Pain Management in Sickle Cell Disease

Jatinder Gill

Pain is not just a symptom demanding our compassion; it can be an aggressive disease that damages the nervous system.

—Gary Bennett

Sickle cell disease is an inherited hemoglobinopathy primarily affecting individuals descended from inhabitants of equatorial Africa and of areas around the Mediterranean Sea, in Saudi Arabia, and in some parts of India. It is a debilitating chronic multisystem disease with variable phenotypic expression. Acute pain is often the first symptom of sickle cell disease and the most common reason that patients seek medical attention.

One third of the patients experience a benign course, one third have two to six hospital admissions for pain per year, and one third have more than six pain-related hospitalizations per year. Hospital personnel often develop a bias about the genuineness of the painful crises in the third group of patients, especially because pain is a subjective sensation. It is, however, this group that is most in need of medical help. The extreme variability in severity of the clinical phenotype of sickle cell disease remains unexplained and probably relates to genetic, microvascular, rheologic, and hematologic factors.

I. PATHOPHYSIOLOGY

Hemoglobin S (HbS) has a tendency to polymerize when deoxygenated, but the polymerized form rapidly reverts with oxygenation. Repeated cycles of polymerization cause oxidative damage to red cell membranes and lead to irreversibly sickled cells, adhesion of the cells to the endothelium of the vessel, and vascular occlusion. The resultant hypoxia causes further sickling and starts a vicious cycle, leading to tissue infarction and pain. Increased intramedullary pressure secondary to inflammation and necrosis within the bone is an important cause of the pain. Sickling seems to correlate directly with high hemoglobin levels and neutrophil counts and indirectly with fetal hemoglobin (HbF) values.

II. CLINICAL FEATURES AND CONTEMPORARY MANAGEMENT

Sickle cell disease is a multisystem disease. Infants and children are at risk for overwhelming infection from encapsulated bacteria such as pneumococcus. The function of the spleen is impaired, thus depressing immune response. Penicillin prophylaxis, vaccination, and a high index of suspicion are advocated. Meningitis, bacterial pneumonias, cholecystitis, and osteomyelitis are common in adults.

Patients with sickle cell disease are chronically anemic, and profound anemia may occur in the presence of splenic sequestration, exaggerated hemolysis, or aplastic crisis, and may require transfusion. Folic acid supplementation is required to support high turnover rates of bone marrow cells.

Neurologic complications caused by cerebrovascular occlusion occur in up to 25% of patients. Monthly transfusion programs are recommended for children to prevent recurrent strokes. Primary prevention using magnetic resonance imaging (MRI) and transcranial Doppler screening, and initiation of transfusion programs for at-risk patients are recommended.

These patients often have restrictive lung disease, hypoxemia, and pulmonary hypertension, probably secondary to earlier pulmonary occlusions and infarctions. They are at risk for acute chest syndrome, with infection usually caused by atypical agents. Acute chest syndrome has a high mortality rate and requires treatment in the intensive care unit (ICU) setting. A high index of suspicion is required in patients presenting with chest pain and fever, especially in the presence of hypoxemia.

Hepatobiliary complications are common, with up to 70% of patients demonstrating gallstones. Many patients eventually need a cholecystectomy. Hepatic dysfunction may relate to transfusion-associated iron overload or infection. Hyperbilirubinemia secondary to benign cholestasis (no fever or pain) should be differentiated from hepatic crisis that presents with fever, pain, abnormal liver function tests, and hepatic failure.

Poor medullary flow in the kidneys leads to papillary infarctions, hematuria, and renal tubular acidosis. In addition, patients may develop glomerular dysfunction. Proximal tubular dysfunction may lead to hyperuricemia, especially with heavy analgesic use. Some patients eventually develop chronic renal failure.

Proliferative sickle cell retinopathy with the potential of bleeding, leading to blindness, should be treated with laser photocoagulation. Occlusion of the central retinal artery requires immediate transfusion.

