Disease-modifying therapies to prevent pain and other complications of sickle cell disease

INTRODUCTION — Acute vaso-occlusive pain is a hallmark of sickle cell disease (SCD) and the most common reason for seeking medical attention. After an acute vaso-occlusive pain episode resolves, it is prudent to ensure that appropriate measures have been taken to decrease the likelihood of future vaso-occlusive pain events and to reduce the intensity of chronic pain.

This topic discusses an approach to using disease-modifying therapies in individuals with SCD, which will help with preventing (or minimizing) vaso-occlusive pain episodes as well as reduce other vaso-occlusive complications, or, in the case of voxelotor, may reduce complications of hemolysis.

While these therapies are being presented in the context of preventing vaso-occlusive pain, their importance goes beyond pain prevention to reducing other disease complications and improving quality of life. Thus, they should be part of any comprehensive discussion of care for SCD patients.

These medications are not used for acute pain treatment, which requires rapid analgesia. Separate topic reviews discuss the evaluation and treatment of acute pain and the general management of SCD:

●Evaluation of pain – (See "Evaluation of acute pain in sickle cell disease".)

●Management of acute pain – (See "Acute vaso-occlusive pain management in sickle cell disease".)

●General SCD management – (See "Overview of the management and prognosis of sickle cell disease" and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

COMPONENTS OF SUCCESSFUL MANAGEMENT

Therapeutic relationship — Individuals with SCD may experience a number of adverse interactions with health care providers related to one of more of the following:

●Lack of clinician knowledge and expertise about the disease; inadequate knowledge about the range of available therapies, their efficacy, and their risk-benefit ratio; and lack of familiarity with acute and chronic pain management

●Concerns about opioid use disorder

●Complex interactions between pain and other disease comorbidities including asthma, renal disease, and cardiopulmonary disease

●Social, emotional, and educational limitations related to the burdens of a chronic illness

●Racism and institutional barriers

●Lack of efficient and evidence-based strategies for chronic disease management

●Difficulties in identifying experienced health care providers and obtaining adequate health care

Individuals with SCD and family members may encounter many obstacles (time, distance, correct payer-provider match) in identifying a health care provider with the appropriate knowledge and time commitment, along with a health care system designed to address chronic disease management.

Steps the clinician can take to facilitate a good therapeutic relationship include the following:

●Examine their own attitudes and misperceptions that may be interfering with appropriate care. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Provider misperceptions that interfere with the assessment'.)

●Avoid pejorative terminology in the medical record, when speaking with colleagues, and when addressing the affected individual or their family members. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Terms and language we avoid'.)

●Ensure good communication (oral and written) between pediatric and adult providers, with input from the affected individual and family, during the transition from pediatric to adult care. (See "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care".)

●Solicit input from other specialists to address social needs, depression, and other disease comorbidities. (See "Overview of the clinical manifestations of sickle cell disease".)

Individualized care plan — Every individual with SCD should have an established care plan for reducing and managing pain at home that takes into account their (and their family's) needs (table 1). The plan should be available to the individual and family members, as well as all treating clinicians, including those providing primary care, those in the emergency department, and the hematology team. The plan should instruct the individual how to appropriately manage mild, moderate, and severe pain, with a predefined threshold for the use of opioids and when to contact health care providers.

The plan should be available in the medical record, so that all involved can have electronic access to the most current, individualized strategy to manage pain.

Several studies have demonstrated that implementation of individualized care plans involving early aggressive treatment of pain has improved outcomes including hospital admissions, lengths of stay, and re-admission rates [1-5]. In one such study, a comprehensive SCD plan including access to analgesics lowered emergency department visits for uncomplicated pain by 84 percent [3]. In another study, a comprehensive individualized care plan reduced hospital admission rates from 51 percent per year to 39 percent per year (a 24 percent reduction) [4]. Financial savings have also been documented [6].

Ideally, input from individuals with SCD, families, nurses, emergency department personnel, hospitalists, and hematologists is solicited in the development of an institutional template, to ensure that the plan will be consulted and followed. Pain treatment plans must be tailored to the individual and may vary considerably depending on the daily symptoms, presence of chronic pain, opioid tolerance, medication side effects, and comorbidities such as renal insufficiency [7,8]. The transition from pediatric to adult care is a frequent setting when interruptions in care can occur and can lead to detrimental outcomes; thus, special attention should be paid to the updating of the care plan during this transition. (See "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care".)

IMPORTANCE OF PREVENTION

Prevalence of pain — Pain is the most common complication of SCD and the most common reason for individuals with SCD to seek medical attention [9,10]. The reported prevalence of pain in SCD is highly dependent on the definition of pain (eg, pain that was relieved with a nonsteroidal antiinflammatory drug [NSAID] versus that requiring an opioid) and the setting in which the pain was documented (home versus hospital or emergency department).

●In a 2010 study of almost 200,000 emergency department visits by children and adults with SCD, 67 percent were for pain [11]. Visits for chest symptoms (pain, shortness of breath, cough) and fever accounted for only 20 and 6 percent, respectively.

