3

Pain Management in Sickle Cell Disease

Pain management in sickle cell disease (SCD) encompasses pain mitigation to reduce the frequency and severity of pain, management of acute pain crises, and treatment of chronic pain experienced by individuals with the disease. In addition to addressing these general topics, this chapter will respond to the specific questions in items 3b and 3c from the Statement of Task:

• When and how often are parenteral opioid pain medications used to manage SCD pain crises?
• What are indicators or contraindicators for their use?
• How have best practices regarding opioid pain medication changed over the past 10 years?
• What circumstances or factors might lead providers not to prescribe narcotic pain medication even when indicated by current best practices?
• What other pain medications might be administered in the context of a severe pain crisis?
• What, if anything, can the choice of alternative medications tell us about a patient’s symptom severity?
• What treatments or interventions used for acute sickle cell crises are equivalent to parenteral narcotic medication in terms of medical severity of the underlying acute crisis (e.g., acute transfusion)?

THE OVERALL STATE OF PAIN MANAGEMENT IN SICKLE CELL DISEASE

Despite the high pain burden experienced by individuals with SCD, most pain does not result in emergency department visits or hospitalizations. Instead, most individuals with SCD manage their pain at home (Smith et al., 2008). Moreover, the expansion of outpatient infusion centers in recent years has further shifted acute pain management for SCD away from emergency departments and inpatient settings. These centers offer timely interventions for pain crises, providing rapid pain relief and reducing hospital admissions. For instance, patients receiving care in infusion centers reported waiting about half as long to receive pain medication compared to those receiving care in emergency departments, and were more likely to have their pain reassessed within 30 minutes and less likely to be admitted to the hospital (see Chapter 4). This shift underscores the efficacy of alternative care models in managing SCD pain and improving individuals’ outcomes (Lanzkron et al., 2021).

Teonna Woolford, co-founder of the Sickle Cell Reproductive Health Education Directive, told the committee she is fortunate to live 45 minutes from the Johns Hopkins Hospital Sickle Cell Center, an infusion clinic, but if her crisis hits outside of the clinic’s 9-to-5 operating hours or if the clinic’s five beds are already filled, she must seek care in the emergency department. During the COVID-19 pandemic, her average wait time in the emergency department was close to 12 hours.¹

The high prevalence of home management of pain and shift toward outpatient care models for pain management highlight that emergency department visits and hospitalizations are too restrictive a measure of SCD severity (see Chapters 2 and 4).³ Moreover, the type and amount of pain medication administered, duration of treatment, and discharge disposition

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¹ Presented at the “Hospitalization and Sickle Cell Disease – public webinar” on December 20, 2024.

² Presented at the “Hospitalization and Sickle Cell Disease – public webinar” on December 20, 2024.

³ This sentence was changed after release of the report to clarify the limitations of the current measure.

vary widely across institutions and even among providers at the same institutions, and, thus, do not necessarily reflect the overall burden of disease. As described later in this chapter, many individuals with SCD avoid seeking emergency care because of stigma, delays in receiving adequate pain relief, or concerns about being perceived as drug seeking. As mentioned in Chapter 2, SCD, unlike many other conditions that present with severe pain, does not have any outwardly visible signs and therefore is often misunderstood. In addition, it is a relatively rare disease in the United States, disproportionately affecting people of African ancestry. As a result, there is a shortage of health care providers with specialized training in SCD pain management (Calhoun et al., 2022; Phillips et al., 2022; Smeltzer et al., 2021), leading to gaps in care and disparities in treatment (Kanter et al., 2020). Addressing these barriers requires increasing health care provider education and increasing access to outpatient and community-based pain management options to ensure that individuals with SCD receive timely, effective, and compassionate care.

PAIN MITIGATION IN SICKLE CELL DISEASE

Mitigating pain in individuals with SCD is a critical aspect of comprehensive care. By focusing on pain prevention, health care providers aim to reduce the frequency and severity of pain episodes and the development of chronic pain, thereby improving the overall quality of life for people living with SCD. Effective pain prevention strategies require a multimodal approach that includes both pharmacologic and nonpharmacologic interventions, making it essential to tailor these strategies to the unique needs of each individual with SCD. This section explores the variety of methods and best practices for preventing pain, emphasizing proactive measures that can help mitigate the onset of both acute and chronic pain episodes.

Disease-Modifying Therapies

Prior to the development of disease-modifying therapies, the approach to pain was reactive, with the focus on the pain and not its pathophysiology. Disease-modifying therapies attempt to decrease the frequency of painful vaso-occlusive crises, or pain crises, and the development of chronic pain. For nearly 20 years, hydroxyurea was the only disease-modifying therapy approved by the Food and Drug Administration (FDA) for adults and children with SCD. However, since 2017, FDA has approved three new disease-modifying drugs for SCD: L-glutamine, crizanlizumab, and voxelotor, although voxelotor’s manufacturer withdrew the drug from the market voluntarily in September 2024 because of safety concerns (Pfizer, 2024; Schneider, 2025).

