There are approximately 100,000 people living with sickle cell disease in the United States and millions more globally. Sickle cell trait (SCT) is even more prevalent and occurs in 1 million to 3 million US adults, with an occurrence rate of 8% to 10% among Black adults. While the sickle gene is more common in people of African descent, it also presents in Hispanic and Latinx Americans, and individuals of Middle Eastern, Asian, Indian, and Mediterranean descent.¹

In fact, studies have shown that median life expectancy for individuals with SCD in high-income countries is reduced by approximately 20 to 30 years compared to individuals without SCD. This reduction is due to various complications associated with SCD, including an increased risk of infections, stroke, pulmonary hypertension, kidney disease, and organ damage.²˒³

However, with improved access to comprehensive care, including preventive measures and disease-modifying therapies, life expectancy in SCD is expected to improve over time.⁴

When it comes to acute pain episodes in SCD, their frequency and severity may change over time; some studies suggest that acute pain flares decrease as individuals with SCD age. Acute episodic pain, known as a vaso-occlusive crisis (VOC), is the hallmark symptom of SCD.⁷ Individuals with VOC often visit the emergency department for pain relief. The standard of care is appropriate hydration and pain management with repeated doses of parenteral opioids and other analgesics, as well as nonpharmacologic measures.⁸

Pain is the most common and distressing symptom experienced by individuals with sickle cell disease. Assessment of pain in SCD is essential to develop an appropriate management plan, including pharmacologic and non-pharmacologic interventions. Assessment of pain should be comprehensive, encompassing pain intensity, location, duration, and associated symptoms such as nausea, vomiting, and fever. Several validated pain assessment tools have been developed for use in individuals with SCD, including the Visual Analog Scale, Numeric Rating Scale, and Faces Pain Scale. These tools can measure pain intensity, but it is also essential to evaluate the impact of pain on the individual’s physical and emotional functioning, and quality of life.

In addition to objective measures, patient self-report is a key component of pain assessment in SCD (some mobile apps and wearable devices can assist in collecting information).⁹˒¹⁰

Pain Presentation in Sickle Cell Disease

Pain episodes in SCD can vary among patient populations.¹⁰ Recurrent episodes of severe, acute pain are common, yet, people with SCD often experience a delay in treatment and their pain is often inadequately treated.¹¹

Acute Pain and Vaso-Occlusive Crisis

Although acute pain can occur without a clinical cause, it is often brought on by factors such as infection, exposure to sudden and/or extreme changes in temperature, dehydration, other painful events, and stress. As noted, a distinctive feature of SCD is the vaso-occlusive crisis, or VOC, which is the most common source of emergency department visits and hospitalizations for people with SCD.¹²

VOC manifests as a sudden onset of extreme, debilitating pain in any part of the body, and often there is no triggering factor, so pain crises may start suddenly and without warning thereby contributing to the severe impact on the quality of life of the patient. As patients age, the pain crises can increase in duration, number, and intensity and research has shown that patients with more pain crises have a higher mortality rate.¹²

Repeated episodes of acute pain can lead to the development of central and peripheral nervous system sensitization, which is a common occurrence in people with SCD.¹³ 30% of adults with SCD report experiencing pain more than 50% of the time.¹⁰ This can lead to adverse impacts on treatment efforts.

The adverse impacts of repeated episodes of acute pain on treatment efforts in individuals with sickle cell disease (SCD) can be significant. Chronic pain and its associated comorbidities, such as depression and anxiety, can lead to poor quality of life, decreased adherence to treatment, and decreased ability to carry out daily activities. Chronic pain can also lead to opioid dependence and addiction, which is a major concern in the management of pain in individuals with SCD.

Moreover, the development of central and peripheral nervous system sensitization can lead to increased pain sensitivity, making pain management more challenging. This can lead to increased healthcare utilization, hospitalizations, and healthcare costs. Additionally, chronic pain can lead to decreased productivity and loss of income, resulting in a significant socioeconomic burden for individuals and their families. Therefore, effective management of acute pain in individuals with SCD is essential to prevent the development of chronic pain and its associated adverse impacts.

Treatment options for both acute and chronic pain management in SCD include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, hydroxyurea, L-glutamine, crizanlizumab, voxelotor, and osteopathic manipulative treatment. Below is a brief look at each and its effectiveness.


Pharmacological therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are considered first-line treatment for mild to moderate pain during VOC associated with SCD. Medications alone, however, have not been proven to be effective in providing relief from the pain and they have potential harmful adverse effects.¹² The ASH guideline suggests the use of a 5- to 7-day course of NSAIDs in addition to opioids for pain management in adults and children with acute pain related to SCD.¹⁴

Special precautions need to be taken with patients who have renal or gastrointestinal issues while using NSAIDs. Specifically, those who have peptic ulcer disease, renal dysfunction, and full-dose anticoagulation are considered to have comorbidities. In these patients, the risks of adverse events may not outweigh the benefit of using the NSAIDs. Identifying patients who are appropriate candidates for NSAID therapy by assessing harms including gastrointestinal, renal, and vascular toxicity as well as cardiovascular disease and anticoagulation requirements will help with tailoring the selection of NSAIDs based on their risk profile.¹⁴

In clinical practice, IV opioids are commonly administered to patients with SCD who present to the ED due to their proven effectiveness as pain relievers. Studies have shown that opioids have been used wisely among patients with SCD; patients who utilize opioids rarely develop drug-seeking behaviors and addiction.¹⁵ Further, mortality in patients with SCD is mainly associated with complications of the disease, such as infection, acute chest syndrome, and renal failure.¹⁶ Although opioids are not the largest contributors to the mortality of SCD, healthcare providers should still weigh the risks and benefits of choosing opioids as first-line therapy. The complex list of both physical and psychological effects of long-term opioid treatment should encourage healthcare providers to consider alternatives to opioids for management of SCD.