●Another study involving 21,112 people with SCD who presented to the hospital or emergency department reported a mean of 2.6 encounters per year (95% CI, 2.5-2.7) [12]. This included a mean of 1.5 encounters that resulted in hospitalization and 1.1 for treatment in the emergency department without hospital admission. The age range with the highest health care use was 18 to 30 year olds. Individuals with public health insurance had a higher rate of health care use than individuals with private insurance.

●In a 1991 study of 3578 individuals with SCD (newborns through adulthood), the annual incidence of acute pain episodes was greatest in the 20 to 29 years age group [13]. Nearly 40 percent of individuals did not seek medical attention for pain, whereas approximately 5 percent of individuals with homozygous sickle cell anemia (Hb SS) had more than three episodes per year, accounting for approximately one-third of the total pain episodes. This may explain the skewed perception of hospital-based clinicians that most people with SCD have frequent pain episodes.

The incidence rate of acute pain episodes cannot be prevented completely. However, certain therapies may be helpful in minimizing the frequency and/or intensity of pain. In the majority of studies, the populations studied included mainly individuals with Hb SS and sickle-beta⁰-thalassemia. However, as noted below, the therapies are likely to be effective in individuals with hemoglobin SC disease who have significant vaso-occlusive pain and require a disease-modifying therapy. (See 'Which patients require preventive therapy?' below.)

Which patients require preventive therapy? — Preventive therapy with one or more of the agents discussed below is appropriate for any individual with a history of frequent vaso-occlusive pain episodes or infants with hemoglobin SS or Hb S-beta⁰-thalassemia, who are expected to develop frequent pain episodes if left untreated (algorithm 1).

The number of pain episodes is somewhat subjective depending on how a pain episode is defined. We generally consider pain episodes to be frequent if they occur more than two to three times a year and are severe enough to require opioid pain medications or treatment at home, emergency department, hospital, or day clinic. (See 'Prevalence of pain' above.)

Use of preventive therapy should involve shared decision making with the sickle cell disease expert and the family. Different factors may be important for different patients/families/caregivers:

●Age of patient – The American Society of Hematology recommends that hydroxyurea be offered at nine months of age; product information cites US Food and Drug Administration (FDA) approval for ≥2 years. Glutamine is approved for children ≥5 years and crizanlizumab for ≥16 years.

●Route of administration – Crizanlizumab is given intravenously every two weeks for the first month and monthly thereafter. Patients with challenging venous access may require central line placement, in addition to monthly admissions to the day hospital. While adherence with oral medication is generally better than with parenteral medication, a subgroup of patients with frequent pain events and difficulty with medication adherence may find monthly injections more suitable.

●Frequency of laboratory monitoring – Hydroxyurea requires ongoing close laboratory monitoring, while the other agents (glutamine, crizanlizumab) do not.

●Toxicity concerns – Hydroxyurea has been used for over 25 years in SCD and has a validated track record of safety and efficacy. There are a number of potential toxicities that are usually minor and can be reversible but are often misunderstood by families, at times leading to reduced acceptance. Temporarily decreased fertility, especially in males, may be important in family planning decisions. Non-serious hair loss, changes in fingernail color, and transient, non-severe myelosuppression can be observed. Hydroxyurea dosing may need to be modified to avoid myelosuppression.

The main toxicity of L-glutamine is gastrointestinal complaints. Glutamine may cause increased ammonia levels in patients with comorbid disease. Older patients may experience greater toxicity.

Crizanlizumab has been associated with rare acute drug reactions, especially at the onset of therapy, and occasional joint pain. Its major adverse consequence is the requirement for venous access and hospital infusions [14].

●Efficacy for pain or other symptoms – Hydroxyurea is the most effective therapy for reducing vaso-occlusive pain and generally is the first drug of choice for all age groups. Hydroxyurea can be safely used in combination with each of the other drugs.

Crizanlizumab is associated with a 45 percent reduction in pain events, compared with a 33 percent reduction with glutamine, indicating that crizanlizumab is the most effective secondary drug for decreasing pain events; addition of crizanlizumab to hydroxyurea may be the best choice for patients who require more control of acute painful events than can be provided with hydroxyurea alone.

Overall analysis of voxelotor from a randomized trial did not show a statistically significant decrease in pain events with voxelotor versus placebo, though unpublished data that stratified patients by hemoglobin response suggest patients with high hemoglobin have improved pain relief [15,16]. Overall, voxelotor does not significantly decrease acute pain events, and we do not endorse its use for attenuating vaso-occlusive pain. Voxelotor may be considered in patients whose morbidity is from severe anemia (hemoglobin ≤6.5 g/dL), excessive fatigue, poor quality of life, and decreased Clinical Global Impression of Change (CGI-C) score [17-21]. The one pain indication for which voxelotor would be a primary indication would be patients with significant pain from skin ulcers [22]. Definitive evidence in healing of leg ulcers is awaited.

