Pain Management Dilemmas of Sickle Cell Disease
Sickle cell disease is a genetic blood disorder involving mutations of the β-globin gene that is seen primarily in the African American population. In patients with sickle cell disease, the molecules of mutated hemoglobin (HbSS) have a propensity to accumulate and coalesce when starved of oxygen. This accumulation in the red blood cell causes the cell to elongate and stiffen, developing into the sickle or crescent shape that is characteristically seen on a blood smear.
These changes can lead to occlusion of the microvasculature and cause subsequent disruption of blood circulation, which may lead to transient ischemia of the affected tissues.1 The knees, shins, low back, hips, arms, and thighs are the most common locations of recurrent acute pain in sickle cell disease (see Figure 1).2
Although the exact cause of the pain is not fully understood, it is suggested that the ischemia caused by the vaso-occlusion in sickle cell disease triggers a release of inflammatory mediators, which then activate afferent nerve fibers in the surrounding tissue.3
The association between sickle cell disease and pain goes back hundreds of years to before the birth of modern medicine. In early literature describing the discovery of the disease, the author noted that ancient African tribal words for the disease were found to be onomatopoeic for pain.4 Centuries later, acute painful episodes remain the most common reason for hospital visits in patients with sickle cell disease.5 This review aims to assess the wide range of problems that are faced in attempts to effectively manage pain in sickle cell disease.
Underestimating Sickle Cell Pain
As noted, pain due to vaso-occlusion is the primary reason for patients with sickle cell disease to seek medical attention. However, what many healthcare professionals do not realize is that the majority of pain episodes are actually self-managed at home by patients.6 According to PiSCES (Pain in Sickle Cell Epidemiology Study), in which 232 adults with sickle cell disease completed daily pain diary logs, home management of pain episodes constituted 13% of the total days, whereas use of healthcare facilities constituted less than 4% of the total days (see Figure 2).5
Contrary to the findings of previous studies, such as CSSCD (Cooperative Study of Sickle Cell Disease), which judged the amount and severity of pain episodes strictly on the number of healthcare utilizations a patient employed, it is now becoming clearer that the majority of pain episodes are unseen by medical professionals.7 This newly discovered phenomenon has been described in recent studies as the “iceberg phenomenon” because most of the pain of sickle cell disease is “submerged” at home and away from the healthcare setting, while only a small fraction of the pain, or the “tip of the iceberg,” is actually communicated to the physician.8
In fact, it can be presumed that the reason most patients utilize healthcare facilities is that their pain exceeds that which can be effectively managed at home. This raises the concern of whether physicians are underestimating patients’ pain and therefore underprescribing appropriate analgesics to patients with sickle cell disease in the ambulatory setting for home management of their pain.
Currently, there are recommended step-wise approaches in place for the use of analgesics in managing sickle cell pain in the home, emergency department (ED), and inpatient setting, respectively. At home, it is recommended that patients be started on nonopioid analgesics (eg, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs], or aspirin) for mild pain. As the severity of the pain increases, opioids (eg, codeine, tramadol [Ultram]) are added along with adjuvant therapies as needed. When the pain becomes severe, the patient may then be started on continuous opioid therapy (eg, morphine, fentanyl).9
In the ED, patients are treated promptly with a reasonable starting dose of opioids (eg, morphine, hydromorphone), which is based on both the treating physician’s clinical assessment of the pain intensity and knowledge of the dosage given in prior pain episodes.8 Finally, for the inpatient treatment of sickle cell pain, successful management is usually achieved with scheduled dosing of opioids (eg, morphine, hydromorphone), typically given every 2 to 3 hours.
In addition, there are usually specific orders written for breakthrough pain, which can be defined as transient pain that occurs while a patient is on opioid therapy.8 In cases when there is a failure to adequately control the patient’s pain in this manner, management can be shifted to continuous opioid infusion, either via a continual drip or patient-controlled analgesia.
However, these methods of management are not always followed “by the book.” There are numerous variations from practice to practice because of the wide range of analgesics available, differing routes of administration and dosing schedules, and patient suitability and susceptibility to treatments with different therapies.10
The various analgesics that are used in sickle cell disease are often associated with their own sets of limitations and drawbacks, which makes it very difficult to establish a protocol for effective pharmacologic pain management. For example, patients with sickle cell disease have an increased risk for acute renal failure because of the compromise of blood flow to the kidneys as a result of vaso-occlusion. This susceptibility can be exacerbated by the use of NSAIDs, which are one of the first lines of home therapy for pain in patients with sickle cell disease.11 It is therefore recommended that NSAIDs be used on a case-by-case basis and renal function closely monitored for patients who are taking those agents.12
Corticosteroids also have been used in the management of sickle cell pain. It was thought that steroids could help to suppress the multiple inflammatory mediators that are elevated in patients with vaso-occlusive crisis.13 Evidence-based retrospective data have shown that although patients had a significant (approximately 50%) reduction in hospital stay with adjunctive steroid therapy, there were overwhelming reports of rebound pain that caused almost one-fourth of patients to be readmitted within a week of discharge.14 Therefore, the use of systemic corticosteroids for pain management of sickle cell disease is not recommended at this time.12