Psychosocial and pharmacological management of pain in pediatric sickle cell disease.

Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Psychosocial and Pharmacological Management of Pain in Pediatric Sickle Cell Disease Aimee K. Hildenbrand BS, Elizabeth G. Nicholls MIT, Brian P. Daly PhD, Meghan L. Marsac PhD, Reem Tarazi PhD, ABPP-CN & Deepti Raybagkar MD, MS To cite this article: Aimee K. Hildenbrand BS, Elizabeth G. Nicholls MIT, Brian P. Daly PhD, Meghan L. Marsac PhD, Reem Tarazi PhD, ABPP-CN & Deepti Raybagkar MD, MS (2014) Psychosocial and Pharmacological Management of Pain in Pediatric Sickle Cell Disease, Postgraduate Medicine, 126:2, 123-133 To link to this article: http://dx.doi.org/10.3810/pgm.2014.03.2748

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Psychosocial and Pharmacological Management of Pain in Pediatric Sickle Cell Disease

Aimee K. Hildenbrand, BS 1 Elizabeth G. Nicholls, MIT 1 Brian P. Daly, PhD 1 Meghan L. Marsac, PhD 2 Reem Tarazi, PhD, ABPP-CN 3 Deepti Raybagkar, MD, MS 4 Department of Psychology, Drexel University, Philadelphia, PA; 2Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Injury Research and Prevention, Children’s Hospital of Philadelphia, Philadelphia, PA; 3Division of Neuropsychology, Department of Psychiatry, Drexel University College of Medicine, Philadelphia, PA; Marian Anderson Sickle Cell Center, St. Christopher’s Hospital for Children, Philadelphia, PA; 4Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA; Marian Anderson Sickle Cell Center, St. Christopher’s Hospital for Children, Philadelphia, PA 1

Correspondence: Aimee K. Hildenbrand, BS, Department of Psychology, Drexel University, 3141 Chestnut St, Stratton Hall, Room 241, Philadelphia, PA 19104. Tel: 215-571-4256 Fax: 215-571-4258 E-mail: [email protected]

DOI: 10.3810/pgm.2014.03.2748

Abstract: For children with sickle cell disease (SCD), pain is associated with significant current and future morbidity and mortality. Unfortunately, few evidence-based guidelines exist for the management of pain episodes in children with SCD. To inform empirically based treatment strategies for pain management in pediatric SCD, this review integrates and evaluates the extant literature on psychosocial and pharmacological approaches to the management of pain. Findings reveal a paucity of rigorous investigations of psychosocial and pharmacological pain management interventions in children with SCD. Psychosocial interventions included were primarily cognitive-behavioral in nature, whereas pharmacological approaches targeted non-opioid analgesics (ie, nonsteroidal anti-inflammatory drugs and corticosteroids) and opioid medications (ie, morphine and oxycodone). However, to date there is not a “gold standard” for pain management among children with SCD. Because psychosocial and physiological processes each play a role in the etiology and experience of pain, effective pain management requires multidimensional, comprehensive treatment approaches. Considering the significant impact of pain on functional outcomes and quality of life among children with SCD, additional clinical trials are warranted to ensure that interventions are safe and efficacious. Keywords: sickle cell disease; pain; pain management; children

Introduction

Sickle cell disease (SCD) is among the most common genetic disorders worldwide, affecting between 72 000 and 100 000 individuals in the United States alone.1 It is especially prevalent among patients of African or Hispanic descent, occurring in approximately 1 in every 500 African-American births and 1 in every 36 000 HispanicAmerican births.2 Sickle cell disease is a heterogeneous, multisystem disease caused by genetic mutations resulting in abnormal, sickle-cell hemoglobin (HbS).3 Whereas healthy individuals have pliable, oxygenated red blood cells, children with SCD have rigid, dehydrated, crescent-shaped erythrocytes. These sickled blood cells are prone to aggregating in blood vessels and thereby blocking blood flow to bones and organs.4 In those with the most severe form of SCD (homozygosity for HbS, HbSS), red blood cells are estimated to survive only 17 days, as compared to 120 days in healthy individuals.3 As a result, many children with SCD experience severe medical complications that contribute to high morbidity and mortality, including chronic anemia, recurrent vaso-occlusive (VOC) pain episodes, acute chest syndrome, sepsis, organ failure, and stroke.5,6 Recurrent pain episodes are considered the hallmark feature of SCD and are the most common reason that children with SCD seek medical services, accounting for . 16 000 hospitalizations in 2003.7 In fact, research suggests that children with SCD

© Postgraduate Medicine, Volume 126, Issue 2, March 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

