Addressing Sickle Cell Disease A Strategic Plan and Blueprint for Action (2020) / Chapter Skim
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4 Complications of Sickle Cell Disease and Current Management Approaches
4 Complications of Sickle Cell Disease and Current Management Approaches
Pages 123-184
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Chapter Summary • Sickle cell disease (SCD) is a multi-organ blood and blood vessel disease, with pain (both acute and chronic)
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INTRODUCTION Sickle cell disease (SCD) is a multi-system disorder resulting from the complex interplay among hemolysis (the destruction of red blood cells [RBCs]
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Individuals living with SCD also experience daily chronic pain. Pain may occur from chronic end-organ or nerve damage from SCD as a result of treatments (e.g., opioid-induced hyperalgesia [OIH]
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. This definition aims to distinguish P acute pain from transient and chronic pain but may not adequately capture pain syndromes that represent a transition from acute to chronic pain.
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. This is in line with the findings of multiple studies and anecdotal evidence that the majority of acute pain in SCD is managed at home, with acute care use occurring in only a minority (3–5 percent)
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The complexity and multifactorial nature of pain in SCD are difficult to dissect by patients, who may struggle to describe pain to health care providers, and by the providers, who may not completely understand it and thus inadequately treat it. Chronic SCD Pain In addition to acute pain, as individuals with SCD age they increasingly develop chronic pain.
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BOX 4-1 American Pain Society Pain Taxonomy Diagnostic Criteria for Chronic Pain Associated with SCD (Chronic SCD Pain) Dimension 1: Core Diagnostic Criteria 1.
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. Despite the fact that neuropathic pain is a common archetype of chronic SCD pain, only 14 percent of adults with SCD and chronic pain in one study reported being prescribed adjuvant drugs that may target neuropathic pain pathways; the majority of the study participants received opioids only (Brandow et al., 2014; WHO, 2018; Wilkie et al., 2010)
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Triggers and Psychological Impact of Pain You can think of any life event, and I can tell you a story of how sickle cell disease impacted it. -- Tosin O
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. The PiSCES study reported a significantly higher degree of catastrophizing among adults with SCD than among those with other temporal chronic pain conditions (Citero et al., 2007)
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With the obvious need to de-emphasize the use of opioids in chronic pain management, there have not been commensurate evidence-based recommendations for alternative approaches. Non-Opioid Medications Acetaminophen Oral acetaminophen has been widely used in multimodal pain management strategies in SCD with variable efficacy (Shah et al., 2019)
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, but it is not generally approved by insurance plans and is rarely used for home management. Ketamine Intravenous ketamine is emerging as an alternative to morphine for acute pain management in SCD and may lead to lower opioid consumption (Lubega et al., 2018; Puri et al., 2019)
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Recent data showed successful conversion to buprenorphine in patients with chronic pain and high opioid doses with a decrease in pain scores and acute care use, and increase in QOL measurements (Osunkwo et al., 2019)
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. Non-Pharmacological Treatments of Pain in SCD Non-Pharmacological Approaches Various non-opioid-based treatments have been proposed for reducing acute pain and the duration of pain and for preventing pain in SCD; these treatments should be incorporated into a multidisciplinary pain control strategy whenever possible (Niscola et al., 2009)
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. Yoga Yoga, a practice that incorporates physical positions, mindfulness, relaxation, and breathing exercises, has been shown to reduce chronic and acute pain in adults, although there are limited data concerning its use for the treatment of SCD pain.
