Sickle-cell disease (SCD) is the most prevalent single-gene disorder, affecting about 100,000 Americans. Sickle-cell disease is a debilitating condition associated with chronic anemia, stroke, splenic and renal dysfunction, susceptibility to bacterial infections in children, acute chest syndrome, and pain crises. Each year in the United States, an average of 75,000 hospitalizations are due to SCD, costing approximately $475 million. Despite a decrease in mortality in children with SCD over the last 25 years, median life expectancy for most SCD patients remains less than 50 years of age. Although tremendous resources have been invested in finding a cure, barriers to analgesia in SCD remain and stereotyping of patients persists. Major barriers to pain management are misconceptions regarding patients’ report of pain, use of opioids and other pain medications, and perception of addiction. This chapter discusses the correlation between SCD pain and mortality; mistrust between patients and health care providers (HCPs) as one reason for undertreated pain; patients’ perceptions of health care system response to their needs; and the need for clinical guidelines to provide appropriate comprehensive care to patients with SCD.

Sickle-cell disease was identified in the United States in 1910, when sickle-shaped red blood cells were found in the blood of a medical student from Africa. Autosomal dominant inheritance was identified in 1923, and oxygen deprivation of tissues was shown to provoke sickling in 1927. Single amino acid substitution of glutamic acid for valine in the sixth amino acid position of the B chain of hemoglobin (Hb) was demonstrated to be responsible for physicochemical features of altered Hb. Further studies demonstrated that both altered erythrocytes and endothelial cells express surface molecules that mediate intracellular adhesions, leading to polymerization of deoxygenated sickle-cell hemoglobin (HbS) and vaso-occlusion. Advances in basic and clinical research did not significantly change the outcomes for patients until recently, when antibiotics, hydroxyurea, and bone marrow transplantation (BMT) were introduced. Bone marrow transplantation, first performed in 1998, is currently available as a cure for a selected group of patients only. Pain management and supportive care have been the cornerstones of the treatment of SCD since its discovery and remain the best intervention to reduce morbidity and improve the quality of life for most patients.

PREVALENCE

The Centers for Disease Control and Prevention (CDC) estimates that

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  SCD affects 90,000 to 100,000 Americans.

  
  
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  SCD occurs in about 1 in every 500 black or African-American births.

  
  
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  SCD occurs in about 1 in 12 blacks or African Americans.¹

MORTALITY

In 1973, the average life span for individuals with SCD was only 14 years.² Current life expectancy for SCD patients is 50 years and more.³ Women with SCD live longer than men.

Vaso-occlusion resulting from Hb polymerization and erythrocyte rigidity, as well as chronic anemia, hemolysis, and vasculopathy, is central to the pathophysiology of this disease. Early death is associated with acute chest syndrome, renal failure, seizures, persistent leukocytosis, and depressed fetal hemoglobin (HbF) levels.⁴ Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, with risk of cognitive impairment, increased prevalence of infections, and impairment in the functions of kidneys, lungs, bones, and the cardiovascular system, which become apparent with increasing age.

Sickle cell-related death among black or African American children younger than 4 years of age decreased by 42% from 1999 through 2002. The decrease coincided with the introduction in 2000 of a vaccine that protects against invasive pneumococcal disease.¹

Relative to the rate for the period 1983 through 1986, the SCD mortality rate for the period 1999 through 2002 decreased by

68% at 0 through 3 years of age;

39% at 4 through 9 years of age; and

24% at 10 through 14 years of age.¹

Pain episodes often signal life-threatening complications, such as sepsis, acute chest syndrome, stroke, blood and fat pulmonary embolism, autosplenectomy, gallstones, leg ulcers, priapism, and others. Among patients older than 20 years of age, the rate of pain episodes correlates with mortality. As many as 22% of deaths in patients with SCD follow acute pain episodes.^4–6

ECONOMIC COSTS

During 2005, medical expenditures for children with SCD averaged $11,702 for children with Medicaid coverage and $14,772 for children with employer-sponsored insurance. Approximately 40% of both groups had at least one hospital stay.¹

Sickle-cell disease is a major public health concern. From 1989 through 1993, an average of 75,000 hospitalizations caused by SCD occurred in the United States, costing approximately $475 million.¹

PAIN

Pain is the most common symptom experienced by patients with SCD.^7,8 Pain profoundly impairs patients’ functioning at home and work, their social interactions, their families, and their careers. Despite the high prevalence of pain episodes, correlating with morbidity and mortality, sickle-cell anemia (SCA) pain remains underestimated and undertreated.