Disease-Modifying Treatments

Multiple studies have shown that hydroxyurea, the first approved drug therapy for HbSS and HbSβ⁰-thalassemia,⁴ decreases the frequency of pain crises that are severe enough to seek medical attention (Agrawal et al., 2014; Charache et al., 1995; McGann and Ware, 2015). There is also some suggestion of decreased pain severity.

Hydroxyurea is a ribonucleotide reductase inhibitor that induces fetal hemoglobin (HbF) production, which is normally suppressed shortly after birth. HbF inhibits sickle hemoglobin polymerization, reducing red cell stiffness and hemolysis. Hydroxyurea also increases circulating levels of nitric oxide, a potent vasodilator; decreases red cell adhesion; and decreases the number of circulating leukocytes, cells that contribute to vaso-occlusion. Consensus guidelines recommend hydroxyurea for all individuals with HbSS and HbSβ⁰-thalassemia beginning at nine months of age, based on randomized studies that demonstrated decreased incidence of acute pain episodes and acute chest syndrome (Charache et al., 1995; Voskaridou et al., 2010; Wang et al., 2011). With the less common genotypes, such as HbSC and HbSβ, clinicians might occasionally consider prescribing hydroxyurea, and one randomized placebo-controlled trial has demonstrated reduction in pain and fewer sickle-related events in children and adults with HbSC (Dei-Adomakoh et al., 2025).

L-glutamine is an oral amino acid supplement that can decrease reactive oxygen species in red blood cells (RBCs), reducing sickling and RBC adhesivity. In a randomized controlled trial of 230 patients aged 5 years and older, L-glutamine, compared with placebo, reduced acute pain crises by 25 percent, hospitalization by 33 percent, and mean length of hospital stay from 11 to 7 days (Niihara et al., 2018). L-glutamine also reduced acute chest syndrome from 23 percent to 9 percent. Patients can receive L-glutamine with or without hydroxyurea.

Crizanlizumab is a monoclonal antibody directed against P-selectin, an adhesion molecule found on activated platelets and endothelial cells that may partially mediate vaso-occlusive or pain crisis (Stevens et al., 2021). Crizanlizumab approval was based on a phase 2 trial in which patients were randomized to receive a monthly infusion with two different doses of crizanlizumab or placebo (Ataga et al., 2017). Compared with placebo, higher-dose crizanlizumab reduced vaso-occlusive crises from 2.98 to 1.63 per year, which was statistically significant. Crizanlizumab was given with or without hydroxyurea (Ataga et al., 2017). Although still approved in the United States, crizanlizumab was pulled from the European market in August 2023 when a phase 3 trial showed lack of efficacy (Karkoska et al., 2025).

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⁴ See Chapter 1 for a discussion of the different genetic variants of SCD.

Voxelotor promotes the defective hemoglobin (HbS) binding to oxygen, thereby decreasing sickle HbS polymerization and resultant hemolysis. In a randomized controlled trial of 198 patients with SCD and severe or symptomatic anemia, voxelotor increased Hb by at least 1.0 g/dL in 51 percent of participants versus 7 percent among patients randomized to receive placebo. The effects of voxelotor on pain crises or quality of life are currently unknown. Voxelotor was appropriate for use in patients with hemoglobin levels between 5.5 and 10.5 g/dl and more than one pain crisis per year despite hydroxyurea therapy or patients unable to take hydroxyurea (Vichinsky et al., 2019).

Other medications in development include those augmenting protective RBC enzyme activity to decrease hemolysis and sickling; drugs that target cell adhesion and inflammatory cytokines; and oral small molecules that increase HbF production more than hydroxyurea does.

Even with the expansion of new therapies since the FDA approval of hydroxyurea to treat SCD in 1998, the uptake of newer therapies for SCD is low. A retrospective cross-sectional analysis of North Carolina Medicaid claims between 2018 and 2022 showed that uptake rates of SCD therapies were low across all therapies examined (hydroxyurea, L-glutamine, crizanlizumab, and voxelotor). Hydroxyurea, the most widely used therapy, had a decline in uptake from 21.9 percent in 2018 to 19.2 percent in 2022. The annual uptake found for L-glutamine, voxelotor, and crizanlizumab was less than 5 percent per year. These therapies were compared to opioid medications, with the annual uptake ranging from 42.3 percent to 38.5 percent. When comparing people with SCD who saw hematologists to those who did not see hematologists, annual uptake was higher across all therapies. Overall, FDA-approved medication use for SCD is low (Rivenbark and Little, 2024).