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has been shown to be effective in the SCD population by addressing coping strategies and normalizing chronic pain. In CBT, individuals learn to differentiate emotional and behavioral reactions from a triggering event, such as pain (Anie and Green, 2015; Schatz et al., 2018)
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Research conducted using data from patients enrolled in the Cooperative Study of Sickle Cell Disease shows that the chances of having a cerebrovascular acci ent (defined as transient ischemic attack, completed infarctive stroke, d and hemorrhagic stroke) for the first time by age 20 years is 11 percent and by age 45 years is 24 percent for those with HbSS (i.e., the form of SCD in which a child inherits a sickle cell hemoglobin gene from each parent)
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140 Organ System Acute Chronic Comorbid Conditions Cardiovascular • Sudden death • Sickle cardiomyopathy • Cardiac iron toxicity • Fatigue • Left ventricular hypertrophy • ethadone related prolonged M • Dyspnea • Diastolic dysfunction QT intervala • Syncope • eart failure with preserved H • Hyperlipidemia • elative systolic hypertension R ejection fraction • Obesity-related cardiovascular • Myocardial infarction • ron-induced cardiomyopathy and I complications dysrhythmias • Venous thromboembolism • Endothelial dysfunction/autonomic dysfunction • Prolonged QT interval • Pulmonary hypertension Central Nervous • Headache • Chronic headaches • osterior reversible encephalopathy P System • Infarctive stroke • eurocognitive disorders due N syndrome • Hemorrhagic stroke to silent cerebral infarcts/overt • Pre-/post-eclampsia • Ruptured aneurysms cerebrovascular accidents or • Arnold Chiari malformation • Moyamoya syndrome strokes and chronic anemia • Cerebral aneurysms • Silent cerebral infarcts • Poor executive functioning • Sino-venous thrombosis • Memory deficits • Increased cerebral blood flow • erebral vasculopathy and C Moyamoya syndrome • Cerebral aneurysms Dental • Dental abscess • Dental caries • Cardiovascular risk • Dental crown fracture • Gingivitis • ental cavities, gingival disease, D • Dental pulp fracture • Cracked teeth malocclusion • Early dental loss • Misaligned dentition Endocrine • ain around menses, pregnancy, P • Growth hormone deficiency D • iabetes and thyroid disease from and menopause • Hypogonadism iron overload • Disturbances in cortisol levels • Early menopause and bone health • Delayed puberty • Hypo/hyperthyroidism • Premature menopause
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Genitourinary • Priapism • Erectile (sexual) dysfunction • enorrhagia leading to worsening M • Enuresis • Postcoital pain anemia • Hematuria • Enuresis/nocturia • ysmenorrhea with increased acute D • Menses-induced VOE • Hematuria care use Hematopoietic • Acute anemia • Chronic hemolysisc • elayed hemolytic transfusion D System • Aplastic crisis • Chronic anemia reactions (excluding • Sequestration crises • Extramedullary hematopoiesis • Parvovirus B19 infection spleen)
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fractures • steonecrosis or avascular necrosis O • axillary hyperplasia and M of the jaw, particularly when bony changes associated with exposed to bisphosphonates extramedullary hematopoiesis • ncreased risk of pathological I • Gout fractures • Osteopenia/osteoporosis from increased bone turnover • Vitamin D deficiency/rickets Ophthalmic • Retinal detachment • ickle retinopathy (proliferative S • Early cataracts • Retinal artery occlusion and nonproliferative) • Early glaucoma • Vitreous hemorrhage • Maculopathy • ncreased intraocular pressure with I • Macular infarction posttraumatic hyphema Pulmonary • Acute chest syndrome • Chronic lung disease • In situ pulmonary thrombosis • Pneumonia • Chronic hypoxemia/hypoxia • Asthma • ulmonary fat embolism syndrome P • Nocturnal hypoxemia • Adenotonsillar enlargement • Airway hyperreactivity • Chronic pulmonary embolism • Obstructive sleep apnea • telectasis from hypoventilation A • Right middle lobe syndrome • Pulmonary embolism
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. cHydroxyurea, chronic transfusion therapy, and other disease-modifying therapies, when initiated early in life, may alter the natural history of SCD phenotype.