Frequency of pain episodes was shown to be a risk factor for early death as long as 20 years ago.⁵ The research to duplicate results continues. A recent study sought to determine the association between frequent vaso-occlusive crises (VOCs) and mortality.⁹ A cohort of 264 adult SCA patients were monitored for 12 months and followed up for 5 years. The frequency of VOCs, ED visits, and hospitalization for acute pain correlated with laboratory data indicating disease severity (hematocrit, ferritin, and HDL cholesterol). Mortality was shown to be higher in patients who required frequent ED visits/hospitalizations for pain. Pain, a subjective experience, similar to the objective findings of higher tricuspid regurgitation, elevated ferritin, and lower glomerular filtration rate, was shown to be a marker predictive of early mortality. The authors concluded that in the contemporary setting, severe painful VOC is a marker for SCA disease severity and premature mortality. The authors suggested that frequency and severity of pain is a prognostic indicator that could identify high-risk patients for disease-modifying therapies.⁹

SICKLE-CELL DISEASE AND HEALTH CARE PROVIDERS

The complex cluster of symptoms and potential for life-threatening complications of SCD, as well as instability of the clinical manifestations, indicate the need for specialized centers to educate, prevent, diagnose, and treat life-threatening complications and pain. Historically, health care provided to patients with SCD was considered to be the responsibility of SCD centers; however, few patients have access to SCD specialists. Both children and adults have limited access to experts in SCD.¹⁰ In a study of children enrolled in Medicaid programs in four states in 1989 through 1992, only 36% of those with SCD had equal to or more than one visit with a subspecialist in a given year.¹¹

Limited access to specialized care brings SCD patients to EDs and general medicine clinics, which introduce them to HCPs who may have limited experience and expertise in SCD. Limited experience of nonspecialists and lack of updated guidelines permit wide variations in attitudes toward SCD patients that can result in delays in treatments and unnecessary suffering.

Distrust between SCA patients with pain and HCPs has been described extensively. Patients have reported that HCPs are at times insensitive and often do not understand or believe the patient’s self-reports of pain.¹² Patients with SCD see the mistrust as a barrier and often avoid health care visits and end up in the ED only after their pain becomes unbearable and they are in crisis.^13,14

In addition, some HCPs lack the skills, training, and preparation to accurately assess and manage SCD-related pain.^14,15 Limited knowledge of the principles and appropriateness of opioid therapy; a lack of evidence-based research on pain control; and misconceptions and prejudices about drug abuse and addiction contribute to this educational void. In a recent review, only 21% of medical textbooks presented treatment regimens that were consistent with available guidelines.¹⁶ Treatment with hydroxyurea to decrease the frequency of VOCs is defined completely in 2 of 19 textbooks.¹⁶ Not surprisingly, this lack of education about hydroxyurea translates into a staggering deficiency of its use: It is estimated that 30% or less of eligible patients are treated with hydroxyurea, a disease-modifying therapy for SCD.³ Thus, most medical texts provided no adequate information for the treatment or prevention of pain caused by VOC in SCD.¹⁶

Upon examination of patients who report severe pain and seek pain medications including opioids, HCPs and hospital administrators may suspect “high utilizers of the ED” and stigmatize “high utilizers” as opioid seeking. To understand and address these suspicions, “low utilizers” were compared with “high utilizers” in a multicenter trial.¹⁶ The authors compared demographics, pain characteristics, health data, psychosocial characteristics, and quality of life of patients who are “high utilizers of the ED” with other SCD patients. Eighty-two (35.5%) of 232 patients were found to be high ED utilizers. Clinically important and statistically significant differences between high ED utilizers and other SCD patients demonstrated that ED visits were legitimately associated with significant anemia, transfusions, pain days, frequency of pain crises, higher mean pain and distress, and worse quality of life on Medical Outcome Study 36 Item Short Form physical function summary scales. A striking outcome of the study was that after controlling for severity and frequency of pain, high ED utilizers did not use opioids more frequently than other SCD patients. The conclusion of the study was in favor of patients: Patients who presented to an ED more frequently were more severely ill, had more pain, and had a lower quality of life.¹⁶

