Sickle Cell Disease: Managing the Pain

Providing patients with information is key to helping them manage sickle cell disease pain.

Sickle cell disease (SCD) affects millions of individuals worldwide, and the Sickle Cell Disease Association of America estimates that 70,000 to 100,000 individuals have SCD and 3 million individuals have the sickle cell trait.¹ While SCD is known to primarily affect individuals of African American descent, individuals from South America, the Caribbean, Central America, the Middle East, and the Mediterranean can also have SCD or the SCD trait.^1-4 SCD is estimated to affect 1 in 500 African American infants, and 1 in 12 African Americans are estimated to have the sickle cell trait.^1-5

SCD is characterized by episodes of acute and chronic pain. By increasing awareness about SCD and promoting patient education, health care professionals can help patients and their families cope with SCD and better manage the associated pain.

The Pain

Recurring episodes of acute and/or severe pain are a hallmark characteristic of SCD.^6,7 SCD pain can often be debilitating, and episodes of pain vary from patient to patient in frequency and intensity. SCD pain can be classified as acute, chronic, or mixed (Online Table 1^4,6,8-12). At some point, most SCD patients experience episodes of pain often referred to as vaso-occlusive crisis (sickle cell crisis), the duration of which may range from hours to days.6,10 Some patients seldom have a sickle cell crisis, while others may experience crises several times a year. Some episodes may be so severe that hospitalization is warranted to manage the pain.

Table 1: Classification of Pain

• An acute pain event is the most common type of pain, and the onset is typically abrupt. It is often the result of an ischemic tissue injury, which is due to the occlusion of microvascular beds by sickled erythrocytes during an acute crisis. Acute pain episodes can also be triggered by factors including extreme temperature changes, changes in altitude, physical and emotional stress, an illness, the presence of infections, dehydration, cold climates, menstruation, and fatigue

• Chronic pain is pain that lasts for 3 to 6 months or longer. Chronic pain often results from the destruction of bones, joints, and visceral organs due to recurrent crises. Sources of chronic sickle cell pain include aseptic necrosis, leg ulcerations, and bony infections.

Adapted from references 4, 6, 8-12.

Pain crisis is considered to be the primary reason for emergency department (ED) visits or hospital admissions among patients with SCD.^6,9,10 It is important for patients to be educated about SCD and learn the early signs of a sickle cell crisis in order to get appropriate treatment as soon as possible.^6-11 Studies show that fewer than 50% of SCD patients can identify precipitating factors of pain crises.^6,12 The most common sites for pain include the thigh, hip, knee, abdomen, chest, and lower back.^6,12

Managing the Pain

Unfortunately, acute and chronic pain associated with SCD is commonly undertreated or inappropriately managed due to patient fear of potential addiction and adverse effects.^6,8-12 Many studies report that some health care professionals are also concerned about the potential for addiction and adverse effects.^8-12

The American Pain Society (APS) developed a clinical practice guideline to provide health care professionals with evidence-based recommendations that can help improve the management of pain among SCD patients.^6,10-13 The initial management of pain should be aimed at providing quick and adequate pain control as well as identifying the cause of pain.^6,10-13 The APS guidelines recommend that primary health care providers of SCD patients conduct a comprehensive clinical assessment annually, or more often if pain is frequent.^6,10-13 The guidelines state that pain management should be aggressive to better manage pain and improve patients’ quality of life. Psychological, behavioral, and physical interventions should also be employed to promote positive outcomes in patient therapy.^6,10-13

Pharmacologic Management

During a pain episode, analgesic therapy is often employed for acute, severe vaso-occlusive pain and for chronic, intermittent, or persistent pain.^6,10-13 According to the APS guidelines, the first comprehensive, evidence-based guidelines for treating pain associated with SCD, the use of analgesics should be tailored to the patient and according to the level of pain.^6,12 The patient’s medical, medication, and allergy histories should be reviewed for potential contraindications and drug—drug interactions.

When appropriate, pharmacologic management of SCD pain may involve the use of 3 major pharmacologic classes: nonopioids, opioids, and adjuvants.^6,12,14,15

For optimal pain relief, management of other SCD complications, or the treatment of adverse effects, many adjuvant treatments (eg, antihistamines, phenothiazines, antiemetics, laxatives, benzodiazepines, anticonvulsants) are used.^6,12-15 Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to treat mild to moderate pain.^6,12 Because patients with SCD may have varying degrees of hepatic impairment, acetaminophen may be contraindicated for use, and NSAIDs are contraindicated for use in patients with gastritis, peptic ulcers, coagulation disorders, and renal failure.⁶ Moderate to severe pain is often treated with opioids, with or without NSAIDs or other adjuvant medications.^6,12