Therapies to Replace HbS

Most clinicians consider the use of chronic RBC transfusions to be a disease-modifying therapy (Howard, 2016). The rationale is to replace most of the HbS with normal hemoglobin (HbA), thus suppressing endogenous HbS production, increasing HbA levels, and reducing the stimulus for erythropoiesis, which is the process by which the body produces RBCs, or erythrocytes, in bone marrow. This can be done by simple transfusion; manual exchange; or erythrocytapheresis, a procedure that removes RBCs from the patient’s blood stream. Typically, erythrocytapheresis is the only way to maintain HbS levels at less than 30 percent, but it requires specialized equipment, facilities, expertise, time, and venous access. Complications of transfusion include iron overload and an immune response to non-self RBC antigens (alloimmunization), which makes finding RBCs appropriate

for transfusion difficult. Alloimmunization also places patients at risk for delayed hyperhemolytic transfusion reactions and may preclude consideration for transformative therapies such as allogeneic hematopoietic stem cell transplantation (HCT) and gene editing.

Robust evidence supports the use of chronic RBC transfusions in the primary prevention of ischemic stroke in high-risk children identified by screening with transcranial Doppler imaging, and in secondary prevention of stroke (Guy et al., 2025; Lee et al., 2006). There is also emerging consensus, albeit based on meta-analysis with the potential for bias rather than on randomized controlled trials, that prophylactic transfusion during pregnancy decreases both sickle cell and pregnancy-related complications in women (AlMoshary and Arabdin, 2024; Malinowski et al., 2015).

People living with SCD who experience frequent pain crises, recurrent acute chest syndrome, and recurrent priapism—a persistent, painful erection lasting for more than four hours and not related to sexual stimulation—are often placed on chronic transfusion therapy, although this practice varies widely based on survey data and evidence of efficacy (Idris et al., 2022). In addition, this practice is based largely on secondary outcomes analysis of randomized trials with other primary outcomes.

Chronic transfusion therapy in children is associated with fewer pain crises, although studies were not definitive because the frequency of pain crises was a secondary outcome in those studies (Beverung et al., 2015; Hilliard et al., 2018; Maxwell et al., 2019). No randomized controlled trials demonstrate that chronic transfusion therapy decreased the frequency of pain crises in adults outside of pregnancy, although in practice many adult hematologists use chronic RBC exchange for individuals who experience frequent pain crises in an attempt to decrease their frequency. Although helpful in reducing the frequency and perhaps severity of pain crises in certain subsets of people living with SCD, chronic transfusion therapy also requires significant transfusion medicine resources, adds to patient and caregiver burden, and includes complications associated with chronic transfusion noted above. For these reasons, chronic transfusion therapy is appropriate only for specific subsets of individuals with SCD. The use of acute blood transfusions is not considered adequate treatment for pain crises and would be used only to address other symptoms such as severe anemia below the individual’s baseline.

Research has shown that allogeneic HCT (Hsieh et al., 2011) and gene-editing therapies can markedly reduce or eliminate pain crises, although chronic pain may persist in some individuals (Jones et al., 2025). Allogeneic HCT, which establishes a new hematopoietic system with a normal hemoglobin gene, is potentially curative but is limited by the availability of matched donors; the development of graft-versus-host disease and other

severe complications; and the requirement to destroy the individual’s existing hematopoietic system, a process that may be too toxic for many individuals with SCD.

In 2024, FDA approved two gene therapies for SCD, including the first gene therapy that uses CRISPR/Cas9 technology (Frangoul et al., 2024). Studies with these two therapies found that greater than 85 percent of patients were free from pain crises, and those that occurred were mild for some (Frangoul et al., 2022; Frangoul et al., 2024; Lesmana et al., 2024). There have been two reported cases of myelodysplastic syndrome (Hsieh et al., 2020) and acute myeloid leukemia (Goyal et al., 2022) in patients receiving one of the two treatments (Leonard and Tisdale, 2021).

Therapy Limitations

Despite these hopeful advances in the management of SCD, there are barriers to widespread use of these therapies. Recent data, for example, show distressingly low rates of hydroxyurea use among people living with SCD (CDC, 2023; Stettler et al., 2015; Treadwell et al., 2022), highlighting the need for implementation science strategies and better care delivery. Similarly, rates of transcranial Doppler imaging screening and chronic transfusion in high-risk patients are low, highlighted by recent data that stroke rates in children with SCD are increasing (Oluwole et al., 2024). In part, these low rates of guideline-concordant care are related to the lack of access to optimal care experienced by many people living with SCD (Adams-Graves and Bronte-Jordan, 2016; Kanter et al., 2021). Lack of adequate insurance and high copays pose additional barriers to obtaining optimal care, including inadequate coverage for SCD-related medications (Phillips et al., 2022).