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experience pain on approximately 10% of all days.8 Not only are VOC pain crises frequent, but they can also be very severe, and in some cases debilitating.9,10 During acute pain episodes, pain is often extensive and migratory.10 Although pain can occur at many sites, it most frequently occurs in the limbs, joints, abdomen, spine, lower back, and sternum in children and adolescents.3,10 Severe pain associated with SCD can begin during infancy and persist at unpredictable intervals throughout the life span.10 Although most acute pain episodes last from 3 to 14 days, many children with SCD also experience more mild yet chronic pain that lasts for 3 to 6 months or longer.10,11 Beyond vaso-occlusion, acute pain episodes in SCD may also result from various medical sequelae, including acute chest syndrome, hepatic crisis, priapism, calculus cholecystitis, hand–foot syndrome, and splenic sequestration.12 Acute pain episodes may also be precipitated by cooling of body temperature and skin, dehydration, infection, or emotional stress; however, many pain crises are spontaneous and without an identified cause.3 Although much remains unclear regarding the complex etiological mechanisms and pathophysiological events that lead to pain in SCD, research has suggested that tissue ischemia and inflammation may be key components.8,12 Vaso-occlusion results in tissue ischemia and necrosis, initiating an inflammatory response that interacts with neuroendocrine pathways to stimulate the release of norepinephrine. When there is tissue injury, this release of norepinephrine causes further tissue ischemia, thereby perpetuating a cycle.8,12 This progressive sequence of ischemic tissue damage and inflammation can help to explain the distinctiveness of SCD pain with regard to its acuteness and severity.12 Pain episodes are associated with significant morbidity and mortality in children with SCD,9,10 underlining the importance of effective pain management for this population. Extensive VOC pain events are themselves problematic but can also result in serious medical complications such as ischemic damage (eg, bone and bone marrow, spleen, pulmonary, and renal infarction), as well as stroke and organ failure.10,13 Additionally, acute pain crises are associated with significantly impaired health-related quality of life.3,14 Children who experience more frequent pain crises may also have shorter overall life expectancy.15 Thus, pain serves as an indicator of clinical severity as well as a risk factor for early mortality.10 Pain impairs not only health-related outcomes but also psychosocial functioning for children with SCD. Children with more frequent pain episodes are more likely to endorse feelings of anger, hopelessness, and depression 124

than are those with less frequent pain.16 Given the unpredictable and disruptive nature of acute pain episodes, they also experience frequent absences from school.17 Moreover, pain episodes disrupt social and recreational activities18,19 and are associated with significant caregiver and family burden.20,21 Finally, at the societal level, pain episodes and associated sequelae in children with SCD result in considerable health care utilization costs.22 Given the substantial medical, psychosocial, and financial impact on children, families, and society, pain in pediatric SCD represents a major public health issue. However, few evidence-based guidelines exist for the management of pain episodes in children with SCD.23 To promote the development of standards of care for pediatric SCD, this review seeks to integrate and evaluate the extant literature regarding psychosocial and pharmacological approaches to pain management and to identify directions for future research.

Methods

Two online literature databases, PsycINFO and PubMed, were surveyed using the following search terms: sickle cell disease, children, pediatric, pain, pain management, psychological, pharmacological, treatment, drug, intervention, therapy, and randomized controlled trial. Studies written in English, published between 1980 and 2013, and containing experimental investigations were included in this review. More specifically, we included randomized controlled trials (RCTs) that (1) examined psychosocial or pharmacological interventions designed to improve pain management, (2) included children with SCD, and (3) assessed pain or proxies for pain (eg, health care utilization). Exclusion criteria included anecdotal reports, editorials and commentaries without original empirical data, case studies, and uncontrolled studies.

Results

The initial literature search using key terms and inclusion criteria search parameters returned 120 articles, excluding duplicates. The authors reviewed each study for full inclusion and exclusion criteria. In instances where the abstract was unavailable or provided insufficient information to determine inclusion criteria, an author reviewed the full article. One hundred and ten articles failed to meet inclusion and exclusion criteria, yielding a final sample of 10 articles included in this review.

Psychosocial Approaches

To our knowledge, only 4 experimental investigations of psychosocial pain management approaches in children with



Pain Management in Pediatric SCD

SCD have been published to date (Table 1). Despite differences in their primary components, designs, and delivery mechanisms (ie, individual, group, or family-based therapy), all 4 interventions are conceptualized as cognitive-behavioral in nature. Cognitive-behavioral interventions focus on the identification and modification of thoughts, feelings, and behaviors using various techniques such as relaxation, distraction, biofeedback, and cognitive restructuring.24 These techniques aim to reduce the subjective experience of, or increase the tolerance to, pain. The family-based interventions included in this review incorporate cognitive-behavioral techniques but also focus on families as interactive systems, with the goal of formulating change at the family (rather than individual) level.25