Priapism develops in many individuals and, if prolonged, may lead to impotence. If a patient responds poorly to conservative treatment for 12 hours, exchange transfusions, corporal aspiration, use of α-adrenergic agents, and even surgical creation of a fistula may be required to prevent impotence. Hormonal or vasoconstrictive preventive therapy may be needed.

Osteonecrosis may occur, leading to vertebral fractures or necrosis of femoral head, and can be acutely painful. Major reconstructive surgery may be required in patients with advanced
disease of the joints who fail to rehabilitate. Bone marrow infarction can be differentiated from osteomyelitis by scans. Arthritis may result from periarticular infarction or from gout. Nonsteriodal antiinflammatory drugs (NSAIDs) are useful adjuncts in patients with bone pains.

Chronic bilateral leg ulcers are common over the shins. In addition to causing chronic pain, these ulcers also may lead to osteomyelitis and septicemia. Subdermal vascular occlusions can cause chronic myofascial pain.

The mean life expectancy in sickle cell disease is approximately 42 years in men and approximately 48 years in women. Patients with severe disease and multiple crises tend to have a shorter life span.

III. ACUTE PAIN CRISIS

Despite the multiple problems associated with sickle cell disease, the most common reason for these patients to be hospitalized is for an acute pain crisis requiring aggressive inpatient management. The usual precipitants are exposure to cold, dehydration, alcohol intake, infections, stress, and menstruation. In more than half the cases, there is no clear cause.

Approximately 5% of patients account for one third of hospital admissions, and, regrettably, caregiver hostility toward this group of patients is common. It is important to remember that these are the patients who tend to die young, and hence pain is a direct marker for mortality. The incidence of pain is highest in young male adults.

Pain typically affects one region of the body. Common sites of pain include the back, bilateral large joints, chest, sternum, ribs, and the abdomen. In children, the smaller joints of the hand and feet may be involved. Fever is present in about half the patients. Patients usually are able to tell whether a new crisis feels like a typical crisis or not.

The etiology of the pain is probably related to ischemia of the tissue undergoing infarction and an increase in intramedullary pressure due to inflammation. The pain in sickle cell disease is often described as excruciating, commonly rating more than nine on the visual analog scale. The importance of ruling out any catastrophic events requires maintaining a high degree of suspicion for acute chest syndrome in a patient with acute chest pain, for osteomyelitis or septic arthritis in a patient with bone or joint pain, or for acute abdomen in a patient with abdominal pain. Furthermore, a work-up may be needed on the basis of the index of suspicion, for example, chest films in a patient with dyspnea and with chest pain or diagnostic aspiration of an acutely tender joint. A good history and a physical examination, together with a review of previous admissions, are indispensable.

1. Management of Mild Vasoocclusive Crisis

Old admission records, previous treatments, complications of the disease, and baseline pain medications are very helpful in directing the treatment. Once it has been established that the patient does not require emergent investigation or intervention, aggressive hydration and pain treatment should be instituted.
Pain treatment should not be withheld during this initial phase. Fluids may be taken by mouth or given intravenously. Opioid medication may be given by mouth if tolerated, but the intravenous (IV) route is usually preferable, at least in the initial period. For oral use, oxycodone, hydromorphone, or morphine are good choices. NSAIDs are useful for bone pain and should be used if no contraindications exist. With NSAIDs, a fixed-dose regimen is preferable to an as-needed regime.

If the patient can be stabilized he or she may be discharged home with a tapering supply of oral opioids. Failure to adequately manage pain is likely to result in readmission; therefore, it is important that the patient be provided with an adequate supply of analgesics. If the pain does not diminish or if the patient has other symptoms such as fever or severe nausea, a longer hospital stay may be required.

2. Hospital Management of Painful Sickle Cell Crisis

(i) Opioids

The pain experienced during a sickle cell crisis is described as excruciating, and opioids are often the first-line treatment. There is no benefit to first trying alternative analgesics in the acute stage. Adjuncts may, however, be used simultaneously.

The care team must take a patient’s reports of pain seriously and must administer medications in a timely manner. Doing so encourages the patient to trust the care team, and also prevents undue suffering.

a) Route Of Administration.

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