Sickle cell disease (SCD) refers to a related group of genetic hemoglobin disorders. Sickle hemoglobin has a single mutation resulting in the replacement of glutamine with valine at the sixth amino acid position in the beta-globin subunit. Molecules of this abnormal hemoglobin polymerize upon deoxygenation into long polymers that physically deform the erythrocyte into the characteristic sickle shape and ultimately obstruct blood flow. This polymerization largely ceases when sickle hemoglobin is combined with adult hemoglobin, so-called sickle trait, or with high levels of fetal hemoglobin, resulting in a relatively benign condition. In contrast, this polymer formation is promoted to varying degrees by the co-occurrence of sickle hemoglobin with other abnormal hemoglobins, such as hemoglobin C, D, E, or O arab , or mutations that reduce the production of normal hemoglobin (thalassemias), resulting in sickling disorders of varying degrees of severity.
The sickle mutation is believed to have arisen independently many thousands of years ago in several areas of Africa and the Middle East or Indian subcontinent. Its prevalence was maintained and expanded in these areas by reproductive advantage as sickle trait provided some degree of protection from severe malaria. Thus, most of the 100,000 to 150,000 individuals with SCD in the United States trace their ethnic origins to Africa, the Middle East, or the Mediterranean where malaria was endemic; the slave trade to the Caribbean and South America also led to the spread of the sickle mutation to many individuals of Hispanic ethnicity.
The pathophysiology of vaso-occlusive pain in SCD is quite complex ( Fig. 73.1 ) and involves mechanisms beyond sickle polymer formation, especially the adhesion of sickled erythrocytes, and perhaps other cellular elements including leucocytes and platelets, to abnormal vascular endothelium. As part of the vicious cycle of sickling, the subsequent ischemic tissue injury from initial vaso-occlusion results in the accumulation of endogenous factors released from cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively, these factors, referred to as the “inflammatory soup,” represent a wide array of signaling molecules, including neurotransmitters, peptides, eicosanoids and related lipids, neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons, which damage local nociceptive nerves leading to increased spontaneous firing that is perceived as acute pain.
Although considerable further research is needed to confirm this process, the intense and repetitive nature of vaso-occlusive events and resulting chronic tissue/bone damage likely drive the experience of chronic pain in adults with SCD ( Fig. 73.2 ) through a process termed central sensitization, which represents an activity- or use-dependent form of functional synaptic plasticity that can occur after intense repetitive noxious stimuli. Central sensitization with its augmented pain response occurs by complex processes involving changes in neurotransmitters, receptors, ion channels, and signaling pathways in spinal cord and cortical neurons that change the response elicited by normal sensory inputs, including those that usually evoke innocuous sensations, resulting in the sensation of persistent pain. Further changes in the pain experienced in chronic pain disorders occur as a result of anatomic and functional connectivity changes in various brain regions and can reverse with treatment.
Epidemiology of Vaso-Occlusive Pain
SCD is a relatively unique pain disorder, as pain can begin early in the first year of life as levels of fetal hemoglobin decline in susceptible individuals. Most children reported to have pain in the first year of life have pain locations (hands/feet) and signs/symptoms (swelling or tenderness) consistent with dactylitis, often referred to as “hand-foot syndrome,” which becomes progressively less prevalent in older children and rare after 5 to 7 years of age. Almost all children with SCD experience increasingly frequent pain throughout childhood and into adolescence and young adulthood; however, the majority of these painful episodes are managed at home rather than in acute care settings. Most episodes are relatively brief, typically 2 to 3 days, with pain of moderate intensity located in a small number of body sites, usually the lower legs, back, and chest wall. However, a small number of children transition, often in their early adolescent years, from a pattern of sporadic episodes of brief acute pain to frequent, recurrent, acute pain or chronic pain, and these individuals represent the majority of pediatric patients hospitalized for acute pain. Pain is a more complex experience in adults with SCD, with features of both acute recurrent and chronic pain, and is more often managed in an acute care setting compared to pain in children. Family characteristics and mental health issues are often comorbidities contributing to frequent health care utilization in SCD adults with chronic pain.