Recent withdrawal of certain drugs from the market based on results of large, randomized confirmatory trials suggests limited effect size for these newer drugs. Finally, the use of gene therapy and HCT is limited by their complexity, high resource demands, expense, adverse events, and, in the case of HCT, the need for a suitable donor. Furthermore, patients and caregivers express concern about the effect of these high-risk treatments on daily functioning such as school and work, peer and social relationships, and future goals and aspirations (Desine et al., 2020; Sinha et al., 2021). Another important consideration is premorbid psychosocial functioning, such as anxiety and depression, that may affect an individual’s treatment success and overall well-being throughout the process (Mishkin et al., 2019). Limited understanding and longitudinal data about treatment risks and benefits also present barriers to acceptance and access to these treatments, with patients and family members raising the potential risk of secondary complications as concerns (Johnson et al., 2024). Therefore, assessing patient readiness

and psychosocial functioning for gene therapy and HCT is imperative for informed decision making to undergo treatment and to guide the delivery of support during the process (Hardy et al., 2024; Ilonze et al., 2025). Thus, despite accelerating activity in the development of new therapeutic interventions for SCD, there is still considerable distance to be traveled before new therapies are both widely effective and accessible.

PAIN MANAGEMENT IN SICKLE CELL DISEASE

Acutely Worsening Pain

For many individuals, management of worsening pain occurs in an emergency department. Other care settings include an outpatient infusion clinic or an inpatient setting. The following is a typical sequence of care for acute SCD pain provided in the emergency department, although patients are encouraged to develop a pain action plan with their providers and to manage pain exacerbations at home, if possible, by using oral analgesics they have at home, which may include opioids (Brandow et al., 2020; NHLBI, 2024). As reported by webinar speakers and respondents to the committee’s Call for Perspectives, other commonly used home pain management strategies include warm baths or showers; heating pads; oral fluids; deep breathing, relaxation, or meditation; distraction techniques; and sleep.

Once a person arrives at the emergency department, they are assessed and triaged by a clinician. Most emergency departments use the Emergency Severity Index that categorizes the situation into levels of urgency. When assessing a vaso-occlusive crisis, emergency department staff consider potential life-threatening complications, such as acute chest syndrome or aplastic or hypoplastic crisis (Lovett et al., 2017). Clinical staff will question individuals with SCD to determine whether the pain they are experiencing is typical or atypical for them and ask about prior pain crises and current medications. Once assessed, the recommended best practice is to administer pain medication within 60 minutes of coming to the emergency department, with frequent reassessments (e.g., every 15 minutes) and tailored opioid dosing based on consideration of baseline opioid therapy and prior effective therapy (Brandow et al., 2020; Yawn et al., 2014). Despite this, studies have shown the average wait time for a physician to first see an individual with SCD in the emergency department is 66.8 minutes, which is 25 percent longer than the wait time for a general patient (Haywood et al., 2013).

Most individuals with SCD in the United States are of Black race or belong to ethnic minority groups, and studies have shown that both SCD-related stigma and racial bias play critical roles in delays in care and ultimately pain management. One well-designed study compared differences in treatment wait times for patients with SCD and patients with a long bone fracture

(Haywood et al., 2013). In this study, wait times were 50 percent longer for an individual with SCD than for someone with a long bone fracture. Black race and the status of having SCD were both independent predictors of longer wait times in the emergency department (Haywood et al., 2013). Another study found that wait times were about 60 percent longer for individuals presenting with acute SCD pain (80 minutes) than for those presenting with kidney stones (50 minutes), despite the former reporting higher pain scores on arrival and often being assigned a higher triage priority level (Lazio et al., 2010). Long bone fractures and kidney stones are both conditions that, similar to SCD, are associated with severe acute pain. One multicenter study found that only 48 percent of children having a pain crisis are seen by a physician within 60 minutes of arriving at the emergency department (Rees et al., 2022).

In addition to longer wait times, people with SCD may be undertreated for their pain. Despite the evidence, clinicians may expect an SCD crisis to involve some change in vital signs or laboratory test values and do not accept a report of pain as valid when they do not see objective measures. As the committee heard from individuals living with SCD, it is not unusual for emergency department personnel to be unfamiliar with SCD and erroneously believe that acetaminophen, for example, is sufficient for treating their pain. While acetaminophen can be used to treat mild to moderate pain, it is insufficient for treatment of severe pain. They also reported that it is common for a person experiencing an SCD pain crisis to be accused of drug seeking.