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Renal osteodystrophy in SCD may confer worsening chronic pain and is often unrecognized and nonresponsive to opioids (Elsurer et al., 2013; Seck et al., 2012)
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. Women with RBC alloimmunization are at risk for having babies with hemolytic disease of the newborn, and those exposed to opioids are at increased risk for neonatal abstinence syndrome (Nnoli et al., 2018)
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. Hematopoietic System Anemia, defined by a decreased hemoglobin concentration, is a hallmark of SCD and is almost invariably present in individuals with homozygous HbS (sickle cell anemia, or SCA)
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. Pulmonary hypertension is an independent risk factor for death in SCD, with a 6-year mortality rate of approximately 40 percent (Mehari et al., 2012)
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The PiSCES study also found high rates of depression, with 27.6 percent of 308 adults reporting depressive symptoms (Sogutlu et al., 2011)
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SCD-Related Complications Acute Chronic Comorbid Conditions Behavioral • Acute psychosis due to pain • Neurocognitive complications • Poor socioeconomic status Health • Opioid-induced psychosis • PTSD • Stigma/racism • Depression • Societal barriers • Anxiety • Catastrophizing • Pica • SUDs • SUDs • School absenteeism • Unemployment Constitutional • Fatigue • Fatigue • Poor exercise tolerance • Fever • Exercise intolerance • Dehydration • General deconditioning Growth • Weight loss • Delayed puberty • verhydration, leading to O • eight gain (particularly during • Delayed linear growth W anasarca prolonged admissions) • Obesity Malignancies • Renal cell carcinoma • bnormal serum protein and urine A • o evidence to support N electrophoresis, causing false alarms increased risk of malignancies in SCD on hydroxyurea Nutrition • Anorexia during acute VOE • Vitamin D, E, A deficiencies • enal tubular acidosis with R • Craving for salt/sugar • Zinc deficiency electrolyte wasting • ncreased caloric demand/hypermetabolism I • Adrenal insufficiency • Parasympathetic dysfunction continued 149
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predisposes • Infections • ithin a few days after W to sudden death • Arrhythmias discharge from acute care NOTE: CS = central sensitization; DVT = deep vein thrombosis; PTSD = posttraumatic stress disorder; ROD = renal osteodystrophy; SCD = sickle cell disease; SUD = substance use disorder; VOE = vaso-occlusive crisis. SOURCES: Adapted from Ballas et al., 2012b; Field et al., 2019; Osunkwo, 2011; Osunkwo et al., 2011; While and Mullen, 2004; Wu et al., 2018.
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People with SCD who report depressive symptoms also appear to have more frequent and severe pain. In the PiSCES study, depression was associated with increased reports of days with pain (71.1 versus 49.6 percent for the non-depressed group)
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Individuals with SCD report experiencing a constant fear of death or feeling that the current trip to the ED will be their last because of the unpredictability of the acute exacerbations. Many people living with SCD settle into an "automatic survival mode," with hypervigilance and hyperreactivity to sound, speech, and movements, and this leads to a chronic fatigue and exhaustion similar to posttraumatic stress disorder (PTSD)
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This is partly due to the concerns about increasing stigma in an already stigmatized population and the fear that applying these terms will reduce access to optimal treatment for pain, which typically requires opioids. Nevertheless, it is important that appropriate terminology and diagnostic criteria be applied equally to all populations to avoid undertreatment, overtreatment, and inappropriate treatment; further worsen clinical outcomes; and reduce access to evidencebased care.
