#94850: Sickle Cell Disease

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].

There are three main types of sickle cell disease defined by the specific genetic combination [2]. The most severe form is HbSS, commonly referred to as sickle cell anemia. Patients with this type have inherited one sickle cell gene from each parent. Persons who have inherited a sickle cell gene from one parent and a gene for abnormal hemoglobin from the other parent have the HbSC type. This is usually a milder form of sickle cell disease. The final type is HbS beta thalassemia, which is characterized by inheritance of a sickle cell gene from one parent and a gene for beta thalassemia, another type of anemia, from the other parent. There are two types of beta thalassemia: "zero" (HbS beta⁰) and "plus" (HbS beta+). Those with HbS beta⁰-thalassemia usually have a severe form of sickle cell disease, while those with HbS beta+ tend to have a milder form [2].

Even more prevalent than sickle cell disease is sickle cell trait. This condition is present in persons who inherit a sickle cell gene from one parent and a normal gene from the other parent. The ratio of infant carriers of hemoglobin variant traits to infants with sickle cell disease is approximately 50:1 [5]. Those with sickle cell trait are usually asymptomatic and live a normal life, but they can pass the trait on to their children.

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]:

In patients with sickle cell disease experiencing pain crises, the lower back, knee/shin area, and hips are the sites most often affected. A higher number of pain sites are found in patients with depression and in those 45 years of age and older [6].

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].

Chronic sickle cell disease pain involves modulation of the afferent nociceptive pathways in the spinal cord (such as the spinothalamic tract) that transmit pain from the periphery to the brain for processing [1]. Neuropathic pain is uncommon [2]. Chronic pain from sickle cell disease can be physically and psychologically debilitating; consistent with chronic pain from other conditions, chronic sickle cell disease pain involves sensation, emotion, cognition, memory, and context [2].

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.

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].

L-glutamine (Endari) is approved for patients 5 years of age and older to reduce acute complications of sickle cell disease [10,11]. Taking L-glutamine may lead to fewer hospital admissions, fewer pain crises, less need for blood transfusions, and a lower risk of acute chest syndrome. L-glutamine comes in powder form that should be mixed with cold or room temperature drink or food (e.g., water, milk, apple juice, applesauce). Side effects may include nausea, fatigue, chest pain, and pain in bones or muscles [10,11].

Crizanlizumab-tmca (Adakveo) is a humanized monoclonal antibody that inhibits interactions between endothelial cells, platelets, red blood cells, and leukocytes, which may result in decreased platelet aggregation, maintenance of blood flow, and minimized sickle cell-related pain crises. It is approved for adults and children 16 years of age and older to reduce the frequency of vaso-occlusive crises. Crizanlizumab-tmca is administered IV at an initial dose of 5 mg/kg once every two weeks for two doses, followed by 5 mg/kg once every four weeks thereafter. It may be administered with or without hydroxyurea [10,11].

Voxelotor (Oxbryta) received approval for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older in 2019 with an expansion to patients aged 4 to 11 in 2021 under the FDA's Accelerated Approval Program. This was based on data from the phase 3 HOPE trial and phase 2 HOPE-KIDS trial. In postmarketing clinical studies in patients with sickle cell disease, higher rates of vaso-occlusive crises and fatal events were reported with voxelotor (compared to placebo) [10,12,13]. In September 2024, the manufacturer announced a voluntary withdrawal of voxelotor and a discontinuation of all active clinical trials and expanded access programs. The decision was based on clinical data that indicates the benefit of the drug does not outweigh the risks for the sickle cell patient population [12,13].

Adjunctive medications may also be indicated. Parenteral NSAIDs can reduce opioid requirements and provide greater ease in transition to oral analgesics [1]. Parenteral corticosteroids can be beneficial during crisis phases, but efficacy data beyond the initial 48 hours is lacking.

