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13 Articles in Volume 11, Issue #5
Case Study: Patient With Fibromyalgia And Sleep Apnea
Current Treatments for Phantom Limb Pain
Doctor Shopping
Effective Protocol for the Management of Plantar Fasciitis
Giving Severe and Chronic Pain a Name: Maldynia
Is the New Pain Vocabulary Helping Patient Care?
Medications for Chronic Pain—Other Agents
New Technique Combines Electrical Currents and Local Anesthetic for Pain Management
Pain Management Dilemmas of Sickle Cell Disease
Sleep Apnea in Patients With Fibromyalgia: A Growing Concern
The Essential FDA/PDR Indications and Warnings For Opioid Prescribing
The Role of the Clinician In Determining Disability and Pain
Why Does Acute Postoperative Pain Become Chronic and Can It Be Prevented?

Pain Management Dilemmas of Sickle Cell Disease

Pain remains a significant problem among patients with sickle cell anemia. Many patients treat their symptoms with over-the-counter agents at home, thus creating an underreported and potentially undertreated disorder.

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.

Analgesic Management

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

Similarly, opioid therapy for the management of sickle cell pain has its own set of concerns. The risk for respiratory depression caused by the sedating effect of opioids can actually put patients with sickle cell pain at an increased risk for acquiring acute chest syndrome—a life-threatening pulmonary complication commonly seen in sickle cell disease.15 In addition, the potential for opioid dependence and hyperalgesia is a growing concern in the use of these drugs for the management of sickle cell–induced pain.7 As noted, the use of analgesics in sickle cell disease is often a double-edged sword. Therefore, the management of a patient’s pain must be carefully tailored to the individual by weighing the potential risks and benefits of each pharmacologic intervention before initiating therapy.

Acute Versus Chronic Pain

Traditionally, sickle cell pain was considered to be an acute exacerbation caused by vaso-occlusive triggers. However, new epidemiologic findings are supporting the theory that chronic manifestations of sickle cell pain may additionally be present.7 Acute pain in sickle cell disease is a direct result of tissue injury caused by vaso-occlusive events and subsequent hypoxia, producing nociceptive pain through signals in the surrounding primary afferent nociceptors.

The mechanism of chronic pain, however, is not as easy to elucidate.3 The theory is twofold. First, it is believed that repeated nociceptive activation from acute sickle cell pain can cause neuronal damage and ultimately lead to the remodeling of neurons, a term known as neuroplasticity. Second, the repeated administration of opioids can cause opioid-induced hyperalgesia. The mechanism, although poorly understood, involves central sensitization, which causes a patient’s pain level to be elevated in parallel to the strength of the opioid dose.5

Statistical studies have shown that early in life, pain is primarily nociceptive in nature.7 However, as time progresses and the patient experiences repetitive painful stimuli, the patient’s verbal pain quality descriptors begin to shift and become more consistent with neuropathic pain. Examples of such descriptors include burning, tingling, shooting, and numbness.3

Could this mean that by effectively controlling acute nociceptive pain early in life, one could avoid the future progression to chronic neuropathic pain? Such studies have not yet been conducted. However, as previously mentioned, long-term opioid administration can also lead to chronic neuropathic pain in the form of opioid-induced hyperalgesia. Therefore, clinicians are often forced to pick a poison, so to speak. There remains the risk for progression to chronic pain in patients with sickle cell disease, whether or not their acute pain is effectively managed.

Healthcare Provider Bias

One of the most common reasons for delays in the treatment of pain in sickle cell disease is the concern about possible underlying opioid addiction.16 The actual prevalence of opioid addiction in patients with sickle cell disease is not significantly higher than in the general population. In sickle cell disease, it is estimated that 0.5% to 8% of patients are truly addicted to opioids. The rate of opioid addiction in the general population has been documented to be 4.8% (excluding heroin addiction).17 However, because patient with sickle cell disease often have frequent and sporadic episodes of acute pain, they are inappropriately stigmatized as addicts without being properly assessed.18 Nevertheless, when assessing the demographics of patients suffering from sickle cell disease, it cannot be denied that they are at considerably higher risk for drug-related problems. Most patient with sickle cell disease are young and from primarily urban areas, which are often socioeconomically disadvantaged.1

The presentation of sickle cell disease is often very variable; thus, it can be very difficult for healthcare providers to delineate between true pain episodes and pain-seeking behavior. The disease is such that a patient may be in severe crisis one week and then appear perfectly healthy the next. Unlike other diseases, in sickle cell disease pain may be the only manifesting symptom, which can present without any pertinent laboratory or physical findings.1 In addition, the fact that sickle cell disease is most prevalent in African Americans, an ethnic minority group, creates the potential for discrimination, miscommunications, and lack of understanding between patients and healthcare staff. Clinicians may often feel conflicted between their duties to alleviate patients’ pain and protect the community from opioid diversion.1


It is becoming apparent that the management of pain in patients with sickle cell disease is not as straightforward as once thought. The frequency of painful episodes is grossly underestimated, largely because of prior beliefs that healthcare utilization adequately represents the incidence of crises. Recent studies, however, have shown that the majority of a patient’s pain is actually managed at home. Although the variety of analgesic medication to treat sickle cell pain is seemingly endless, we have seen that each medication has its own set of drawbacks. It is therefore imperative that the clinician tailor medication regimens to the individual patient while being vigilant in recognizing and managing possible complications of each treatment.

We have also observed that the nature of the patient’s pain, whether acute or chronic, can vary during the course of the illness. The subtleties distinguishing these two types of pain can often be overlooked, especially when clinicians fail to recognize key descriptors the patient may use to describe the pain. Better communication between patients and physicians may help to create a clearer understanding of what the pain patients are experiencing away from the healthcare setting. Not only does this aid in more effective management of the patient’s pain, but it also helps to foster a stronger doctor–patient relationship, which in turn works to dissolve many of the social stigmas that currently exist regarding sickle cell disease.


Last updated on: March 5, 2019
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