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⁵ Presented at the “Hospitalization and Sickle Cell Disease – public webinar” on December 20, 2024.

⁶ Excerpt from Call for Perspectives Response.

Black individuals are undertreated for pain of any etiology, and those living with SCD may face greater barriers because of the frequency of their pain crises or acute-on-chronic pain episodes and their use of effective coping strategies, and because they know about specific medications and dosages, such as a particular opioid and dose, that have previously proven effective for them (Ezenwa and Fleming, 2012; Hoffman et al., 2016). As Caroline Freiermuth, associate professor of clinical emergency medicine at the University of Cincinnati College of Medicine, told the committee,⁷ emergency department physicians can be skeptical about an individual’s pain report given that most are walk-ins. Many seem to be of the mindset that “if it was not bad enough for them to call 911, it cannot be that bad,” and “if they are trying to nap or have their eyes closed, they must be exaggerating if they are telling me their pain is 8 or 9.” The problem, said Freiermuth, is that pain is multifactorial, and in SCD, severe pain indicates underlying ischemia and a vaso-occlusive crisis, which is associated not only with pain but also with increased mortality (Elmariah et al., 2014; Platt et al., 1994). In fact, people experiencing a pain crisis can die without any evidence of chronic underlying organ damage. “When patients are in pain and it looks like it is an uncomplicated vaso-occlusive episode, we want to make sure we rule out other complications and [are] not overlooking this,” said Freiermuth.

The initial approach outlined in national guidelines to treating acute pain has centered on parenteral opioids, such as morphine, hydromorphone, and fentanyl. The dose and route of administration, whether intravenous, subcutaneous, sublingual, or intranasal, vary by facility and setting, as does the mode of delivery, such as intravenous push versus patient-controlled analgesia. The duration of therapy prior to a decision to escalate the level of care and admit the individual to the hospital also varies. Non-opioid pharmacological therapy includes intravenous nonsteroidal anti-inflammatory drugs (NSAIDs), either oral or parenteral ketamine, and intravenous acetaminophen. There have been increasing reports of successful use of ketamine in the management of pain from vaso-occlusive crisis, with suggestion of better pain mitigation and reduced opioid use (Onyebuchi et al., 2024). At some centers, it is common practice to administer intravenous fluid for volume repletion and rehydration in an effort to reduce pain (Brandow et al., 2020; Yawn et al., 2014).

If an individual is admitted to the hospital, they continue to receive the same types of therapies, titrated to effect and adverse events. As Chapter 2 discussed, the duration of a pain crisis is highly variable, both within and among individuals. In addition, the choice of analgesia may be driven by factors other than pain severity, such as the care team’s inexperience with

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⁷ Presented at the “Hospitalization and Sickle Cell Disease – public webinar” on December 20, 2024.

treating SCD or their reluctance to use higher-dose opioids, as well as systems barriers and individual preferences.

Local policies may also dictate which medications can be used. The rise of the opioid epidemic in the United States led to changes in opioid prescribing practices. The Centers for Disease Control and Prevention (CDC) issued guidance specific to chronic pain in 2016 that provided “recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care” (Dowell et al., 2016). Studies have shown both a decrease in opioid prescriptions and an increase in hospitalizations for vaso-occlusive crises among people living with SCD, but the relationship between the change in prescribing practices and increase in hospitalizations is not clear (Kang et al., 2024; Xu et al., 2024). The CDC issued updated guidance in 2022 (Dowell et al., 2022), including consideration of SCD, stating that “the

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⁸ Excerpt from Call for Perspectives Response.

⁹ When a nurse takes a medication dose and puts it in intravenous fluids to dilute it.

¹⁰ Presented at the “Pain Management and Sickle Cell Disease – public webinar” on February 7, 2025.

¹¹ Presented at the “Pain Management and Sickle Cell Disease – public webinar” on February 7, 2025.

recommendations do not apply to pain related to sickle cell disease or cancer or to patients receiving palliative or end-of-life care” (Dowell et al., 2022).

The National Heart, Lung, and Blood Institute and the American Society of Hematology (ASH) have issued guidelines for managing acute pain for patients with SCD (Brandow et al., 2020; NHLBI, 2014). Barriers to their use include lack of knowledge of their existence and systems barriers to implementing the protocols, such as state legislative mandates that prescribers register with or use prescription drug monitoring programs (The other opioid epidemic, 2019; Ruta and Ballas, 2016; Zhang et al., 2021).

Chronic Pain

To manage chronic pain in SCD, expert guidelines recommend multimodal, whole-person, holistic, opioid-sparing strategies that combine pharmacologic and nonpharmacologic interventions as part of a multidisciplinary care delivery strategy (Brandow et al., 2020; Imperial College Healthcare, 2023; Osunkwo et al., 2020). However, adherence to these guidelines is inconsistent, at least in part because one-third of the health care providers surveyed in a 2021 study did not know such guidelines existed. In addition, many SCD centers lack the multidisciplinary specialists and resources to implement these guidelines (Smeltzer et al., 2021).

