In the United States, an estimated 100,000 people are afflicted by sickle cell disease and 2,000 infants are born with sickle cell disease annually [1,2]. Sickle cell disease is predominantly found in persons of African descent; other groups with heightened risk include those of South or Central American, Caribbean, Mediterranean, Indian, and Saudi Arabian descent (typically areas in which malaria is endemic) [2,3]. The condition is chronic and lifelong and is associated with a decreased lifespan. Median survival in the United States is 42 years for men and 48 years for women, although innovations in disease management are improving long-term survival [4].

Pain is the primary reason that medical care is sought by persons with sickle cell disease, usually during an acute pain crisis. Acute pain crises are commonly triggered by dehydration, infection, stress, and changes in body temperature and unfold in four distinct phases [1]:

Pain is the primary reason that medical care is sought by persons with sickle cell disease, usually during an acute pain crisis. Acute pain crises are commonly triggered by dehydration, infection, stress, and changes in body temperature and unfold in four distinct phases [1]:

A single nucleotide mutation is the underlying basis of sickle cell disease. It involves alteration of the glutamate for valine in the sixth position of the beta-globin protein, which predisposes hemoglobin to polymerize when deoxygenated, causing red blood cells to assume the characteristic sickle shape. This red blood cell deoxygenation and sickling accounts for sickle cell disease characteristics of anemia, hemolysis, and acute and chronic complications from vascular occlusion that affect multiple organs [7]. The deformed red blood cells tend to clump together to increase blood viscosity, leading to microvascular blockage and ischemia. Pain during an acute crisis is due to ischemic occlusion of the microcirculation from red blood cell aggregation and resultant decreased blood flow to distal tissues. The most common cause of recurrent pain episodes is vaso-occlusion of the microcirculation and destruction of bones, joints, and visceral organs [8]. Chronic pain can occur from complications of sickle cell disease such as avascular necrosis or ankle ulcers superimposed on acute sickle cell pain. Additionally, frequent episodes of acute pain in sickle cell disease can resemble chronic pain [8].

The most common chronic pain syndromes in sickle cell disease include [2]:

No single treatment is effective for all people with sickle cell disease; instead, appropriate treatment options are determined according to symptom severity [2]. Nonpharmacologic prevention includes avoiding dehydration, extreme temperatures, high altitudes (including flying), and low oxygen levels from intense exercise or athletic training [2,9].

For prevention of acute pain episodes, hydroxyurea is most often used [3]. This agent acts by ribonucleotide inhibition and induction of fetal hemoglobin, which possesses superior affinity for oxygen binding. It is FDA-approved for use in adults and children 2 years of age and older and is the only treatment for sickle cell disease that modifies the disease process. Hydroxyurea is effective in reducing pain crises, painful symptoms, need for blood transfusion, and mortality. As such, it represents the backbone of sickle cell disease management. The usual daily oral dose is 15–35 mg/kg [3,10]. Inconsistent adherence reduces its efficacy, and patient adherence can be challenged by the three- to six-month delay between treatment initiation and the onset of clinical response. More frequent follow-up contact with support and encouragement may be needed in some patients.

For prevention of acute pain episodes, hydroxyurea is most often used [3]. This agent acts by ribonucleotide inhibition and induction of fetal hemoglobin, which possesses superior affinity for oxygen binding. It is FDA-approved for use in adults and children 2 years of age and older and is the only treatment for sickle cell disease that modifies the disease process. Hydroxyurea is effective in reducing pain crises, painful symptoms, need for blood transfusion, and mortality. As such, it represents the backbone of sickle cell disease management. The usual daily oral dose is 15–35 mg/kg [3,10]. Inconsistent adherence reduces its efficacy, and patient adherence can be challenged by the three- to six-month delay between treatment initiation and the onset of clinical response. More frequent follow-up contact with support and encouragement may be needed in some patients.

Management of acute pain episodes may include intravenous fluids, pain-reducing medication or hospitalization (for severe pain crises). Management typically requires stronger analgesic agents, with codeine and tramadol useful for moderate pain and morphine, oxycodone, hydrocodone, and hydromorphone more effective in treating severe and breakthrough pain [2]. For first-time opioid therapy for severe pain, the use of morphine sulfate or hydromorphone is favored. With recurrent pain, the best initial choice of opioid and dose for severe sickle cell pain is that which previously provided adequate analgesia. Intravenous administration is recommended in severe pain. Patients and clinicians may prefer a 5–10 mg loading dose of parenteral morphine or equivalent [2].

For chronic pain associated with sickle cell disease, long-acting and short-acting opioids, NSAIDs and acetaminophen, and adjuvant medications form the basis of long-term management [1]. Aspirin should be avoided due to the risk of Reye syndrome. Codeine, low-dose oxycodone, or low-dose hydrocodone are preferred for treatment of moderate chronic pain.