Opioid maintenance therapy for patients with SCD should be considered only after all other reasonable attempts to achieve pain relief with nonopioids have been made.^6,12 Morphine is considered the drug of choice for treating acute SCD pain crisis when no contraindications are present; the pharmacokinetics and dosing vary among patients.^6,8,9 Other opioids commonly used for pain relief include hydromorphone, codeine, hydrocodone, oxycodone, methadone, and fentanyl.^6,8-12 While meperidine is often the opioid of choice and is most commonly prescribed in EDs, the use of meperidine for acute or chronic pain is often discouraged due to the risk for seizures.^6,8 Many patients with SCD may be at greater risk for seizures due to reduced renal function, high meperidine doses, and altered pharmacokinetics of meperidine.^6,8,14-17

Patients should be counseled about the various adverse effects associated with the use of opioid analgesics, including sedation, hives, nausea, vomiting, constipation, and respiratory depression.^6,8,14-17

Preventive Therapy

While several drugs have been studied as potential treatments for SCD, in 1998, the FDA approved hydroxyurea for use in symptomatic adult SCD patients. Currently, hydroxyurea is the only approved prophylactic agent for SCD, and it is indicated to decrease the frequency of painful crises and to reduce the need for blood transfusions in adult patients with SCD who have recurrent moderate to severe painful crises (at least 3 during the preceding 12 months).^6,10,18-23 While the use of hydroxyurea is not a cure for SCD, it has been shown to decrease the number of hospitalizations, vaso-occlusive complications, and pulmonary tissue damage from acute chest syndromes by at least 50%, thus making SCD crisis less intense.^6,10,24

Hydroxyurea is readily absorbed after oral administration, and peak plasma levels are achieved within 1 to 4 hours after administration.^6,10,18-23 It is classified as a Pregnancy Category D medication; therefore, its use is contraindicated in pregnancy.^6,10,18-23 Its use is also contraindicated in individuals with severe anemia, hypersensitivity to any component of the formulation, and severe bone marrow suppression.^18-23 Although the use of hydroxyurea in patients younger than 18 years is off-label, many SCD treatment facilities use hydroxyurea to treat pediatric patients with severe disease.^18-23 Ongoing studies on the use of hydroxyurea in the pediatric population have demonstrated a favorable hematologic response and a lack of significant toxicity.^10,25 The emerging data are encouraging.¹⁰

The primary adverse effect of hydroxyurea therapy is myelosuppression of blood cells, most importantly, neutrophils and thrombocytes.^18-23 Patients at risk for infection and bleeding problems may be at risk for severe neutropenia and thrombocytopenia.^18-23 It is strongly advised that patients have their blood counts routinely monitored by a hematologist and their dosages adjusted when warranted. Other possible adverse effects are gastrointestinal upset, nausea, rash, an increased creatinine level, and nail and skin hyperpigmentation.^18-23

Clinical Trials and Ongoing Research

In 2013, researchers from the La Jolla Institute for Allergy and Immunology, the Dana-Farber/Children’s Hospital Cancer Center in Boston, the Blood Center of Wisconsin in Milwaukee, and other researchers announced the launch of the phase 2 clinical trials of the drug Lexiscan (regadenoson; Astellas Pharma US, Inc).^2-28 This clinical trial will investigate the potential use of regadenoson in treating SCD. Lexiscan is approved as a pharmacologic stress agent for myocardial perfusion imaging.^26-28 The phase 1 results appeared to be promising and were published in the journal Blood in April 2013. Researchers are investigating whether this agent’s anti-inflammatory effects can appreciably decrease the pain and the blood flow issues associated with SCD.^26-28 The phase 2 trial is being primarily funded by the National Institutes of Health. More information about the status of phase 2 studies can be found at www.clinicaltrials.gov/ct2/show/NCT01788631.

Endnote

While there is no cure for SCD and managing the disease can be very challenging, the encouraging news is that most SCD pain episodes can be well managed with prompt and effective treatment. Patients should be aware of potential triggers of pain and avoid them when possible. Patients should be encouraged to discuss any concerns with their primary health care provider because uncontrolled pain can negatively impact a patient’s quality of life.

Initial management should focus on providing rapid and adequate pain relief and on enabling patients to function in their daily routine. Therapy should be individualized based on the severity and frequency of pain as well as the patient’s medical, medication, and allergy histories.

Patients with SCD should be encouraged to take an active role in managing their condition, to adhere to their therapy, and to maintain routine follow-up visits with their primary health care providers. Patients should be educated about the importance of getting rest, avoiding tobacco and alcohol use, staying hydrated, eating a healthy and balanced diet, and obtaining vaccinations recommended by their physician, including the annual influenza vaccination.^6,10,29 Empowering patients through education is key in helping them manage SCD (Online Table 2).