Cognitive-Behavioral Interventions Individual Therapy

Gil and colleagues26 evaluated a cognitive-behavioral coping skills intervention to improve pain coping strategies and decrease pain perception. Participants included 49 children and adolescents with SCD who were randomly assigned to either the intervention or a standard care control condition. The intervention was delivered in a single session and involved education about how coping skills can reduce

pain, as well as training in 3 key skills: (1) deep breathing/ counting relaxation, (2) pleasant imagery, and (3) calming self-statements. Each of the 3 strategies were described, modeled, and practiced with children using a pressure stimulator. Children were also provided with audio-recorded instructions of these techniques, a tape player, and homework assignments to encourage daily practice. Children received a phone reminder to practice the skills and attended a brief review session approximately 1 week after the initial training session. Children in the control condition continued to receive routine medical care. At the posttest assessment, children in the intervention group reported less negative thinking and lower pain sensitivity when exposed to a laboratory pain stimulus (ie, focal pressure stimulator) compared with the control group. However, the groups did not differ in negative thinking or pain sensitivity 1 month later, suggesting that this brief intervention may result in only transient improvements.27 Furthermore, children who participated in the intervention did not differ from those in the control group with regard to pain (ie, frequency, duration, and severity) or health care utilization at the 1-month follow-up. However, daily diary records revealed that children in the intervention group who used the cognitive coping strategies on days of pain had significantly fewer health care contacts and were

Table 1. Randomized Controlled Trials of Psychosocial Interventions for Pain in Pediatric SCD Patients Author

Design

Participants

Study Conditions

Results

Barakat et al (2010)30

Randomized controlled trial

N = 53, aged 12–18 years

Intervention: Family-based therapy including training in deep breathing, relaxation, positive coping statements, and guided imagery Control: Disease education

No differences between groups in change in pain, health service utilization, pain-related hindrance of goals, pain coping, and psychosocial outcomes from baseline to posttest or 1-year follow-up.

Broome et al (2001)28


N = 97

Intervention: Individual training in distraction, relaxation, and imagery skills Controls: Art therapy and attention-control

Intervention group demonstrated greater use of intervention strategies from baseline to 1-year follow-up. No differences between groups in health care utilization.

Gil et al (1997, 2001)26, 27



Intervention: Individual psychoeducation and skills training in deep breathing/ relaxation, imagery, and calming self-statements Control: Treatment as usual

At posttest, less negative thinking and lower pain sensitivity for intervention group. At 1-month follow-up, no differences between groups in negative thinking, pain sensitivity, pain frequency, duration, or severity, or health care utilization.

Thomas et al (1999)29



Intervention: Group therapy focused on modifying maladaptive pain-related cognitions, increasing perceived control over pain, relaxation training, and health education Controls: Attention placebo and no-intervention control

CBT group reported lower affective pain, greater use of positive coping strategies and engagement in behavioral activities, and higher selfefficacy and perceived self-control for pain management as compared with controls. No differences between groups in sensory pain.

Abbreviation: CBT, cognitive behavioral therapy. © Postgraduate Medicine, Volume 126, Issue 2, March 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

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more likely to remain involved in school activities. The authors conclude that although between-group analyses do not provide compelling evidence for this intervention, withingroup analyses suggest that cognitive coping skills training may be effective when children use these skills consistently during pain episodes. Similarly, Broome and colleagues28 implemented a selfcare intervention to improve coping with pain in children and adolescents with SCD. Following an initial education class that focused on living with SCD, subjects (N = 97) were randomly assigned to a cognitive-behavioral intervention, art therapy, or an attention-control group. The cognitive-behavioral therapy (CBT) intervention involved 4 weekly classes that provided training in distraction, relaxation, and imagery skills, as well as videotapes, audiotapes, and written materials for practice. The art therapy intervention focused on teaching children ways to express their feelings about pain through art and helping them share their experiences. The attention-control condition involved spending the same amount of time (4 weekly sessions) engaged in fun activities (eg, picnics, museums). Findings suggest that children in the CBT group demonstrated significantly greater use of targeted strategies (eg, relaxation, problem solving) from baseline to a 1-year follow-up. Participants in all 3 groups demonstrated reduced health care utilization within the year post-treatment (eg, emergency department visits), but there were no between-group differences in health care visits.

Group Therapy

Research suggests that CBT may also be beneficial when delivered in a group setting. Although not developmentally targeted for children, Thomas and colleagues29 investigated a CBT group therapy intervention for adolescents and adults with SCD. One of the largest RCTs for psychosocial pain management, this study assigned 97 participants with HbSS aged 15 to 35 years to a CBT group, an attention placebo group, or a no-intervention control condition. Those in the CBT group attended weekly 1 hour group sessions for 2 months, resulting in 8 total hours of therapy. In this group setting, participants learned to identify and modify maladaptive pain-related cognitions, change the meaning they assign to their pain, and increase perceived control over pain. These participants also received relaxation training (eg, progressive muscle relaxation) and health education, and completed weekly homework assignments for skill practice. Participants in the attention placebo group also attended weekly 1-hour group therapy sessions over a 2-month period; however, 126

these patient-led sessions were composed of discussion of problems related to living with SCD rather than learning pain management skills. Participants in the no-intervention control condition received standard medical treatment. Findings revealed that those in the CBT group reported greater use of positive coping strategies and engagement in behavioral activities, as well as higher self-efficacy and perceived self-control for pain management compared with the control groups. Although participants in the CBT intervention endorsed lower affective pain (ie, feeling of unpleasantness), there were no differences between groups on sensory pain (ie, intensity and quality of pain). These results suggest that the group CBT intervention significantly reduced the affective but not the sensory component of pain. However, these findings have not yet been replicated in exclusively pediatric samples and may only apply to older adolescents and adults.