Based on prior studies, we know that mortality correlates with frequency of pain crises: 50% of adult patients with more than three VOCs per year survive to 40 years of age, whereas patients with less than one VOC per year have a 50% chance of survival to 55 years of age.⁴

Data have been available for years but have not yet translated into change of behavior. Pervasive delays in administration of analgesics to SCD patients in EDs have been demonstrated recently in a prospective, multisite longitudinal cohort study performed in three midwestern EDs.¹⁷ Three sites formed a multidisciplinary team charged with improving analgesic management for patients with SCD, and each site developed a nurse-initiated analgesic protocol for SCD patients. Despite clinicians’ dedication and interest in the problem, the median time to initial analgesic for the cohort in the study was 74 minutes (IQR = 48–135 min). Even in this group of patients, delay in the initial analgesia was from three-fourths of an hour to more than 2 hours. Differences between choice of analgesic agent and route selected were evident between sites. For the cohort, 680 initial analgesic doses were given (morphine sulfate, 42%; hydromorphone, 46%; meperidine, 4%; morphine sulfate and ibuprofen or ketorolac, 7%) using the following routes: oral (2%), intravenous (IV) (67%), subcutaneous (SC) (3%), and intramuscular (IM) (28%). Patient satisfaction with pain was suboptimal. The patients in this study desired their level of pain to be at or below 4 points on 0 to 10 pain scale; however, they were discharged with a pain level of 6.

Without widely accepted treatment protocols, pain management in an ED remains a function of attitudes and experiences of HCPs that have been shown to be handicapped with stereotyping and misperceptions.¹⁸ National guidelines are necessary to empower the staff and hospital administration to provide sufficient resources, including trained staff, medications, and access to the SCD expert. National guidelines are needed to break the barriers and ensure comprehensive pain assessment and timely treatment of patients with SCD pain in EDs. Without such guidelines, despite knowledge obtained in research, pervasive delay in pain treatment remains a barrier.

Components of the management of SCD include prevention and treatment of complications, as well as the potential cure for the disease. Most interventions do not lead to cure but are palliative, only aimed at harm reduction and improving quality of life in patients with significantly shortened life and high morbidity.

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  Prevention of complications. Primary prevention of the acute complications of SCD includes routine health management with a hematologist or an HCP with expertise in SCD. Initial prevention of complications includes penicillin prophylaxis initiated in the newborn period, appropriate immunizations, and blood transfusions for those at risk for stroke.

  
  
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  Hydroxyurea is a potent inducer of HbF with documented efficacy for both adults and children with SCA. In a randomized, double-blind, placebo-controlled study among 299 patients with three or more pain crises a year, hydroxyurea effected a significant decrease in pain crises and acute chest syndrome by increasing HbF to 20% and greater.¹⁹ Taking hydroxyurea was associated with a 40% decrease in mortality. More recently, the results were confirmed in a phase III study of hydroxyurea administered to infants for 2 years (BABY HUG), which resulted in significant benefits for pain, acute chest syndrome, hospitalizations, and transfusions.²⁰ Current reports document the benefits of hydroxyurea on reducing mortality in adults and children: patients with HbS/β-thalassemia and hydroxyurea exposure had improved 10-year overall survival (OS) compared to patients without hydroxyurea exposure (87% vs 54%), and HbSS patients receiving hydroxyurea had a 10-year OS of 100% compared to 10% in those without hydroxyurea exposure.²¹ The treatment is considered mostly safe. Concerns about long-term genotoxicity and specifically possible carcinogenicity with long-term exposure have been addressed by clinical investigators. Recent results from the HUSTLE protocol suggest minimal genotoxicity or carcinogenicity with long-term hydroxyurea exposure.²²