Overall recommendations/summary — General recommendations for shared decision making with the family include the following (these recommendations are the author's approach; each patient has individual comorbidities and family/caregiver considerations, and there are no prospective head-to-head comparative trials done).

●Hb SS or Hb S-beta⁰ thalassemia age >12 months:

•Hydroxyurea – Initiating hydroxyurea and titrating to maximum dose is the first primary treatment in all patients (algorithm 2). (See 'Hydroxyurea' below and "Hydroxyurea use in sickle cell disease", section on 'Indications and appropriate age to start therapy'.)

•Crizanlizumab and L-glutamine – If pain episodes are present after ≥6 months of hydroxyurea with documented adherence, adding a second medication is reasonable. Crizanlizumab would be the second choice if the patient continues to have frequent pain and venous access is not an issue. L-glutamine would be the choice in patients who have problems with monthly infusions and/or difficult venous access. (See 'Options if hydroxyurea is not tolerated or ineffective in individuals with Hb SS or Hb S-Beta(0)-thalassemia' below.)

•Voxelotor – In patients on hydroxyurea who have significant hemolytic anemia, fatigue, decreased global performance, and poor quality of life, voxelotor would be indicated. It increases hemoglobin and decreases hemolysis and there is no evidence of increased sickle complications with its use. Its benefits to the patient over time should monitored. Early concerns about voxelotor causing increased viscosity and symptoms as hemoglobin rises have not been observed. Patients with the highest hemoglobin had the least amount of pain in their study. Based on these observations, the hemoglobin rise appears safe [23]. Included in decision-making about combination therapy should be the understanding of the burden of polytherapy.

An expanded discussion of these decisions is presented below. (See 'Disease-modifying medications' below.)

●Transfusions – Transfusions are not used routinely to prevent pain. However, selected individuals with frequent acute pain episodes despite disease-modifying therapy such as hydroxyurea, chronic pain, or both, may benefit from a six-month period of regular blood transfusion therapy to keep the hemoglobin S concentration less than 50 percent or even 30 percent [24]. Evidence suggesting decreased pain events, emergency department visits, and 30-day readmission rates is accumulating; however, most data come from single-institution, non-randomized studies [25-28]. (See 'Refractory pain: Role of regular transfusions' below.)

Chronic transfusion may also be used in other settings such as stroke prevention or pregnancy. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

The primary studies evaluating the preventive therapies have focused on homozygous sickle cell anemia (Hb SS) and sickle-beta⁰-thalassemia. However, the therapies are likely to be effective in individuals with hemoglobin SC disease (Hb SC) who have significant vaso-occlusive pain and require a disease-modifying therapy. Since increased blood viscosity is characteristic of Hb SC, attention to the increase in hemoglobin levels is required, especially with hydroxyurea, voxelotor, or transfusions [29-33]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Risk of hyperviscosity syndrome from simple transfusion'.)

●Potentially curative therapies and investigational approaches – Allogeneic transplant and modified autologous transplant using gene therapy or gene editing are not in routine use for sickle cell disease. Transplant is a potential curative option and appropriate in some cases; however, agreement is lacking on the indications for stem cell transplantation. Due to the absence of randomized trials of transplantation and a paucity of long-term follow-up data, universal recommendations have not been made. In general, children who have had a stroke, life-threatening acute chest syndrome, acute pain or recurrent major priapism unresponsive to maximum disease-modifying therapy are accepted candidates for HLA matched sibling transplantation, after excluding undiagnosed/untreated asthma and acute psychosocial stressors that may exacerbate pain, including sexual trauma. Hematologists, transplant physicians, and psychologists or psychiatrists should evaluate all transplant candidates to address these potential confounders to severe SCD.

The highest success rates after allogeneic transplantation are seen with HLA-identical matched related donors [34]. Curative therapies are undergoing rapid advances and families should be educated about their progress, including alternative donor options and genetic approaches. Families should be routinely informed about open research protocols, including their risks and benefits. (See "Hematopoietic stem cell transplantation in sickle cell disease".)

Numerous therapeutic targets and approaches are under investigation in SCD, as discussed in a separate topic review. (See "Investigational therapies for sickle cell disease".)

●Oxygen – We do not use prophylactic oxygen to prevent vaso-occlusive episodes, either during routine activities or commercial airline travel, as there are no high-quality data demonstrating a benefit [35,36]. Furthermore, administration of oxygen for individuals with normal oxygen saturation may obscure detection of acute lung disease if it occurs. (See "Overview of the pulmonary complications of sickle cell disease".)

Several large case series and our own experience have shown that hypoxic events related to airlines are rare [37]. An exception would be an individual with known hypoxic lung disease or who is already receiving oxygen at home. Individuals with SCD can and should request oxygen if they become short of breath during air travel, similar to those without SCD. Our advice differs from a 2003 guideline that suggests all individuals with SCD should bring prophylactic oxygen during airline travel [38].