Family-Based Therapy

Cognitive-behavioral therapy interventions targeting pain management have also been delivered within a family-based treatment framework. Barakat and colleagues30 conducted an RCT of a family-based cognitive-behavioral intervention designed to reduce pain and improve health-related and psychosocial outcomes among adolescents with SCD. Adolescents aged 12 to 18 years (N = 53) and their families were randomly assigned to either a brief pain intervention or a disease education control condition. The pain management intervention consisted of training in deep breathing, relaxation, positive coping statements (ie, developing positive statements for use during pain episodes), and guided imagery. The disease education control condition was developed from existing psychoeducational programs and involved cathartic activities (eg, writing or drawing about SCD), disease information, adolescent health issues related to SCD, and effective communication with the health care team. For both the intervention and control conditions, adolescents and family members attended 4 home sessions that were each 90 minutes as well as biweekly phone calls. Change in pain, health service utilization, pain-related hindrance of goals, pain coping, and psychosocial outcomes (eg, disease knowledge, self-efficacy, family communication) did not differ between groups from baseline to posttreatment or 1 year follow-up assessments. Although both groups improved overall between assessments, results suggested small effect sizes in favor of the pain management intervention for percentage of days with pain, routine health service use, SCD knowledge, and family cohesion. However, given low recruitment rates (49%) and attrition (64% retained to 1 year follow-up), this study had



insufficient power to detect group differences. The authors highlight the need for innovative strategies to overcome barriers to treatment engagement and retention among children with SCD and their families.


Pharmacological Approaches

Pharmacological treatments are more frequently employed for SCD pain management than cognitive-behavioral or physical pain-management activities.8 The 3 classes of drugs generally used to treat acute VOC pain in children with SCD are (1) non-opioid analgesics, (2) opioids, and (3) adjuvants.12 Unfortunately, there are no consensus evidencebased strategies established for management of acute pain in SCD, and thus each medical center typically develops its own guidelines.23 The New England Pediatric Sickle Cell Consortium’s recommendations for treatment of pain crises call for a multidisciplinary approach to pain management.31 More specifically, these recommendations call for administration of analgesia within 30 minutes of arrival at the hospital and effective pain management within 1 hour, followed by a focus on identifying the underlying cause for pain. Recommendations by the World Health Organization for pharmacological management of acute pain in SCD are based on whether the reported pain is mild, moderate, or severe, with the goal of providing rapid pain control.31 In this recommended 3-step

“ladder,” mild pain is treated with non-opioid ± adjuvant, with the addition of weak or strong opioids as reported pain is more severe. As needed approaches to pain medication are not typically used or recommended.23 Few RCTs have investigated the safety and efficacy of pharmacological treatments in the pediatric SCD population, resulting in a limited evidence base for prescribing clinicians (Table 2).

Non-Opioids

Although a variety of non-opioid analgesics are recommended to treat pain crises in children with SCD,31 the only non-opioid pain medications investigated for safety or efficacy through RCTs in this population are nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. These medications tend to be used on their own for mild to moderate pain or in conjunction with other medications for more severe pain.32 Both of these agents ameliorate pain by reducing inflammation. Although the mechanism of VOC pain is not well understood, it is believed that tissue damage caused by vaso-occlusion initiates an inflammatory response, which can enhance sympathetic activity by interacting with neuroendocrine pathways and triggering release of norepinephrine. This, in turn, causes more tissue ischemia, thus propagating a vicious cycle of pain.12,31

Table 2. Randomized Controlled Trials of Analgesic Medications for Acute Pain in Pediatric SCD Patients Author

Design

Participants

Study Drug

Results

Randomized, doubleblind, parallel group


Treatment: Piroxicam (1 mg/kg/day) Control: Soluble aspirin (100 mg/kg/ day)

Greater reductions in pain and fewer adverse effects for group receiving piroxicam.

Griffin et al (1994)39

Randomized, double-blind, placebo-controlled


Treatment: Methylprednisolone (15 mg/kg × 2 doses) Control: Saline placebo All patients: Morphine sulfate (0.1–0.15 mg/kg per 2 hours)

Patients given methylprednisone required shorter duration of opioid therapy, but reported more recurring pain after discontinuing opioids.

Grisham and Vichinsky (1996)41

Randomized, double-blind


Treatment: Ketorolac (1 mg/kg) Control: Pethidine (1.5 mg/kg)

Greater reductions in pain reported by group receiving ketorolac. Fewer adverse effects reported by ketorolac group.