Other Pain Etiologies in SCD
Vaso-occlusive pain in SCD remains a clinical diagnosis as laboratory and imaging studies largely show nonspecific increases in inflammatory markers and increased hemolysis. Other pain syndromes distinct from vaso-occlusive episodes are not uncommon and always need to be considered when evaluating an individual with SCD and pain ( Table 73.1 ). Children and, occasionally, young adults can experience acute left-upper-quadrant visceral pain from rapid enlargement of the splenic capsule consistent with acute splenic sequestration, an often life-threatening trapping of sickled erythrocytes and platelets in the spleen. Almost all children with SCD will experience episodic right-upper-quadrant colicky abdominal pain and jaundice from cholelithiasis or bile duct obstruction and ultimately require cholecystectomy, as chronic hemolysis results in bilirubin accumulation in the gallbladder and the subsequent production of pigment stones. Avascular necrosis in the vertebral column, shoulder, or hips can be a source of acute pain as well as chronic pain in adolescent and young adult patients, who often respond to physical therapy for initial symptom management of hip pain; some patients, however, 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 functioning. Although 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 and are difficult to manage. Headaches, as an isolated pain syndrome or as part of a vaso-occlusive event, can occur but are not well characterized. Some have features characteristic of migraine headaches, others may be more typical of tension-type headaches, and a small number of individuals satisfy current diagnostic criteria for chronic daily headache. Use of the triptan class of medications to treat migraine-like headaches in SCD individuals is contraindicated because of cardiovascular concerns.
| Pain Syndrome | Typical Locations | Pain Characteristics |
|---|---|---|
| Acute splenic sequestration | Spleen | Acute visceral pain related to stretch of splenic capsule from splenic enlargement |
| Splenic infarction | Spleen | Acute visceral pain from splenic infarction involving splenic tissue extending to splenic capsule |
| Acute bone infarction | Ribs, sternum, or long bones | Acute pain from necrosis of bone marrow |
| Avascular necrosis | Hips, shoulders, or vertebrae | Acute and chronic pain from progressive collapse of bone cortex related to persistent vascular compromise |
| Osteomyelitis | Any bone | Acute and chronic pain from bacterial infection of bone cortex or marrow, often related to chronic ischemia |
| Acute cholelithiasis | Gallbladder | Acute visceral pain from irritation or common bile duct obstruction by pigment gallstones |
| Leg ulcers | Medial or lateral ankles | Acute and chronic pain from ischemic damage to skin and underlying soft tissue |
| Headache | Head | Acute or chronic headache pain with or without migrainous aura or characteristics |
Other Pain Etiologies in SCD
Vaso-occlusive pain in SCD remains a clinical diagnosis as laboratory and imaging studies largely show nonspecific increases in inflammatory markers and increased hemolysis. Other pain syndromes distinct from vaso-occlusive episodes are not uncommon and always need to be considered when evaluating an individual with SCD and pain ( Table 73.1 ). Children and, occasionally, young adults can experience acute left-upper-quadrant visceral pain from rapid enlargement of the splenic capsule consistent with acute splenic sequestration, an often life-threatening trapping of sickled erythrocytes and platelets in the spleen. Almost all children with SCD will experience episodic right-upper-quadrant colicky abdominal pain and jaundice from cholelithiasis or bile duct obstruction and ultimately require cholecystectomy, as chronic hemolysis results in bilirubin accumulation in the gallbladder and the subsequent production of pigment stones. Avascular necrosis in the vertebral column, shoulder, or hips can be a source of acute pain as well as chronic pain in adolescent and young adult patients, who often respond to physical therapy for initial symptom management of hip pain; some patients, however, 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 functioning. Although 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 and are difficult to manage. Headaches, as an isolated pain syndrome or as part of a vaso-occlusive event, can occur but are not well characterized. Some have features characteristic of migraine headaches, others may be more typical of tension-type headaches, and a small number of individuals satisfy current diagnostic criteria for chronic daily headache. Use of the triptan class of medications to treat migraine-like headaches in SCD individuals is contraindicated because of cardiovascular concerns.
| Pain Syndrome | Typical Locations | Pain Characteristics |
|---|---|---|
| Acute splenic sequestration | Spleen | Acute visceral pain related to stretch of splenic capsule from splenic enlargement |
| Splenic infarction | Spleen | Acute visceral pain from splenic infarction involving splenic tissue extending to splenic capsule |
| Acute bone infarction | Ribs, sternum, or long bones | Acute pain from necrosis of bone marrow |
| Avascular necrosis | Hips, shoulders, or vertebrae | Acute and chronic pain from progressive collapse of bone cortex related to persistent vascular compromise |
| Osteomyelitis | Any bone | Acute and chronic pain from bacterial infection of bone cortex or marrow, often related to chronic ischemia |
| Acute cholelithiasis | Gallbladder | Acute visceral pain from irritation or common bile duct obstruction by pigment gallstones |
| Leg ulcers | Medial or lateral ankles | Acute and chronic pain from ischemic damage to skin and underlying soft tissue |
| Headache | Head | Acute or chronic headache pain with or without migrainous aura or characteristics |
SCD Pain Management
Education is the Foundation
A lifespan approach is most applicable for these sickling disorders, as pain will likely be experienced throughout childhood and adult life. A focus on the family is essential for children, whereas adolescents must be encouraged and supported to accept progressively more responsibility for their own pain management so that they can function appropriately in the adult health care system. Thus, initial disease and pain management education involves parents and other caregivers for young children and broadens to include the school system in older children; finally, organized transition programs starting in early adolescence focus on self-management skill education. Self-management skill development should include learning psychological approaches to pain management, similar to other pediatric chronic pain disorders for which one meta-analysis indicated the superiority of cognitive-behavioral interventions (multicomponent, relaxation, and biofeedback approaches) for pain management.
