip force were lower in h omozygous and hemizygous Berkley mice, which express only human sickle hemoglobin, compared with control mice express- ing human hemoglobin A consistent with deep/musculoskeletal and cutaneous hyperalgesia (Kohli et al., 2010 ). Th is mechani- cal hypersensitivity is furth er exacerbated when hypoxia is used to induce acute sickling (Hillery et al., 2011 ). Sever al research groups are working with these and similar mouse models to defi ne unique molecu lar mechanisms of pain and identify poten- tial therapeutic targets. Preliminary human studies suggest similar sensory changes consistent with hyperalgesia in c hildren and adults with SCD. Early studies suggested reduced pressure pain thresholds in sc hool-age and adolescent SCD children compared to age- matched children with juvenile idiopa thic arthritis, or com- pared to control children with asthma (Walco et al., 1990 ). In a r ecent cross-sectional study using quantitative sensory testing to thermal and mechanical st imuli in SCD pediatric patients in 3 7 11 15 19 23 27 31 35 39 43 47 51 55 61 72 Figure 25.1 Age distribution of opioid usage in the year prior to registry enrolment. Bars represent the number of individuals in each year of age, with bars on the left representing SC or SB + thal subjects, while bars on the right represent the number of subjects with SS or SB0thal. Dark bars within each group represent the number of subjects reporting chronic daily opioid usage. 20 0 20 40 60 All SC-SB subjects All SS-SB0 subjects SC-SB and prior year opioids SS-SB0 and prior year opioids SECTION 4 pain in specific populations and diseases 254 Case example clinical response. With the assistance of her volunteer tutors, she was able to graduate fr om high school with her class, and will be starting a reduced schedule of community college classes in preparation for a healthcare-related degree program. JK is a 18-year-female with homozygous sickle cell disease (SS) diagnosed at birth through the local state newborn hae- moglobinopathy screening program. Her mother noticed prominent swelling of the dorsum of left hand and fi ngers of her daughter associated with reduced v oluntary movement and discomfort with palpation at age 18 months preceded by a mild upper r espiratory infection that responded to oral ibuprofen. Several subsequent episodes involvin g one or both hands and feet or sometimes her lower legs occurred over the next several yea rs and were managed at home with oral ibuprofen and oral acetaminophen/codeine. Her family would oft en apply warm compresses and massage her limbs to help relieve swelling and pain. At age 5 she was admitted for several days with more severe pain managed with intravenous fl uids, NSAIDs, and intravenous opioids (morphine). By age 12, similar admissions began to occur once to twice per year, which were interspersed with less severe episodes once or tw ice a month lasting several days. She began to miss considerable amounts of school and beca me somewhat withdrawn and spent less time with her friends. Oral hydroxyu- rea was started but had little impact on her pain complaints, in part because of poor adherence. More poten t intermittent oral opioids were started, and provided some initial improvement in pain rel ief, but subsequently poorly controlled pain necessitated a switch to daily oral methadone. A variety of adjuvant medica- tions were tried but were found to be too sedating or had ot her signifi cant side eff ects. A TENS unit was provided, which she found to be useful for mild to moderate pain. At age 13, her phys- ical activity was further compromised by persis tent right-sided hip pain; hip X-rays and MRI demonstrated signifi cant avascular necrosis of her right femoral head with partial collapse. References Abdulmalik , O. , Safo , M. K. , Chen , Q. , Yang , J. , Brugnara , C. , Ohene- Frempong , K. , et al . ( 2005 ). 5-hydroxymethyl-2-furfural modifi es intracellular sickle hemoglobin and inhibits sickling of red blood cells . Br J Haematol , 128 , 552 \200\2235 61. Akinsheye , I. , Alsultan , A. , Solovieff , N. , Ngo , D. , Baldwin , C. T. , Sebastiani , P. , et al . ( 2011 ). Fetal hemoglobin in sickle cell anemia . Blood , 118 , 19 \200\22327. Anie , K. A. , and Green , J. ( 2012 ). Psychological therapies for sickle cell disease and pain . Cochrane Database Syst Rev , 2 , CD001916 . Barakat , L. P. , Patterson , C. A. , Daniel , L. C. , and Dampier , C. ( 2008 a). Quality of life among adolescents with sickle cell disease: mediation of pain by internalizing symp toms and parenting stress . Health Qual Life Outcomes , 6 , 60 . Barakat , L. P. , Schwartz , L. A. , Salamon , K. S. , and Radcliff e , J. ( 2010 ). A fami ly- based randomized controlled trial of pain intervention for adolescents with sickle cell disease . J Pediatr Hematol/Oncol , 32 , 540 \200\223547. Barakat , L. P. , Schwartz , L. A. , Simon , K. , and Radcliff e , J. ( 2007 ). Negative th inking as a coping strategy mediator of pain and internalizing symptoms in adolescents with sickle cell disease . J Behav Med , 30 , 199 \200\223208. Barakat , L. P. , Simon , K. , Schwartz , L. A. , and Radcliff e , J. ( 2008 b). Correlates of pain-rating concordance for adolescents with sickle cell disease and their caregivers . Clin J Pain , 24 , 438 \200\223446. Benjamin , L. J. , Dampier , C. D. , Jacox , A. , Odesina , V. , Phoenix , D. , Shapiro , B . , et al . ( 1999 ). Guideline for the management of acute and chronic pain in sickle-cell disease . Glenview, IL : American Pain Society . Bockbrader , H. N. , Wesche , D. , Miller , R. , Chapel , S. , Janiczek , N. , and Burger , P. ( 2010 ). A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and g abapentin . Clin Pharmacokinet , 49 , 661 \200\223669.