Hardwick et al (1999)43

Prospective, randomized, singledose, double-blind, placebo-controlled


Treatment: Ketorolac (0.9 mg/kg) Control: Saline placebo All patients: Morphine (0.05–0.1 mg/kg per 2 hours)

No differences in pain ratings between ketorolac and saline placebo groups.

Jacobson et al (1997)51

Randomized, doubleblind, parallel group


Treatment: Oral morphine (1.9 mg/kg per 12 hours) Control: Intravenous morphine (0.04 mg/kg per hour)

No differences in pain ratings between oral and parenteral morphine groups.

Rogers et al (1996)45

Randomized, double-blind, placebo-controlled

N = 80

Treatment: Dexamethasone (0.3 mg/kg per 12 hours × 4 doses Control: Saline placebo All patients: Opioid therapy

Patients in corticosteroid group demonstrated shortened duration of need for opioid therapy.

Eke et al (2000)

44


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These medications may be administered enterally or parenterally, but differences exist in terms of mechanisms of action and risk for adverse side effects. Nonsteroidal anti-inflammatory drugs are peripherally acting analgesics and act at the level of nociceptors.12 This class of medication decreases pain and inflammation by inhibiting the cyclooxygenase inhibitors, thereby inhibiting the production of prostaglandins in damaged tissues.12,33 Nonsteroidal antiinflammatory drugs are contraindicated in patients with renal complications, peptic ulcers, and coagulopathies,34 and can cause significant adverse side effects (eg, hemostatic defects, gastrointestinal bleeding).12 As such, it is recommended that NSAIDs should not be continuously administered to children for . 5 days.12 With regard to the specific NSAIDs evaluated in studies included in this review, recommended dosages for children are as follows: (1) for ketorolac (Toradol), 0.5 mg/ kg followed by either injections of 1.0 mg/kg every 6 hours or an intravenous infusion of 0.17 mg/kg/h35; and (2) for piroxicam (Feldene), 0.4 mg/kg once daily.36 In contrast to NSAIDs, corticosteroids suppress inflammation by binding to glucocorticoid receptors, thereby activating anti-inflammatory proteins and reducing proinflammatory proteins.37 Evidence-based safety guidelines and contraindications for corticosteroids specific to pediatric SCD do not yet exist.38 The higher incidence of rebound pain and subsequent hospital readmission as well as potential adverse reactions (eg, increased risk of avascular necrosis, stroke, and renal infarction) associated with corticosteroids, however, preclude its routine use for children with SCD.39,40 For intravenous administration of methylprednisolone and dexamethasone, 2 corticosteroids used in controlled trials reviewed below, conventional dosages for children range from 10 to 30 mg/kg every 4 to 6 hours (methylprednisolone) and 0.2 to 0.4 mg/kg of body weight daily (dexamethasone). To date, 3 RCTs have investigated the efficacy of NSAIDs in children and young adults experiencing acute SCD pain. Two trials utilized ketorolac, a heterocyclic acetic acid derivative. Grisham and Vichinsky41 compared the efficacy of intravenous ketorolac to pethidine (ie, meperidine), a synthetic opioid. Twenty children (aged 11 to 19) were administered intravenous ketorolac (1 mg/kg of body weight, readministered if pain still present after 2.5 hours) or pethidine (1.5 mg/kg) during a pain crisis. They were asked to rate their pain at 30, 120, and 150 minutes after administration. The ketorolac group reported greater reductions in pain as compared with the pethidine group, with the greatest difference between groups observed at 30 minutes postadministration. Fewer adverse effects were reported among patients given 128

ketorolac (15%) as compared with pethidine (37%). Because of pethidine’s poor efficacy and serious side effect profile (eg, serotonergic crisis including seizures; anticholinergic effects), many authors have discouraged the use of this agent (for a comprehensive review, see Latta et al42). In a second RCT aimed at investigating potential synergistic effects between ketorolac and opioid medications, Hardwick and colleagues43 administered a single dose of intravenous ketorolac (0.9 mg/kg) or saline placebo to 29 SCD patients (aged 5 to 18). Each patient also received intravenous morphine (0.05 to 0.1 mg/kg) at 2-hour intervals. Analysis of hourly pain ratings revealed that pain decreased in both treatment conditions; however, symptom reduction did not differ significantly between groups. As such, a synergistic analgesic effect between ketorolac and morphine was not identified in this trial. A second NSAID, piroxicam (Feldene), has also been evaluated for pain management among children with SCD. In a double-blind RCT, Eke and colleagues44 compared the efficacy of oral piroxicam (1 mg/kg/day) with soluble aspirin (100 mg/kg/day) among 58 children with SCD (aged 3–14 years) experiencing severe osteoarticular pain requiring hospitalization. The piroxicam group reported significantly greater reductions in pain, with 66% achieving immediate sedation and disappearance of symptoms # 24 hours postadministration compared with only 3.4% of the aspirin group. Additionally, there were no adverse effects noted for the piroxicam group, whereas 31% of those treated with aspirin reported nausea and vomiting. The authors conclude that oral piroxicam appears to be a well-tolerated and effective treatment for osteoarticular pain in children with SCD. Two RCTs have also investigated the efficacy of corticosteroids for treatment of acute pain in pediatric SCD. In the first of these studies, Griffin and colleagues39 compared a 2-day course of high-dose intravenous methylprednisolone (15 mg/kg, maximum 1000 mg) to placebo among 36 pediatric SCD patients. In addition to the study drug, patients also received intravenous morphine sulfate (0.1 to 0.15 mg/kg) at a maximum of every 2 hours. Patients given methylprednisolone required a significantly shorter duration of opioid therapy compared with patients receiving placebo (31.0 vs 62.5 hours), although the methylprednisone group reported more recurring pain after discontinuing opioids. Results were supported by a second RCT45 in which 80 pediatric SCD patients were given parenteral corticosteroids (dexamethasone, 0.3 mg/kg every 12 hours for 48 hours) or placebo in addition to an opioid. Again, patients in the corticosteroid