●Investigational agents – Clinical trials investigating new approaches may be appropriate for selected motivated individuals. Numerous therapeutic targets and approaches are under investigation in SCD, as discussed in a separate topic review. (See "Investigational therapies for sickle cell disease".)

●Day hospital pain program – Day hospital management of acute pain can dramatically reduce emergency department visits and hospital admissions and can dramatically improve pain resolution. All studies of day hospitals have demonstrated this remarkable benefit in managing pain. Supporting evidence is discussed separately. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Day hospital/infusion center'.)

If no day hospital facility is present, we encourage the hematology oncology service to ensure that patients that they follow routinely have the ability to come to the hematology oncology clinic for outpatient management of their acute pain rather than being triaged to the emergency department.

●Chronic pain – Chronic pain contributes significantly to morbidity and health care utilization in adults with SCD [39]. Multiple underlying causes of chronic pain confound the diagnosis and management of SCD. Etiologies may include (but are not limited to) inflammatory pain, neuropathic pain, and opioid-induced hyperalgesia [39]. Many adults with SCD, however, have chronic daily pain without indicators of vaso-occlusive pain. Adults with a chronic-pain phenotype have nerve damage, chronic inflammation, and sometimes central sensitization. They often have allodynia and hyperalgesia complicating therapies and may continue to have chronic pain following hematopoietic stem cell transplant or gene therapy [40].

In the general population, a bidirectional relationship between trauma and chronic pain has been established [41]. Multiple trauma etiologies, including sexual violence, have been described as precipitators of chronic pain. A temporal relationship between trauma and chronic pain has also been described in individuals with SCD, suggesting that a history of traumatic exposure is a risk factor for chronic pain [42,43]. We recommend a culturally sensitive interview, preferably with a trusted health provider with a pre-existing relationship, to elicit a thorough history of traumatic events that may lead to acute and chronic pain. (See 'Reducing pain triggers' below.)

The triggers and underlying biologic mechanisms of acute and chronic pain following a traumatic event are not well documented. However, reasonable working hypotheses include roles of mental stress, fear, and anxiety as triggers of acute vaso-occlusive pain episodes [44]. Anticipation of a noxious trigger causes precapillary arteriolar constriction, leading to vaso-restriction and increased red blood cell transit time [45].

We avoid therapies that lack evidence of benefit in the acute pain management setting (eg, antiplatelet agents), due to lack of evidence for efficacy and clear evidence of potential harm [46]. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Therapies we do not use'.)

DISEASE-MODIFYING MEDICATIONS

Choice of medication — The optimal sequence or combination of therapies that maximizes benefits and minimizes side effects is unknown. Until randomized trials are available to answer these questions, we recommend shared decision making to personalize selection of therapy, as summarized in the algorithm (algorithm 1).

Decision-making should include the affected individual, family members and caregivers (for children), and other clinicians involved in the care of the affected individual. After initiation of treatment, it is important to have ongoing objective and patient-reported assessments of the efficacy in reducing vaso-occlusive episodes. If no benefit is obtained, evaluation is warranted to determine the reasons for lack of benefit and the possible role of using a different treatment approach.

Given the lack of comparative studies and long-term data, at our institution we initiate hydroxyurea at least at 20 mg/kg/day up to maximum tolerated dose in all symptomatic patients. If pain continues to contribute to a decreased quality of life despite hydroxyurea, with the family’s agreement, we add crizanlizumab to the treatment regimen. If chronic venous access and hospitalization cannot be accomplished, we initiate L-glutamine.

We generally adhere to the age restrictions recommended by the US Food and Drug Administration (FDA). However, we are willing to discuss off-label use of these therapies on a case-by-case basis, and the discussion below should not be interpreted to restrict choices for affected individuals, especially in light of the limited clinical data available for the newer therapies.

●For children and adults with Hb SS or Hb S-beta⁰-thalassemia, hydroxyurea is the main preventing therapy for decreasing the incidence rate of acute vaso-occlusive pain. (See 'Hydroxyurea' below.)

●Other therapies that can further reduce acute vaso-occlusive pain episodes are L-glutamine and crizanlizumab. All of these therapies can be used concurrently with hydroxyurea. (See 'Options if hydroxyurea is not tolerated or ineffective in individuals with Hb SS or Hb S-Beta(0)-thalassemia' below.)

Ultimately, the decision among these agents will depend on patient age, patient preferences and values related to the burdens of therapy and adverse events, and patient access to the therapy.

•These agents have not been directly compared to each other or to hydroxyurea. They have different mechanisms of action and appear to have additive effects, although the baseline frequency of pain events and the clinical parameters evaluated in published studies were different. Thus, their relative efficacy is unknown.

•Furthermore, these agents carry different burdens of administration, monitoring needs, and adverse event profiles that need to be considered when determining the best therapy for each patient, as summarized in the table (table 2). As an example, L-glutamine requires oral administration twice a day, while crizanlizumab requires monthly intravenous administration of approximately 30 minutes. Patient preferences and clinical utility of these therapies without or without hydroxyurea must be evaluated.