Table 2: Sickle Cell Disease Web Resources

• National Institutes of Health National Heart, Lung and Blood Institute
• Sickle Cell Disease Association of America
• Centers for Disease Control and Prevention
• American Sickle Cell Anemia Association
• American Pain Society guidelines on managing sickle cell disease pain

Ms. Terrie is a clinical pharmacist and medical writer based in Haymarket, Virginia.

References

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• Sickle cell disease data & statistics. Centers for Disease Control and Prevention website. www.cdc.gov/ncbddd/sicklecell/data.html. Accessed September 4, 2014.
• Anderson N. Hydroxyurea therapy: improving the lives of patients with sickle cell disease. Medscape website. www.medscape.com/viewarticle/552354. Accessed September 4, 2014.
• Who is at risk for sickle cell anemia? National Heart, Lung and Blood Institute website. www.nhlbi.nih.gov/health/health-topics/topics/sca/atrisk.html. Accessed September 4, 2014.
• Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease. Glenview, IL: American Pain Society; 1999.
• Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120(18):3647-3656.
• Treatment of acute and chronic complications. Sickle Cell Information Center website. http://scinfo.org/the-management-of-sickle-cell-disease-4th-ed/treatment-of-acute-and-chronic-complications-chapter-10-pain. Accessed September 4, 2014.
• Brousseau DC, Owens PL, Mosso AL, Panepinto JA, Steiner CA. Acute care utilization and rehospitalizations for sickle cell disease. JAMA. 2010;303(13):1288-1294.
• Yale SH, Nagy NT. Approach to the vaso-occlusive crisis in adults with sickle cell disease. Am Fam Physician. 2000;61(5):1349-1356, 1363-1364.
• Maakaron J. Sickle cell anemia. Medscape website. http://emedicine.medscape.com/article/205926-overview#showall. Accessed September 4, 2014.
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• Preboth M. Management of pain in sickle cell disease. Am Fam Physician. 2000;61(5):1544, 1549-1550.
• Nursing practice guidelines: care of the patient with sickle cell disease experiencing pain. International Association of Sickle Cell Nurses and Physician Assistants website. www.iascnapa.org/guidelines/Guidelines_Pain.pdf. Accessed September 4, 2014.
• Benjamin L. Pain management in sickle cell disease: palliative care begins at birth. Hematology Am Soc Hematol Educ Program. 2008:466-474.
• Ballas S. Current issues in sickle cell pain and its management. Hematology Am Soc Hematol Educ Program. 2007:97-105.
• Sickle cell disease. The Merck Manual Professional Edition website. www.merck.com/mmpe/sec11/ch131/ch131i.html?qt=sickle cell&alt=sh. Accessed September 4, 2014.
• Nursing practice guidelines: care of the patient with sickle cell disease receiving hydroxyurea. International Association of Sickle Cell Nurses and Physician Assistants website. www.iascnapa.org/guidelines/Guidelines_Hu.pdf. Accessed September 4, 2014.
• Droxia [package insert]. Bristol-Myers Squibb website. http://packageinserts.bms.com/pi/pi_droxia.pdf. Accessed September 4, 2014.
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• Waknine Y. Hydrea, droxia linked to cutaneous vasculitic toxicities. Medscape website. www.medscape.com/viewarticle/522371. Accessed September 4, 2014.
• Hydroxyurea. Medscape website. http://reference.medscape.com/drug/droxia-hydrea-hydroxyurea-342100. Accessed September 4, 2014.
• Strouse JJ, Lanzkron S, Beach MC, et al. Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children. Pediatrics. 2008;122(6):1332-1342.
• Amid A, Odame I. Improving outcomes in children with sickle cell disease: treatment considerations and strategies. Paediatr Drugs. 2014;May 6.
• Neville K, Panepinto J. Pharmacotherapy of sickle cell disease. World Health Organization website. www.who.int/selection_medicines/committees/expert/18/applications/Sicklecell.pdf. Accessed September 4, 2014.
• Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a huge review. Am J Epidemiol. 2000;151(9):839-845.
• La Jolla Institute for Allergy and Immunology. New sickle cell anemia therapy advances to phase II clinical trials. Science Daily website. www.sciencedaily.com/releases/2013/06/130612092953.htm. Accessed September 4, 2014.
• Phase II of Regadenoson in sickle cell anemia. National Institutes of Health Clinical Trials.gov website. www.clinicaltrials.gov/ct2/show/NCT01788631. Accessed September 4, 2014.
• New sickle cell anemia therapy advances to phase II clinical trials. La Jolla Institute website. www.liai.org/pages/New_Sickle_Cell_Anemia_Therapy_Advances_to_Phase_II_Clinical_Trials. Accessed September 4, 2014.
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