group demonstrated shortened duration of need for opioid therapy. Notably, no significant adverse effects were associated with corticosteroid use in either trial.


Opioids

Opioid agonists (eg, morphine, hydromorphone, oxycodone) are powerful analgesics that represent the most commonly used drugs for the treatment of acute pain crises in children with SCD.46,47 Opioids relieve pain by binding to opioid receptors in the brain and inhibiting neuronal excitability in pain-related brain areas (ie, thalamus, spinal cord, primary sensory neurons).48 It is important to note that opioids do not have a ceiling effect, with the exception of mixed agonistantagonist and partial agonist opioids such as buprenorphine. However, they do carry known adverse side effects, such that administration of these agents must balance pain relief with the potential for harm.47 The most salient side effects of opioid drugs in pediatric SCD care are respiratory depression47 and sedation.12 Opioids can be administered via several routes, but parenteral administration through patient-controlled analgesia (PCA) devices in the emergency department or inpatient setting is a standard practice for children with SCD. However, PCA use varies as a function of patient age and comprehension about using the device. Continuous intravenous infusion may also be an option for very young children or those with cognitive disability who cannot use PCA.32 Typically, individuals treated with PCA receive larger daily doses than those receiving time-contingent dosing.46 However, findings from 1 controlled study with adult SCD patients suggest that PCA use is associated with lower cumulative consumption of morphine as compared with continuous infusion.49 Because few controlled studies have investigated the optimal use and dosing of opioids for pediatric SCD,50 guidelines for opioids are often drawn from the larger pain literature (eg, for PCA, 0–20 µg/kg/h with demand dosing of 0.02–0.025 mg/kg every 6–12 minutes until pain is reduced or resolved). Appropriate dosage and scheduling of opioids requires frequent observation of pediatric patients and effective communication between the child and medical staff to evaluate opioid effects and need adjustments. Although 2 RCTs have compared opioids with NSAIDs or included opioids as part of a treatment regimen,39,41 only 1 study has specifically investigated the efficacy of opioid drugs in children with SCD.51 In this study, 56 children (aged 5–17 years) experiencing severe pain crises received an initial open-label administration of intravenous morphine (# 0.15 mg/kg). Participants were then given either

controlled-release oral morphine (1.9 mg/kg every 12 hours) or continuous intravenous morphine (0.04 mg/kg/h). Findings revealed similar pain ratings for children on oral versus parenteral treatment regimens, suggesting that oral morphine represents an efficacious alternative to intravenous administration. Adverse side effects including fever, nausea, constipation, and vomiting were reported in each group, but rates of reporting did not differ between groups. Notably, 41% of patients demonstrated evidence of chest involvement or crisis, but it was unclear whether this finding was opioid related.51

Discussion

Findings reveal a paucity of rigorous empirical investigations of psychosocial and pharmacological pain management interventions for children with SCD. Although psychosocial interventions show promise in meeting proximal targets (eg, perceived pain control and self-efficacy, positive coping strategies), most of the interventions included in this review did not reduce the severity, duration, or frequency of pain or utilization of health care services among children with SCD pain. The only exception to this finding was a study conducted by Thomas and colleagues29 in which participants in the CBT group reported lower affective pain than the control groups. However, this study included both adolescents and adults, and the groups did not differ on measures of sensory pain. Although there is general consensus that pain coping, perceived control, and disease knowledge are appropriate intermediate intervention targets, additional research is needed to more thoroughly evaluate the mechanisms by which these psychological processes can affect functional outcomes. As noted by Barakat and colleagues,30 future research should also examine methods to improve treatment engagement and retention among children with SCD and their families. Many barriers may prevent children with SCD from receiving and maintaining health care services (eg, socioeconomic challenges, mistrust of medical institutions, lack of perceived benefit, anxiety and fear about hospitalization and treatment). As a result, psychosocial interventions must be developed and implemented with stakeholder input to ensure adequate cultural and developmental sensitivity, acceptability, and feasibility. In particular, Kaslow and colleagues52 highlight the importance of therapist training in providing culturally competent services, developing treatments that are flexible enough to be tailored to each child and family, and overcoming socioeconomic barriers for children with SCD. To best target future pain management interventions for pediatric SCD, research should also examine the relative