Intraspinal analgesics should be considered only with insufficient response to maximum-dose systemic opioids and adjuvant medications. Epidural anesthetics alone or with fentanyl can be effective in acute refractory pain [1].

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.

In patients requiring chronic opioid therapy, extended-release, sustained-release, or long-half-life opioid formulations are favored because of ease in administration and more consistent analgesia. Specifically, transdermal fentanyl is effective for chronic pain management in patients who are opioid tolerant. Short-acting opioids may be used for rescue dosing early in the treatment regimen, for acute episodes of breakthrough pain or for analgesic bridge until steady-state is achieved with a long-acting formulation [2].

Adjunctive therapy with SNRIs and TCAs can alter pain perception in the spinothalamic tract. Blood transfusion may be necessary for severe anemia. Common antecedents for transfusion necessity include sudden worsening of anemia due to infection and splenomegaly [2,9].

Massage therapy may be effective as a therapy adjunct. Participants in one trial reported significant decreases in pain intensity following massage with a mean pain scale score of 9.6 before massage versus 2.8 after massage [14].

Transplantation is the only known cure for sickle cell disease and involves blood or bone marrow stem cell transplantation. To prevent potentially severe complications, donor-recipient stem cells should be closely matched using human leukocyte antigen (HLA) tissue typing. Unfortunately, only a small number of patients with sickle cell disease are appropriate candidates for stem cell transplantation [9].

Patient A, a Black woman 26 years of age, presents with two days of escalating bone pain centered in the lower back and shins, radiating to the hips. She reports recent stress as the result of the breakup of a long-term relationship.

The patient notes that she noticed marked lethargy and mild localized pain at home a few days ago. The pain intensified from mild to moderate, and she noted mood changes. Today, the pain intensified to severe, leading her to seek emergency care. Her laboratory tests show elevated reticulocyte count and lactate dehydrogenase, with a marked rise in C-reactive protein.

After assessment and laboratory testing, Patient A is diagnosed with HbSS sickle cell disease, defined by inheritance of a sickle cell gene from each parent. The underlying single nucleotide mutation causes hemoglobin to polymerize when deoxygenated, producing sickled red cells that increase blood viscosity and occlude the microvasculature. The resultant ischemia explains the acute and chronic pain patterns and multi-organ risks.

In the emergency department, Patient A is started on intravenous fluids. To address her severe pain, parenteral morphine and corticosteroids are initiated. After she stabilizes, a parenteral NSAID is added to reduce opioid requirements and facilitate transition to oral therapy. Transfusion is not required for this episode, as she did not have severe anemia. If severe anemia were present—particularly with infection or splenomegaly—blood transfusion would be considered.

Hydroxyurea at a daily dose 15 mg/kg of is initiated as the backbone of disease modification to reduce pain crises, transfusion needs, and mortality. The patient is counseled on the importance of adherence, noting clinical response often begins after three to six months; more frequent follow-up and encouragement are planned to support adherence. L-glutamine is discussed as an option to reduce acute complications and hospitalizations, but use is deferred.

Prevention counseling focuses on avoidance of dehydration, extreme temperatures, high altitudes (including flying), and low-oxygen states from intense exercise or athletic training.

Hematopoietic stem cell transplantation is the only known cure for sickle cell disease. It requires close donor-recipient HLA matching and is suitable for a limited subset of patients. Patient A is informed about indications and risks, with agreement to revisit this option if a suitable donor is identified.

Close follow-up was arranged to titrate hydroxyurea as necessary and monitor clinical response. Pain management follow-up is also scheduled to optimize long-acting and rescue medications and incorporate adjuvants, as needed.

At two-week follow-up, Patient A reports improved baseline pain and no new crises. She is adhering to hydration and temperature-avoidance guidance, remains adherent to hydroxyurea therapy, and feels supported by the outlined plan. Ongoing monitoring is planned to evaluate response over the next three to six months, with consideration of adding crizanlizumab or L-glutamine if breakthrough crises persisted despite optimized hydroxyurea therapy.