Recognizing that pain experiences and responses to treatment can vary widely among individuals, it is essential to develop personalized multimodal (Kenney and Smith, 2022) pain management plans. Such plans are tailored to the specific needs of each patient, accounting for factors such as the severity and frequency of pain episodes, previous treatment responses, psychological comorbidities, and patient preferences. They should be developed by the treating provider in partnership with the patient and made readily accessible to treating providers in the electronic medical record or a patient portal so it can be shown to providers at any care facility. However, individual pain management plans have not been widely adopted (Baumann et al., 2023; Siewny et al., 2024).

Pharmacologic Interventions

The cornerstone of pain management in SCD includes pharmacologic treatments. NSAIDs and acetaminophen are commonly used to manage mild to moderate pain, but there are limitations for individuals with SCD who may have other gastrointestinal, cardiovascular, and renal risk factors in addition to the potential for toxicity (Han et al., 2017). For more severe pain, opioids are often prescribed, although their use must be balanced with

the risk of tolerance, habituation, addiction, and side effects. However, over the last 10 years, research has shown that chronic opioid therapy is only minimally effective at controlling chronic pain in individuals with SCD, while resulting in a high rate of adverse effects (Carroll et al., 2016; Chou et al., 2020; Sidhom et al., 2023). Regular opioid use can lead to significant side effects, including increased sensitivity to pain, or hyperalgesia, which may worsen pain levels and reduce overall quality of life. Despite this, many adults with SCD remain on high doses of chronic opioids. Contrary to the beliefs among some clinicians, the rate of opioid use disorder in individuals with SCD is no greater than in the general population, and, for some patients, opiate use allows them to meet functional goals with acceptable adverse effects. Access to long-acting chronic opioids is limited by prescription drug monitoring programs and the hesitancy of providers to prescribe them resulting from lack of experience or concerns about scrutiny from regulatory bodies (Kavanagh et al., 2022).

Over the past five years, using buprenorphine formulations to treat chronic pain associated with SCD has become more common, and one group of investigators has developed a protocol of induction, dosing, and management of withdrawal from opioids combined with interdisciplinary care (David et al., 2022). At a six-month follow-up, the overall rate of emergency department visits for acute pain episodes fell from a mean of 10.5 visits in the six months preceding induction of buprenorphine therapy to 2.9 in the six months after induction.

Another study evaluated health care utilization among individuals who switched from full agonist opioid pain management to buprenorphine (Torres et al., 2024). Emergency department visits in the six months following the start of buprenorphine therapy fell from a mean of 3.5 to 1.2, infusion visits fell from a mean of 6.7 to 3.2, acute care visits fell from a mean of 10.2 to 4.4, and hospitalizations fell from a mean of 1.8 to 0.3, while six-month routine follow-up visits with the individuals’ SCD team increased from a mean of 4.9 to 8.5. In a small descriptive study of adults with SCD who received buprenorphine for chronic pain, the participants reported improvements in functioning and relationships after starting buprenorphine (Prince et al., 2024).

In addition to NSAIDs and opioids, additional therapies, including anticonvulsants such as gabapentin and pregabalin and antidepressants such as duloxetine, milnacipran, amitriptyline, and nortriptyline, may be prescribed to alleviate neuropathic pain in individuals with SCD (Brandow et al., 2015; Smith et al., 2023). Muscle relaxants are often used in patients with muscular back pain. Given the overlapping adverse effects of many of these medications with opioids, careful titration and attention to adverse effects of these drug combinations is necessary. Outpatient ketamine infusion can

also be used to treat chronic pain by reducing opioid-induced hyperalgesia (OIH) and central sensitization. OIH can occur when an individual experiences an enhanced sensitivity to a painful trigger. Chronic use of opioids may lead to chronic pain in SCD from OIH or cyclic opioid withdrawal, further emphasizing the need for multimodal pain management (Osunkwo et al., 2020).

Studies have explored peripheral nerve blocks using local anesthetics as a treatment for opioid-refractory pain, particularly for acute pain crises (Karsenty et al., 2022). While there is limited evidence of efficacy, case studies suggest that these interventions may provide effective localized pain relief. However, the need for specialized expertise and the typically widespread nature of SCD pain constrain the widespread use of nerve blocks.