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feasibility and efficacy of interventions delivered individually versus those using group or family-based modalities. Although not yet evaluated in controlled trials, other psychosocial pain management approaches have shown promise as emerging treatments for pediatric SCD. For instance, a pilot study of biofeedback involving thermal and electromyography training suggested decreased self-reported pain, medication use, and anxiety symptoms from pre- to posttreatment for children with SCD.53 However, no differences were found for health care utilization postintervention. Another small study found that training in self-hypnosis led to reductions in the number of self-reported pain days and use of pain medications among a sample of children and adults with SCD.54 However, pain severity during VOC episodes was not significantly reduced, suggesting that hypnosis may be more beneficial for mild chronic pain than for acute pain crises. Although these findings are encouraging, this intervention was extremely time intensive (ie, 18 months of group training sessions) and may be challenging to implement. Furthermore, because this sample was not composed exclusively of children, the generalizability of findings to pediatric SCD must be interpreted with caution. Given the limitations of these small pilot studies, future research should thoroughly examine the efficacy of biofeedback and self-hypnosis for children with SCD in studies with more robust designs. In terms of pharmacological management of pediatric SCD pain, findings from several controlled trials suggest that corticosteroids are potentially efficacious in reducing duration of opioid need. However, 1 study found that children treated with methylprednisone reported more recurring pain after discontinuation of opioids. In addition, a recent retrospective analysis of . 5000 pediatric SCD hospitalizations for acute chest syndrome revealed that after controlling for confounding variables (eg, indicators of disease severity), corticosteroid treatment was associated with an increased length of hospital admission and a higher 30-day readmission rate.38 Given conflicting findings about the efficacy of corticosteroids, physicians must be cautious and consider the ratio of potential risks to benefits for children with SCD. Additional RCTs are needed to clarify these discrepancies and to determine optimal recommendations regarding corticosteroids for children with SCD. Although evidence suggests that NSAIDs are safe and efficacious, controlled investigations involving more commonly available NSAIDs (eg, ibuprofen) are notably absent in the extant literature. The RCTs conducted to examine the efficacy of NSAIDs have utilized ketorolac (Toradol) and piroxicam (Feldene), medications used extensively in inpatient settings. However, 130

it is important to note that NSAIDs have several important advantages over more powerful opioids. For example, given the primary role of inflammation in the pathophysiology of VOC pain, NSAIDs are critical in the initial treatment of acute pain crises. Furthermore, these medications can be combined with opioids for additional pain relief, are inexpensive and available over the counter, and may be administered at home by parents or other caregivers.47 On the other hand, pure opioid agonists (eg, morphine) confer some unique advantages in that they do not have a ceiling beyond which additional analgesic properties disappear.12,47 Although opioids carry less risk for systemic adverse effects, however, there is greater risk for potentially serious side effects requiring continuous cardiorespiratory monitoring. Unfortunately, evidence-based guidelines for safe use of opioid agents in children with SCD have yet to be developed. Although fears of opioid addiction or dependence are likely misguided in the context of brief treatment for acute pain episodes,10 overuse of over-the-counter medications can be dangerous. This risk underscores the need for caregivers to communicate and collaborate with the medical team to ensure safe and effective pain management using primarily prescribed medications. A number of adjuvant medications are commonly coadministered with analgesics for management of pediatric SCD pain, although the evidence base for these drugs is minimal. For example, anticonvulsant medications may be useful to address SCD pain with a neuropathic component (ie, pain caused by a lesion or disease of the somatosensory system),55 but data are insufficient to provide physicians with treatment guidelines. Psychostimulant drugs (eg, dextroamphetamine and methylphenidate) may also help ameliorate pain crises in SCD, as they contain inherent analgesic properties, and greater cognitive alertness can potentially afford larger opioid doses. However, research regarding the efficacy of psychostimulants for pediatric SCD is limited.56 Some adjuvant medications are coadministered with opioids to counteract adverse effects of more established treatments, such as antihistamines to minimize histaminergic effects of opioids55 or low-dose naloxone to counter adverse side effects (eg, nausea, pruritus). Dehydration is also common in children with SCD admitted with pain crises. Although intravenous hydration is used as a supportive treatment measure in these situations, this intervention must be administered with caution given the increased risk for pulmonary edema.46 Some children admitted with pain crises also receive blood transfusions secondary to acute chest syndrome or hypoxemia.46 Finally, given the relationship between depressive symptoms and frequency of VOC episodes,57,58