Home Management: “it takes a Village”
A number of studies in children and adults suggest the preference to manage vaso-occlusive pain at home. The home setting is likely to be more comfortable for children and less disruptive to the families’ normal activities and routines. Surprising to most health care providers, many SCD individuals avoid care in acute care settings, as they frequently encounter negative attitudes toward patients with SCD and a pervasive fear among health care providers of catering to opioid addiction, which often compromises analgesic therapy. Successful home management requires a parent or other caregiver skilled in pain assessment and administration of appropriate analgesic medications. Extended family also is critical for psychological and physical support, as most pain episodes may last for several days and usually require around-the-clock medication for adequate management. Support by trusted medical health professionals with experience in SCD and pain management also facilitates home management and appropriate emergency department utilization. Clergy and local complementary and alternative medicine practitioners and mental health professionals also can facilitate the use of both medical and psychological interventions to assist with the management of pain symptoms. Several studies of caregivers of children with SCD have found that a large percentage of families use prayer, spiritual healing, massage, and relaxation in addition to medication to manage their child’s pain at home. In both studies, complementary medicine approaches were used more frequently with higher levels of pain or medication use.
Low-potency analgesics, such as acetaminophen and ibuprofen, are recommended as initial therapy at the onset of typical vaso-occlusive pain and are often adequate for mild to moderate pain, particularly in younger children. These analgesics are often chosen out of concern for the adverse consequences of opioid analgesics and have the advantage of less sedation and subsequent disruption of age-appropriate activities. A substantial number of oral hydrocodone and oxycodone analgesics of varying potency, often in combination with acetaminophen, are available in liquid and tablet formulations for management of more intense pain in children with SCD. There has been some shift away from the use of codeine containing analgesics because of pharmacogenetic issues of excessive toxicity or inadequate efficacy. Although labeled dose amounts and frequency of potent oral opioid analgesics are usually prescribed, the enhanced hepatic and renal clearance of morphine in this population and the potential impact of prevalent pharmacogenetic genotypes impacting morphine metabolism suggests that the dose and frequency of these opioids may need to be further individualized.
There have been few comparative studies of adjunctive nonopioid analgesic medications in this population. A study using pharmacy claims data suggested that pharmacologic treatments for sickle pain consisted mainly of nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids. Significantly more severe SCD patients, those with more than three yearly inpatient or emergency department (ED) visits for pain management, were prescribed more potent opioids, antidepressants, or anticonvulsants. Prescription of both stronger opioids and antidepressants or anticonvulsants was significantly associated with lower frequencies of acute sickle pain visits. Further clinical trial data are needed in SCD individuals to support these observations and to establish comparative efficacy and safety data for various analgesic and anticonvulsant or antidepressant combinations, particularly as many of these classes of medications are not currently labeled for use in pediatric age groups.
Management of SCD Pain in the Acute Care Setting
Authoritative guidelines have been published for the management of severe SCD pain in the acute care setting, but they are somewhat outdated. However, a number of pediatric hospitals have published more contemporary single site pain management practices, and an update of the National Institutes of Health’s Sickle Cell Treatment Guidelines will be available in 2013. Nurse-initiated ED analgesic protocols for adults with SCD also have been developed and their implementation has been shown to improve pain relief over the period of ED treatment.
Intravenous doses of potent opioids, usually morphine or hydromorphone, are the typical initial treatment for vaso-occlusive pain in both adults and children, as all are assumed to have failed a course of oral analgesics at home prior to arrival in the ED. In some pediatric centers, intravenous nalbuphine is also used, as it is often associated with fewer complaints of nausea and pruritis, but it is seldom used for SCD adults because it may precipitate opioid withdrawal symptoms in opioid tolerant individuals. The use of oral and subcutaneous routes of opioid administration is increasing in adults with limited intravenous access. Administration of opioids by patient-controlled analgesia (PCA) devices is not a common practice in the ED, but where available it allows more frequent dosing, which can be problematic in a busy ED. The concurrent use of a parenteral NSAID, usually ketorolac, is a widespread clinical practice in the ED setting as an additional analgesic, and it may have additional benefit as an anti-inflammatory agent given the increased evidence for the role of inflammation in SCD pathophysiology. Parenteral NSAID doses administered to SCD adults are often reduced for renal insufficiency, which is not uncommon.
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