Nonpharmacologic Approaches

Pharmacotherapy alone has limited effectiveness in reducing the burden of chronic pain in individuals living with SCD and associated psychosocial comorbidities that commonly occur. Nonpharmacological strategies for pain management include psychological techniques such as cognitive behavioral therapy (CBT), mindfulness, acceptance and commitment therapy, coping skills training, and operant therapy; physical therapies including exercise, physical activities, and yoga; and integrative medicine approaches such as massage, acupuncture, and other complementary and alternative therapies. Limited data, mostly from studies with small sample sizes, suggest these nonpharmacological approaches can improve chronic pain in SCD, although a recent systematic scoping review concluded that “small sample sizes limit the ability to translate findings to clinical care” and “more research is needed to identify non-opioid, chronic pain treatments for SCD” (Sidhom et al., 2023). In addition, many of these therapies are not available even in higher resource settings and may be cost-prohibitive and not covered by public and private insurance providers.

Cognitive Behavioral Therapy

CBT, one of the most well-studied behavioral interventions for chronic pain of any origin, helps individuals modify dysfunctional thought patterns related to pain and develop effective coping strategies (Forden et al., 2024; Knoerl et al., 2016; Lim et al., 2018). Research has shown that CBT can provide clinical benefits for various patient groups. However, despite its widespread use in pain management for other conditions, it is not commonly included in treatment plans for individuals with SCD because of a lack of large-scale efficacy data in SCD, limited provider availability,

and stigma associated with seeking mental health services (Dampier et al., 2002; Jonassaint et al., 2024; Palermo et al., 2016, 2024; Van Veelen et al., 2023; Williams and Tanabe, 2016). Studies in the SCD population suggest CBT can reduce pain intensity, improve self-efficacy, increase daily functioning, and reduce health care utilization (Gil et al., 2001; Schatz et al., 2015; Van Veelen et al., 2023; Williams and Tanabe, 2016). Other approaches, including acceptance and commitment therapy, mindfulness-based treatments, and coping skills training, may be beneficial, and digital and internet-based CBT programs have also shown promise in increasing accessibility and engagement (Badawy et al., 2018; Connolly et al., 2023; Dev et al., 2024; Jonassaint et al., 2024; Lalloo et al., 2022; Palermo et al., 2024; Simmons et al., 2019). However, research has yet to establish a standardized CBT model specific to SCD.

Relaxation and Distraction Techniques

Methods such as biofeedback, hypnosis, meditation, and deep breathing exercises can help shift focus away from pain and promote relaxation. Studies indicate these techniques can reduce pain episodes and opioid reliance, particularly for mild to moderate SCD pain (Balsamo et al., 2019; Van Veelen et al., 2023; Wallen et al., 2021; Williams and Tanabe, 2016; Zaidi et al., 2023). However, most evidence is anecdotal.

Psychosocial Support

Given the high prevalence of psychological comorbidities such as depression and anxiety in individuals with chronic pain, routine screening and integrated mental support are recommended (Adeyinka and Griggs, 2025; Essien et al., 2023). Support groups and patient education programs can enhance self-efficacy and improve disease management (Clayton-Jones et al., 2023; Desine et al., 2021; Hazzard et al., 2002; Hsu et al., 2016; Porter et al., 2017).

Physical Therapy and Exercise

While strenuous exercise can trigger an acute pain crisis, recent studies have shown that low-to-moderate intensity activities such as gentle stretching, light resistance training, and regular endurance exercises of sub-maximal intensity can help individuals living with SCD better manage their chronic pain (Connes et al., 2024). One study, for example, demonstrated that a home-based therapeutic exercise program reduced lower back pain and increased functionality in individuals with SCD (Zanoni et al., 2021).

Another study found that a moderate intensity endurance exercise program increased capillary density around muscle fibers and partly reversed the microvascular deficits often seen in skeletal muscle of individuals with SCD (Merlet et al., 2019).

Programs that employ an interdisciplinary approach for treating chronic pain, such as combining CBT with neuromuscular exercise, show promise for improving pain in individuals with SCD. Between 82 and 90 percent of the individuals participating in one such program being evaluated in children reported their pain improved, and none experienced worsening pain (Sil et al., 2024).

Acupuncture

Acupuncture is a common treatment for chronic pain in general, with one meta-analysis concluding that “acupuncture has a clinically relevant effect on chronic pain that persists over time,” and that “referral for acupuncture treatment is a reasonable option for chronic pain patients” (Vickers et al., 2018). One small study, for example, found that individuals with SCD who had 10 acupuncture treatments experienced reduced pain intensity and pain interference (Li et al., 2021), while a larger randomized controlled study of individuals with SCD found that pain intensity, pain interference, and neuropathic pain symptoms were reduced following acupuncture treatments (Barrett et al., 2022). This study also found that anxiety, depression, sleep quality, chronic fatigue, and quality of life improved, while the number of body sites reported as painful decreased.