some physicians prescribe tricyclic antidepressants to children with SCD. The utility of these agents and the mechanism by which these psychotropic drugs may lessen pain are not yet well understood.12 Lastly, although it does not target pain specifically, hydroxyurea is considered a safe and effective treatment that can indirectly reduce pain episodes in children with SCD through downstream effects.59,60 Hydroxyurea results in the induction of fetal hemoglobin production, increases in total hemoglobin, and decreases in hemolysis, as well as reductions in white blood cell count and the expression of molecules that are associated with vaso-occlusion, with no associated severe adverse effects.59,60 Strouse and colleagues60 reviewed a number of studies investigating the efficacy of hydroxyurea use in children with SCD and concluded that it reduced the number of hospitalizations and reported pain episodes in the majority of pediatric studies. Additional research is needed to establish clear guidelines to standardize administration of hydroxyurea in children with SCD. In addition, preliminary evidence suggests that nitric oxide, which may underlie physiological disturbances contributing to vaso-occlusion, might be effective for reducing pain and morphine use during VOC episodes.61 Similarly, purified poloxamer 188 has shown initial promise for effectively reducing pain among patients with SCD by acting on physiological mechanisms related to vaso-occlusion.62 However, a systematic review of purified poloxamer 188 suggested that its effects are pronounced only in children and when used in conjunction with hydroxyurea.63 Further research is warranted to determine the efficacy of nitric oxide, purified poloxamer 188, and other therapies based on mechanisms of disease for children with SCD.

Future Directions

It is important to acknowledge that most current psychosocial and pharmacological pain interventions are designed to address acute pain crises. Although acute pain is a hallmark feature of SCD, emerging epidemiological research has revealed that pain in pediatric SCD is more chronic than was initially theorized.8 Although severe pain can often present suddenly in children with SCD, lower intensity pain is also prevalent in this population and is more likely to be managed at home without the assistance of medical professionals. Chronic pain among children with SCD may be a result of chronic vaso-occlusion as well as neuropathic pain mechanisms and opioid-induced hyperalgesia.8 These advances in understanding the multifactorial etiology and presentation of pain in pediatric SCD call for an expansion

of current pain management practices in order to address both acute and chronic pain. Furthermore, most current pain management interventions are designed to manage acute pain crises once they occur, yet preventive daily practices (eg, high fluid intake, avoiding extreme temperatures) that may help avert pain crises are often not incorporated.64 This practice is contrary to guiding pain management principles, which stipulate that prevention of pain (when possible) is always preferred to treatment.65 Therefore, future intervention efforts should consider combining preventive measures for pain episodes and related complications with psychological and pharmacological strategies to manage acute pain episodes.

Conclusion

Pain in pediatric SCD represents a significant public health concern, yet few controlled investigations of psychosocial and pharmacological pain management approaches are available to guide clinical practice. Given that both psychosocial and physiological processes are involved in the etiology and presentation of pain in pediatric SCD, optimal management of pain likely requires multidimensional, comprehensive treatment approaches that target psychological (eg, coping, pain tolerance, and control), social (eg, parent responses to pain, home management techniques), and physiological (eg, inflammation, tissue ischemia) factors. Considering the importance of adequate pain management for functional outcomes, quality of life, and productivity, additional prospective, controlled, and adequately powered studies are warranted to best target future intervention efforts.

Conflict of Interest Statement

Aimee K. Hildenbrand, BS, Elizabeth G. Nicholls, MIT, Brian P. Daly, PhD, Meghan L. Marsac, PhD, Reem Tarazi, PhD, ABPP-CN, and Deepti Raybagkar, MD, MS have no conflicts of interest to declare.

References

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Sickle cell disease pain management in adolescents: a literature review.

Sickle cell disease pain management and the medical home.

Pain in sickle cell disease.

Gout and sickle cell disease: not all pain is sickle cell pain.

Teasing Apart Pain in Sickle Cell Disease.

Examining Biopsychosocial Factors in Relation to Multiple Pain Features in Pediatric Sickle Cell Disease.

Asthma management in sickle cell disease.

Management of patients with sickle cell disease.

Management of Sickle Cell Disease Super Utilizers.

Management of patients with sickle cell disease.

WITHDRAWN: Pain management for sickle cell disease in children and adults.

Pain in sickle cell disease. Rates and risk factors.

Consequences and management of iron overload in sickle cell disease.

Comorbidity, Pain, Utilization, and Psychosocial Outcomes in Older versus Younger Sickle Cell Adults: The PiSCES Project.

Morphine for the treatment of pain in sickle cell disease.

Family Engagement in Pediatric Sickle Cell Disease Visits.

Sickle cell disease: management options and challenges in developing countries.

Emerging science of hydroxyurea therapy for pediatric sickle cell disease.

Pulmonary hypertension in sickle cell disease: diagnosis and management.

Survey of pain management therapy provided for children with sickle cell disease.

Mistrust of Pediatric Sickle Cell Disease Clinical Trials Research.

Abdominal pain in children with sickle cell disease.

Obstetrician-gynecologists' knowledge of sickle cell disease screening and management.

Orofacial pain in patients with sickle cell disease.