Hydroxyurea — Hydroxyurea (Siklos, Hydrea; approved in 1998; mechanism involving increased hemoglobin [Hb]F, decreased white blood cells [WBC], and others) is the preferred initial therapy for all children and adults with Hb SS or Hb S-beta⁰-thalassemia. Limited exceptions include women who are pregnant or individuals who are attempting conception (males or females).

We recommend hydroxyurea in all individuals with Hb SS or Hb S-beta⁰-thalassemia regardless of a history of vaso-occlusive pain (algorithm 1), including infants, children, and adults, based on evidence of benefit in randomized trials, consistent with National Heart, Lung, and Blood Institute (NHLBI) guidelines published in 2014 [7]. Assessment of frequent pain episodes reinforce the clinical utility of hydroxyurea and should be based on a thorough history of self-reported pain rather than hospitalizations because most pain episodes are treated at home. The benefits of hydroxyurea are summarized in the table (table 3).

Also per NHLBI guidelines, we recommend hydroxyurea for infants ≥9 months with Hb SS or Hb S-beta⁰-thalassemia who are asymptomatic.

For other SCD compound heterozygotes such as hemoglobin SC disease (Hb SC), hydroxyurea should be administered on a case-by-case basis weighing the pros and the cons, as the clinical utility of hydroxyurea in these individuals is far less well established. There is also a concern that hydroxyurea may exacerbate the pre-existing hypercoagulable state of individuals with Hb SC disease and/or may increase the risk of hyperviscosity [47]. Randomized trials of hydroxyurea have not been performed in individuals with Hb SC disease, but observational studies suggest benefit in children and adults with Hb SC [48-53].

Hydroxyurea has the greatest long-term evidence for benefit in reducing acute painful episodes as well as reducing other vaso-occlusive complications of SCD such as acute chest syndrome and in some cases stroke (see "Prevention of stroke (initial or recurrent) in sickle cell disease"), decreasing the requirement for blood transfusions, and improving survival (table 3).

Monitoring adherence and individualizing the dose for maximum benefit and limiting toxicity (predominantly myelosuppression) is critical.

Details of the benefits, supporting evidence, and dosing are presented separately. (See "Hydroxyurea use in sickle cell disease", section on 'Evidence for efficacy' and "Hydroxyurea use in sickle cell disease", section on 'Administration and dosing'.)

Despite the well-recognized advantages of hydroxyurea in individuals with Hb SS or Hb S-beta⁰-thalassemia, many individuals who would benefit do not receive hydroxyurea for a number of reasons:

●Lack of clinician knowledge about and familiarity with benefits, dosing and monitoring, and adverse effects

●Limited access to hydroxyurea oral solution for infants and children

●Patient concerns about carcinogenicity, teratogenicity, and other side effects

●Burdens of daily use and frequent clinical and laboratory monitoring

●Magnitude of other routine evaluations and interventions for disease monitoring and treatment

●Delay in benefit during initiation of therapy and titration to maximum tolerated dose

●Inadequate health insurance coverage, especially in the United States and for those who live in poverty

Further, among those who do receive hydroxyurea, many do not receive optimal benefit because the maximum tolerated dosing is not used. (See "Hydroxyurea use in sickle cell disease", section on 'Monitoring and dose titration'.)

Clinicians should be educated about the pros and cons of hydroxyurea and work closely with patients and families to address barriers to effective therapy and to ensure that adequate dosing is provided. The approach in our center is to provide a handbook for the families to read prior to and during treatment with hydroxyurea therapy. Typically, the benefit of hydroxyurea in reducing pain episodes does not occur for at least three months. Thus, discussion about the benefits and risks of hydroxyurea and the decision about its initiation should occur on an outpatient basis after the acute pain episode has resolved. (See "Hydroxyurea use in sickle cell disease", section on 'Eliminating barriers to appropriate therapy' and "Hydroxyurea use in sickle cell disease", section on 'Administration and dosing'.)

As discussed separately, the extensive experience with hydroxyurea over more than three decades does not demonstrate any increased risk of malignancy. Boxed warnings on the product information sheets for these drugs were based on observed associations in individuals with myeloproliferative neoplasms, in whom the baseline risk of malignancy is substantially increased (association, not causation). No increased risk of malignancy has been observed in children and adults with SCD after several decades of clinical use with close monitoring. However, some individuals may have intolerable side effects such as hair loss. Effects on fertility are less clear. (See "Hydroxyurea use in sickle cell disease", section on 'Adverse effects'.)

Hydroxyurea can cause embryo fetal toxicity and should not be used in individuals (male or female) planning conception or during pregnancy or breastfeeding. However, some programs are using hydroxyurea cautiously during the second and third trimesters.