Other Approaches

Researchers have explored yoga, guided imagery, and music therapy as adjunctive treatment for chronic pain accompanying SCD (Alsabri et al., 2023; Bakshi et al., 2021; Brandow et al., 2020; Rodgers-Melnick et al., 2022). These approaches may help reduce stress, enhance relaxation, and improve overall well-being. While studies suggest these approaches can lower pain scores and opioid use, more rigorous research is needed to validate their effectiveness. Nonetheless, ASH suggests massage, yoga, virtual reality, and guided audiovisual relaxation as adjuncts to standard pharmacologic management for acute SCD pain (Brandow et al., 2020). While there is limited evidence of efficacy, these interventions pose minimal risk and may improve pain perception and coping. As of the 2020 guidelines, ASH does not make a recommendation for or against acupuncture and biofeedback for acute SCD pain given insufficient evidence. However, clinicians and patients together may consider these modalities based on patient preference and feasibility.

SUMMARY AND CONCLUSIONS

Pain is the most common symptom for which individuals living with SCD seek unscheduled medical care and is the most common morbidity causing functional impairment. Mitigating pain in individuals with SCD is a critical aspect of comprehensive care. By focusing on pain prevention, health care providers aim to reduce the frequency and severity of pain episodes and the development of chronic pain, thereby improving the overall quality of life for people living with SCD. Effective pain prevention strategies require a multimodal approach that includes both pharmacologic and nonpharmacologic interventions, making it essential to tailor these strategies to the unique needs of each individual with SCD. Mitigating pain focuses on prevention, with the most efficacious therapies to date being hydroxyurea, allogeneic HCT, and gene-editing or insertion therapy. Despite advances in the management of SCD, there are barriers to widespread use of pain-mitigating therapies. Even use of hydroxyurea among people living with SCD is low, highlighting the need for implementation and care delivery.

Treatment of SCD pain remains challenging given its complex pathophysiology and the variability in individual responses to treatment. The overlap of acute and chronic pain, along with factors such as OIH that can lead to central sensitization and psychosocial stressors, underscores the need for personalized multidisciplinary care. OIH can occur when an individual experiences an enhanced sensitivity to a painful trigger. Chronic use of opioids may lead to chronic pain in SCD from OIH or cyclic opioid withdrawal, thus further emphasizing the need for multimodal pain management. Recognizing that pain experiences and responses to treatment can vary widely among individuals, it is essential to develop personalized multimodal pain management plans. Such plans are tailored to the specific needs of each patient, accounting for factors such as the severity and frequency of pain episodes, previous treatment responses, psychological comorbidities, and patient preferences.

The cornerstone of pain management in SCD includes multimodal pharmacologic treatments. NSAIDs and acetaminophen are commonly used to manage mild to moderate pain. For more severe pain, opioids are often prescribed, although their use must be balanced with the risk of dependency and side effects. Most individuals with SCD manage their pain at home, and the increase in outpatient infusion centers in recent years has further shifted acute pain management for SCD away from emergency departments and inpatient settings.

When individuals experiencing a pain crisis do seek medical care in an emergency department, the recommended best practice is to administer pain medication within 60 minutes of their arrival, with frequent reassessments

and appropriate dose titration. Despite this, individuals with SCD, and Black Americans in general, experience prolonged wait times in the emergency department. Black Americans also are often undertreated for pain of any etiology, and those living with SCD may face greater barriers because of the frequency of their pain crises or acute-on-chronic pain episodes and because they know about specific medications and dosages that have previously proven effective for them. Emergency department personnel are often unfamiliar with SCD and erroneously believe that acetaminophen, for example, is sufficient for treating SCD pain. They may also misinterpret individuals’ coping strategies, such as distraction techniques or sleep, as indications that their pain is less severe than reported and individuals’ knowledge of and request for specific drugs and dosages, especially requests for a particular opioid and dose to be administered intravenously, as indicators of red-flag drug-seeking behavior. Despite the evidence, clinicians may expect an SCD crisis to involve some change in vital signs or laboratory test values and do not accept an individual’s report of pain as valid when they do not see objective measures.

Most adults living with SCD experience chronic pain. This complicates the treatment of acute SCD pain, because chronic SCD pain is poorly understood and lacks effective evidence-based interventions. To manage chronic pain in SCD, expert guidelines recommend multimodal, whole-person, holistic, opioid-sparing strategies that combine pharmacologic and nonpharmacologic interventions as part of a multidisciplinary care delivery strategy. However, adherence to these guidelines is inconsistent.

Based on its review of the literature and its expert assessment, the committee reached the following conclusions:

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¹² This sentence was changed after release of the report to clarify the limitations of the current proxies.

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