Hydroxyurea is often considered one of the most successful medications for the treatment of SCD. One reason that makes hydroxyurea an ideal treatment option is that it has a cytotoxic effect of inhibiting ribonucleotide reductase.¹⁷˒¹⁸ Ribonucleotide reductase is an enzyme that mediates the synthesis of DNA by transforming ribonucleosides into an essential precursor, deoxyribonucleotides.¹⁸ Inhibition of ribonucleotide reductase reduces the production of red blood cells that contain high levels of sickle hemoglobin while increasing the amount of fetal hemoglobin.¹⁶⁻¹⁹ In addition to its cytotoxic effects, hydroxyurea has the ability to reduce leukocyte and platelet counts, both of which play a role in exacerbating VVOC events in patients with SCD.¹⁸˒²⁰

L-glutamine is used to reduce VOC. This drug is an essential amino acid needed to produce nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and glutathione. (These metabolites are antioxidants important in neutralizing the oxidative stress that causes the sickling of red blood cells.) Research has shown a statistically significant reduction in pain crises and hospitalization after 48 weeks of treatment with l-glutamine. Despite the promising results of one study, the twice-daily powder dosage form added to the patient’s current regimen led to non-adherence. The annual cost was also 20 times more expensive than the drug of choice, hydroxyurea, at $30,000, posing a significant obstacle to adherence.¹⁸


Crizanlizumab prevents sickled red blood cells from attaching to the vascular endothelium and platelets, thereby preventing VOC. As a monoclonal IgG2 kappa antibody, it binds to and prevents P-selectin proteins from generating adhesions responsible for the vascular obstruction seen in SCD. In one study, high-dose crizanlizumab reduced annual VOC rates (median 1.63 vs. 2.98, = 0.01) in comparison to the placebo, but hospitalization incidents were not reduced.¹⁶˒¹⁹


Voxelotor inhibits intracellular polymerization in deoxyhemoglobin. It mechanistically increases the oxygen affinity of hemoglobin S and thereby functionally reduces viscosity, hemolysis, and sickling. Unlike previous treatments, voxelotor is administered primarily to increase the amount of hemoglobin per red blood cell (Hgb) and secondarily to decrease VOC rates. As noted in a review article, Hgb levels increased while VOC rates remained unchanged. Adherence to a once-a-day oral dose was more plausible in comparison to L-glutamine and crizanlizumab. Nonetheless, patients risk taking a treatment that has shown a statistically insignificant reduction in VOC events and which may increase them with non-adherence or discontinuation of its use.¹⁶˒¹⁹

Overall, available medications for SCD pain demonstrate the need for innovative alternatives that are economical and safe.²¹ Osteopathic manipulative Treatment (OMT) may be an option. A non-invasive manual therapy, OMT utilizes physical contact to assess and treat neuromusculoskeletal dysfunction, leading to short-term neurobiological effects on the peripheral parasympathetic nervous system that are anti-inflammatory.²²

OMT techniques, such as myofascial release, soft tissue mobilization, and lymphatic pump techniques, can help to reduce pain and inflammation by improving blood flow and lymphatic drainage. Additionally, OMT can help to improve joint mobility and reduce muscle tension, which can help to alleviate pain.²³

Specifically, myofascial release is a common OMT technique that involves applying sustained pressure to specific areas of the body to release tension and tightness in the fascia, a connective tissue that surrounds muscles and organs. By releasing tension in the fascia, myofascial release can help to improve joint mobility and reduce muscle tension. Soft tissue mobilization involves applying manual pressure to the soft tissues surrounding the joint. This technique can help to increase circulation, reduce inflammation, and improve joint range of motion. Lymphatic pump techniques are another OMT technique that can help to improve joint mobility by increasing lymphatic flow and reducing inflammation. This technique involves applying rhythmic compression to the lymphatic vessels and surrounding tissues to stimulate lymphatic flow and drainage.

It is difficult to make a direct comparison between the cost of OMT and pharmaceutical treatments for SCD pain as the cost can vary depending on various factors such as location, practitioner, insurance coverage, and severity of the condition. However, in general, OMT is considered to be a cost-effective treatment option for chronic pain conditions such as SCD as it can reduce the need for medications and other more invasive procedures that can be expensive.²⁴

Practical Takeaways

Pain in sickle cell disease has many facets, and VOC remains one of the most frequent reasons that patients seek medical treatment in the hospital. The effective pain management of acute and chronic etiologies of SCD requires both pharmacologic and nonpharmacologic approaches, with osteopathic manipulation as a growing option. It is important to note that each patient is different and individual pain care plans should be used.

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