  
  
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  Blood transfusions are commonly used to treat worsening anemia and SCD complications. A sudden worsening of anemia due to an infection or enlarged spleen is a common reason for a blood transfusion. Blood transfusion remains the most common form of disease modification by suppression of HbS production.²³

  
  
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  In a recent Cochrane group review, prevalence of stroke in SCD patients receiving regular blood transfusions was significantly reduced. The review analyzed randomized and quasi-randomized controlled trials comparing blood transfusion as prophylaxis for stroke in persons with SCD to alternative or no treatment.²⁴ Regular blood transfusions not only reduced the risk of stroke, but stopping transfusions returned the patients to the baseline high-risk status for a stroke. The combination of hydroxyurea and phlebotomy is shown to be less effective than “standard” transfusion and chelation in preventing secondary stroke and iron overload.

  
  
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  Pain prevention. The only US Food and Drug Administration (FDA)-approved agent to prevent pain episodes in SCD is hydroxyurea to reduce sickle hemoglobin polymerization process by increasing the production of HbF.

  
  
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  Treatment of complications. A number of treatments are available for complications of SCD, such as hydration, administration of oxygen, pain medications for VOCs, and antibiotics for infection.

  
  
  
  
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     General supportive measure. Because dehydration is a trigger of VOC, hydration is the most consistent intervention listed in each SCD guideline.²⁵ Supplemental oxygen should be administered if hypoxia is determined.

     
     
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     Permanent organ damage resulting from VOC needs to be evaluated and treated by specialists.

     
     
     
     
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       – Retinal injury

       
       
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       – Strokes

       
       
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       – Acute chest syndrome

       
       
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       – Liver failure

       
       
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       – Kidney injury/insufficiency

       
       
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       – Multiple organ failure

       
       
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       – Leg ulcers (may need skin grafts)

       
       
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       – Gallstones

       
       
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       – Priapism

  
  
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  Cure. A cure for SCD is available only by means of hematopoietic stem cell transplantation (HSCT). However, HSCT is limited to individuals younger than 16 years of age because of the risk of severe toxicities and death among individuals older than 16 years of age with a human lymphocyte antigen (HLA)-matched sibling transplant. In a selected population, overall and disease-free survival following HSCT is 90% and 95%, respectively. Multicenter trials are now evaluating the safety and efficacy of unrelated HLA-matched transplantation in children and modified myeloablative programs for adults; however, the results are mixed.²⁶

Early BMT may offer the obvious advantages. However, SCA poses a challenge with prognostication: It is impossible to select the individuals with potentially severe SCA early on. Accurate predictors of future severity of SCA on case-by-case basis are lacking. The role of early transplantation for the reversible complications of SCD needs to be defined.

In addition to prognostication, other barriers to early BMT exist. In a study of availability of potential donors and families’ interest in BMT, a pediatric SCA cohort receiving chronic transfusions between July 2004 and January 2011 was analyzed.²⁷ Among 113 patients, 35% had an unaffected full sibling who could serve as a BMT donor. The families of 58% patients agreed to HLA-type sibling, 35% of whom were matched. Common reasons to decline HLA typing or transplantation included fear of the process, toxicities of the procedure, and comfort with current quality of life on transfusions. Ultimately, only 7% were eligible for matched BMT, and only 3% underwent HLA-matched transplantation. Two unmatched children received haploidentical transplantation. In this study, when a matched sibling was identified, most families declined to proceed with matched-sibling transplantation.

Other supportive medications. Corticosteroids remain a controversial modality because these agents were shown to shorten the duration of analgesia requirement but after discontinuation led to more episodes of recurrent pain.²⁸ A recent study did not support the association between discontinuing steroids and recurrent VOCs.

PAIN ASSESSMENT IN SICKLE-CELL DISEASE

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.”²⁷

Pain is the reason for up to 90% of hospital admissions in a patient with SCD.³⁰ Rate of pain is highest in patients between 19 and 39 years of age. Frequency of pain crises correlates with mortality of SCD. Pain was reported to be more severe than pain after major surgery. Typical crisis in adults lasts 10.3 days.³⁰