The mechanism of action of hydroxyurea is complex and may involve a number of changes including increased production of fetal hemoglobin, increased nitric oxide, improved red blood cell (RBC) rheology, decreased WBC count, and decreased WBC adhesivity to the vasculature. (See "Hydroxyurea use in sickle cell disease", section on 'Mechanism of action'.)

Options if hydroxyurea is not tolerated or ineffective in individuals with Hb SS or Hb S-Beta(0)-thalassemia — The optimal combination of available medications other than hydroxyurea is unknown, and until randomized trials have been conducted, shared decision making is required to personalize the selection of combination therapy. (See 'Choice of medication' above.)

Crizanlizumab — Crizanlizumab-tmca (crizanlizumab; approved in 2019; mechanism anti-P-selectin) is an option for individuals ≥16 years with SCD who have acute vaso-occlusive pain episodes unresponsive to hydroxyurea, L-glutamine, or both (table 2).

In 2023, the European Medicines Agency (EMA) recommended revoking authorization for crizanlizumab [54]. The recommendation was based on preliminary analysis of data released from the ongoing STAND randomized trial [55]. We do not recommend changing the indications for crizanlizumab until the trial is completed and reviewed; our plan is to continue the use of crizanlizumab until the results are published.

●Potential indications – Crizanlizumab may be a good option for individuals who have difficulty with adherence to a once or twice daily oral medication, those who are able to tolerate monthly intravenous therapy, those who would prefer a fixed schedule for monthly interactions with their providers during which other health care needs could be addressed, and those who have access to the infrastructure for its delivery (algorithm 1). It may be especially useful for those with frequent and/or severe acute vaso-occlusive pain episodes. For some individuals, the need for monthly clinical visits for the infusion may be an obstacle to use.

●Dosing – Crizanlizumab is given at a dose of 5 mg/kg by intravenous infusion (30 minutes) on week 0, week 2, and every 4 weeks thereafter.

●Supporting evidence – The efficacy of crizanlizumab in reducing the painful episodes was demonstrated in the SUSTAIN trial but questioned in the STAND trial.

•SUSTAIN – This trial randomly assigned 198 individuals with SCD to receive placebo or one of two doses of crizanlizumab [56]. Participants included individuals with SCD ages 16 years or older who had at least two painful episodes per year; approximately two-thirds were also receiving hydroxyurea at a stable dose upon trial entry. Acute pain episodes were defined as events with no medically determined cause (other than vaso-occlusion) that resulted in a medical facility visit and treatment with an oral or parenteral opioid or with a parenteral nonsteroidal antiinflammatory drug (NSAID). Treatment was given for one year with placebo, crizanlizumab at 2.5 mg/kg every four weeks (low-dose), or crizanlizumab at 5 mg/kg every four weeks (high-dose).

The primary endpoint of the study was the annualized pain rate. The rates of pain episodes per year were as follows:

-Placebo: 2.98

-Crizanlizumab, 2.5 mg/kg: 2.01

-Crizanlizumab, 5 mg/kg: 1.63

A greater number of individuals in the high-dose crizanlizumab group had no pain episodes during a year of treatment (36 versus 18 percent with low-dose crizanlizumab and 17 percent with placebo). Subgroup analysis confirmed efficacy in individuals with a greater frequency of painful events per year, various SCD genotypes, and concomitant hydroxyurea use [57].

•STAND – This trial, which also evaluated two doses of crizanlizumab (5.0 and 7.5 mg/kg) versus placebo in adolescents and adults with SCD, has not been published, but a preliminary interim analysis determined that the average number of pain episodes requiring a health care visit was 2.5 per year in the crizanlizumab group versus 2.3 per year in the placebo group [55]. Total pain episodes (treated at home or requiring a health care visit) were 4.7 with crizanlizumab versus 3.9 with placebo.

Crizanlizumab was well-tolerated in both trials (SUSTAIN and STAND), with no major increase in serious or minor adverse events [57]. There is small increased risk for arthralgias and other symptoms; they are typically minor. Therapy is expensive.

●Mechanism of action – Crizanlizumab is a monoclonal antibody directed against P-selectin, an adhesion molecule expressed on activated platelets and endothelial cells. It is thought to reduce vaso-occlusive pain by reducing interactions between endothelial cells and circulating blood cells [58].

L-glutamine (pharmaceutical grade) — L-glutamine (glutamine, Endari; approved in 2017; mechanism possible effect on oxidative state of RBCs) is an option for children and adults who continue to have vaso-occlusive pain episodes despite appropriately dosed hydroxyurea or who cannot tolerate hydroxyurea for any reason (table 2).

●Potential indications – L-glutamine is a good option for those who prefer oral medication and can be adherent to twice daily dosing (algorithm 1). However, follow-up of the efficacy and biologic effects of L-glutamine has not yet been published after the phase 3 trial in 2018, and our recommendations will be reassessed over time.

