Sickle cell anemia is a progressive hemoglobinopathy producing chronic hemolytic anemia, microvascular thrombosis, ischemic pain, tissue infarction, decreased quality of life, and ultimately shortened life expectancy. In sickle cell anemia, valine is substituted for glutamic acid in the sixth amino acid of the β-globin chain. In a person who is homozygous, all hemoglobin is of the abnormal HbS type, and repeated episodes of sickling result in a less malleable molecule even at sites of normal atmospheric pressures of oxygen. The hemoglobin variant HbS gene is found throughout Africa, Asia, the Caribbean, the Middle East, and southern Europe. The pain experienced during a sickle cell crisis is the product of sickled, less malleable red blood cells adhering to the vascular endothelium, plugging arterioles and capillaries and ultimately leading to occlusion and infarction. Nociceptive fibers are stimulated in response to tissue irritation or injury; they can be classified into type A δ fibers, which are thinly myelinated and allow fast conduction, and the unmyelinated and more slowly conducting type C. Hypoxia, acidosis, and the release of chemical mediators of inflammation, such as potassium, adenosine triphosphate, bradykinin, prostaglandins, and substance P, activate and/ or sensitize nociceptors. When tissue injury first occurs, the acute pain, which lasts several days to several weeks, is characterized by sympathetic, somatic, and endocrine adaptations along with fluctuations in intensity. If the pain becomes chronic, ie, persisting longer than 3 to 6 months, facilitation of pain pathways could occur, resulting in a heightened response to a variety of painful stimuli. Chronic pain is typically accompanied by vegetative signs (sleep disturbance, decreased appetite, weight loss, and diminished libido) and subsequent psychological malady with few identifiable autonomic changes. The vasoocclusive crisis of sickle cell anemia has been described as progressing through 4 distinct phases: (1) prodrome: symptoms of numbness, aches, and parasthesias that develop in areas subsequently affected by pain and that last up to 2 days, (2) initial infarct: crisis pain that increases gradually and peaks by the second or third day, (3) postinfarct: persistent and severe pain with signs and symptoms of inflammation, and (4) resolution: gradual remission of pain. Nevertheless, much variability remains in the frequency and intensity of painful crises, ranging from painful episodes that readily respond to conservative treatment to chronic persistent pain with acute exacerbations. The initial management of a sickle cell crisis should be aimed at providing rapid pain control. Once the pain is controlled, treatment guidelines recommend addressing underlying complications, including infection and severe anemia; providing adequate hydration; administering supplemental oxygen; and employing narcotic analgesics for pain relief. Both the American Academy of Pain Medicine and the American Pain Society promote the use of opioid analgesics for the treatment of moderate to severe sickle cell pain. For sickle cell pain that does not respond to nonopioid analgesics, they endorse the administration of sustained-release opiate preparations, such as morphine sulfate controlled-release tablets, which provide convenient and consistent analgesia. Pain relief also can be effectively achieved with the patient-controlled analgesia system.