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. Deaths from opioid overdose in people living with SCD are markedly lower than in other non-cancer pain conditions, including low back pain, migraine, and fibromyalgia (Ruta and Ballas, 2016)
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. The premise for the creation of Comprehensive Sickle Cell Centers of Excellence, which began with the National Sickle Cell Anemia Control Act of 1972, was the provision of early diagnosis and supportive care (Bonds, 2005; Manley, 1984; Scott, 1979)
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. Analysis of data from The Stroke Prevention Trial in Sickle Cell Anemia also showed that participants with normal internal carotid artery or middle cerebral artery elocity had a higher risk of stroke (10 times greater)
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. The 12-month open label Hydroxyurea European Sickle Cell Disease Cohort study (ADDMEDICA SASA, 2015)
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Transfusion Therapy RBC transfusions remain a cornerstone of supportive care for both acute and chronic life-threatening SCD complications. Transfusions provide non-sickle RBCs that correct the severe anemia from hemolysis and
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An ongoing, multi-center, international clinical trial (NCT04084080) is exploring whether exchange transfusions improve morbidity and mortality in patients with high-risk disease (defined by high tricuspid regurgitant velocity [TRV]
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. Self-Management Developing adequate self-management skills is essential for individuals to effectively manage a complex disease; disease self-management leads to increased medication adherence, improved pain management, and better health outcomes (Matthie et al., 2015; Nicholas et al., 2012)
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In addition, an in-depth review of mHealth tools is necessary to ensure that data security and patient confidentiality are preserved. CDC has developed the Living Well With Sickle Cell Disease Self-Care Toolkit to provide SCD education, prevention tips, and selfmanagement tools (e.g., pain diaries)
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. Following certain extreme triggers, however, individuals with SCT may experience medical problems, including an increased risk for prevalent and incident chronic renal disease, pulmonary embolism, and rhabdomyolysis (Naik et al., 2018)
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The pathophysiology of acute and chronic pain in SCD is complex, which is the main reason why treatment remains suboptimal. The treatment of pain is further complicated by racial, cognitive, and socioeconomic factors.
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There is a strong link between psychological comorbidities and both acute and chronic pain. Neurocognitive deficits can also influence pain perception, ability to cope with pain, and response to treatment.
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Recommendation 4-1: Private and public funders and health profes sional associations should fund and conduct research to close the gaps in the existing evidence base for sickle cell disease care to inform the development of clinical practice guidelines and indicators of high quality care. Recommendation 4-2: The National Institutes of Health should fund research to elucidate the pathophysiology of sickle cell trait.
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2018b. Patient-centered eHealth interventions for children, adolescents, and adults with sickle cell disease: Systematic review.
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2009. Cocaine abuse complicating acute painful episodes in sickle cell disease.
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2020. Opioid treatment for acute and chronic pain in patients with sickle cell disease.
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2006. Circumstances of death in adult sickle cell disease patients.
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2016. Safety and utility of quantitative sensory test ing among adults with sickle cell disease: Indicators of neuropathic pain?
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2012. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease.
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2018. Parent pain catastrophizing predicts child depressive symptoms in youth with sickle cell disease.
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2016. A systematic review of the association between depression and health care utilization in children and adults with sickle cell disease.
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2012. A comparison of chronic manual and automated red blood cell exchange transfusion in sickle cell disease patients from two comprehensive care centres in the United Kingdom.
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2016. Systematic and meta-analytic review: Medication adherence among pediatric patients with sickle cell disease.
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2017. Inci dence and predictive score for delayed hemolytic transfusion reaction in adult patients with sickle cell disease.
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2011. Vitamin D deficiency and chronic pain in sickle cell disease.
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2019. Use of buprenorphine/ naloxone in ameliorating acute care utilization and chronic opioid use in adults with sickle cell disease.
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2009. DNA array analysis for red blood cell antigens facilitates the transfusion sup port with antigen-matched blood in patients with sickle cell disease.
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2019. Management of chronic pain in adults living with sickle cell disease in the era of the opioid epidemic: A qualitative study.
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2014. Bone marrow necrosis and fat embolism syndrome in sickle cell disease: Increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection.
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2010. Patient-reported outcomes: Descrip tors of nociceptive and neuropathic pain and barriers to effective pain management in adult outpatients with sickle cell disease.
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2019. Similar burden of type 2 diabetes among adult patients with sickle cell disease relative to African Americans in the U.S.
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