●Dosing – L-glutamine is supplied in 5 g packets of powder to be mixed with food or beverages and taken twice daily. The dose is based on body weight (5 to 15 g twice daily; total daily dose 10, 20, or 30 g [maximum]) [59]. The pharmaceutical grade formulation evaluated in clinical trials should be used as the benefit of other glutamine formulations, including those available over-the-counter, have not been studied with similar rigor.

●Supporting evidence – The clinical efficacy of L-glutamine has been demonstrated in individuals >5 years of age and appear to be independent of hydroxyurea use:

•A randomized trial assigned 230 children >5 years of age and adults with SCD who had at least two pain events in the prior year to receive glutamine in powder form (0.3 g/kg orally twice per day; maximum daily dose 30 g) or placebo [60]. Participants were monitored for approximately one year. Approximately two-thirds of the participants in both arms were also receiving hydroxyurea on a stable dose that was continued during the trial. Compared with placebo, L-glutamine was associated with the following benefits:

-Fewer acute pain events (4 versus 3)

-Fewer hospitalizations (3 versus 2)

-Fewer days in the hospital (11 versus 7)

-Fewer patients with acute chest syndrome (23 versus 9 percent)

These benefits were independent of hydroxyurea use.

•Similar results were reported in a smaller trial from the same group and in small observational studies [61,62].

However, the long-term efficacy is unknown and requires additional study.

Significant adverse effects have not been observed with L-glutamine, with only a slight increase in mild gastrointestinal symptoms over placebo [60]. Therapeutic drug monitoring is not required [60]. Some clinicians have raised concerns that use of L-glutamine may be hindered by the need to mix the powder with food or beverages, that use of glutamine may interfere with administration of hydroxyurea, and that the high cost of pharmaceutical-grade glutamine may be a barrier to its use [59,63].

●Mechanism of action – The mechanism by which L-glutamine decreases acute painful episodes is incompletely understood. It is thought to involve reduction of oxidative stress in red blood cells (RBCs) that contain sickle hemoglobin. Glutamine is a precursor of nicotinamide adenine dinucleotide (NAD), and preclinical studies showed that glutamine treatment of sickle RBCs in vitro lead to reduced sickling, decreased adhesivity to the vasculature, and increased redox potential [61,62,64]. Glutamine is also used in the synthesis of proteins and nucleic acids, and as such, is important in rapidly dividing cells such as hematopoietic precursors [59,63]. L-glutamine is a conditionally essential amino acid; it is synthesized in the body, but production becomes inefficient during times of stress [63].

ADJUNCTIVE INTERVENTIONS — Pain is complex and influenced by more than just vaso-occlusion. Attention to other aspects of pain management may also reduce the frequency and severity of acute pain events.

These interventions discussed below should be an adjunct to therapies that have been documented to reduce pain, not a substitute. They should be used to the extent that the affected individual and/or family finds them helpful, and they should not distract from other aspects of medical care.

Reducing pain triggers — Triggers for pain may be obvious to the patient, family, or both. Reducing these triggers may lessen the frequency and/or severity of acute pain, and many individuals with SCD develop strategies to avoid or minimize these triggers. Common triggers for pain may include cold temperature, dehydration, overexertion, hormonal changes such as onset of menses, and respiratory exposures (tobacco smoke, wind, air pollution, asthma exacerbation) [65-76].

Avoidance of other triggers for pain may be individualized, such as extreme temperatures, cold showers, swimming in an unheated swimming pool, asthma exacerbations, stress, and/or exhaustion.

Overall health maintenance — All individuals with SCD should be educated about the importance of hydration, healthy diet, psychosocial support, and adequate sleep. Hydration is especially important during strenuous exercise or travel. Depression and insomnia can accentuate acute as well as chronic pain.

●General health – As with other conditions that cause chronic pain, attention to general health and well-being may be especially helpful to some individuals. This may include one or more of the following:

•Exercise.

•Nutrition and hydration.

•Sleep hygiene and/or interventions for insomnia.

•Stress reduction, which may include a number of strategies such as those discussed in other topic reviews. (See "Complementary and integrative health in pediatrics" and "Complementary and alternative treatments for anxiety symptoms and disorders: Physical, cognitive, and spiritual interventions".)

•Avoidance of smoking and limiting exposure to environmental tobacco smoke. (See "Overview of smoking cessation management in adults".)

●Healthy diet – Nutrition is an important factor in the overall well-being of individuals with SCD. Nutritional deficiencies are prevalent in SCD and may be associated with worse pain outcomes, and patients require a proactive approach from the health care system and family. Lack of adequate nutrition is a serious, often overlooked factor in disease manifestations. Food insecurity linked to health inequities may contribute.

Unless addressed, inadequate nutrition may lead to growth retardation and disease exacerbation in children and to metabolic syndrome in adults [77-79]. Many families would benefit from nutrition and dietary counseling. Undernutrition in low-resource settings is a risk factor for mortality in both infants and children in SCD. The mortality rate in underweight children ages 5 to 12 years with SCD ages was increased. Close monitoring of weight in children can result in early calorie intervention and improved outcome [80,81].

Vitamin D deficiency is observed in a majority of patients and is linked to reduced bone mineral density and possibly disease severity [82,83]. People with pain SCD also have higher rates of other deficiencies including magnesium, zinc, arginine, glutamine, vitamin A, and vitamin E [84]. Lower levels of the antiinflammatory precursor fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EHA) have been proposed as possible factors contributing to increased vaso-occlusive pain [85]. A randomized trial of DHA and EHA demonstrated a positive trend, with improvements in laboratory and clinical features [86].

Recommendations that include dietary advice are available from the Centers for Disease Control (CDC) on their website in a self-care document [87]. Additional dietary recommendations for children are presented separately. (See "Dietary recommendations for toddlers and preschool and school-age children".)

●Depression and anxiety – As with any condition that produces chronic pain, SCD pain may be associated with various psychosocial stresses that contribute to depression, anxiety, and social isolation [9]. The Pain in Sickle Cell Epidemiology Study, a prospective cohort study in 232 adults with SCD, collected data on health-related quality of life, depression, and anxiety at baseline in daily diaries for up to six months and found high levels of depression (28 percent) and anxiety disorder (7 percent) [88]. Individuals with depression had significantly more days with pain than individuals without depression (71 versus 50 percent, p <0.001). Individuals with anxiety alone had more pain, distress from pain, and interference from pain, and they used opioids more often. Individuals who had both depression and anxiety did not function as well on all eight SF-36 subscales.

Psychosocial support should be appropriate to the individual's needs and may include cognitive-behavioral approaches, relaxation or breathing exercises, yoga, or self-hypnosis [7,89-92]. Preliminary data testing whether acupuncture or guided relaxation reduces chronic pain when compared with usual care have been encouraging in the ongoing GRACE trial to evaluate their efficacy. We encourage psychologic therapy when appropriate due to the potential benefit without any evidence of harm [93]. These approaches are discussed in more detail separately [94]. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Nonpharmacologic therapies'.)

●Adequate sleep – Insomnia can be a serious problem that may be exacerbated by anxiety and inadequate pain control, and in turn, it may contribute to emotional distress and pain perception. Additional disorders may contribute to insomnia in SCD, including unrecognized sleep-disordered breathing (eg, obstructive sleep apnea, nocturnal hypoventilation) with hypoxia and/or restless legs syndrome [95]. Interventions to address these disorders may help reduce pain as well as other SCD complications. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Sleep-disordered breathing' and "Restless legs syndrome and periodic limb movement disorder in children" and "Overview of the treatment of insomnia in adults" and "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)

There are effective treatments for depression and insomnia that may improve pain as well as other symptoms. (See "Overview of the treatment of insomnia in adults" and "Screening for depression in adults".)

The time required in determining the individual's needs and providing education may be substantial; the benefits in overall pain management as well as other aspects of comprehensive care are also likely to be great.

Cannabinoids — Among individuals with SCD, a questionnaire-based study found that approximately one-third or more self-medicate with cannabinoids for pain [96]. Our experience suggests that the proportion using cannabinoids for pain may be as high as 50 percent. Trials in non-sickle cell populations suggest that cannabinoids can be effective in some individuals; however, data from randomized trials are lacking for SCD pain. Therefore, it is appropriate to be aware of cannabinoid use in SCD patients and not to label these individuals as drug-seeking merely because they are using cannabinoids for pain prevention.

However, we do not recommend cannabinoids for pain prevention in SCD, pending data from randomized trials specific to SCD patients. Individuals using cannabinoids should be followed for potential adverse effects such as effects on neurocognitive function, gastrointestinal symptoms, and broncho-reactive airway disease. CBD has significantly less psychotropic effects compared with tetrahydrocannabinol; thus, it offers a relatively safer alternative to cannabis and a better therapeutic choice.

Available evidence includes the following:

●Sickle cell pain – Preclinical models suggest that cannabinoids have analgesic and antiinflammatory effects on sickle cell-related pain, perhaps by inhibiting mast cell activation and reducing hyperalgesia [97].

•A 2020 retrospective review of 50 individuals interested in receiving certification for medical marijuana found that those who obtained medical marijuana to manage pain had a reduction in hospital admissions compared with individuals who were certified but did not obtain the medication or those who did not obtain certification [98]. Compared with illicitly obtained marijuana, participants found medical marijuana to be safer, more effective, and stronger, but also more expensive and burdensome to obtain. A randomized controlled trial is needed to determine the short-term and intermediate-term benefits of medical marijuana versus standard therapy.

•A 2017 retrospective review of 72 patients with SCD identified by toxicology screens found no clinical benefit, but the individuals who used cannabinoids may have had greater pain at baseline [99].

•A randomized trial comparing inhaled (vaporized) cannabis with placebo for SCD pain in 23 adults with chronic pain showed improved mood interference and a non-significant trend towards decreased opioid use, with no increase in adverse effects [100]. The vaporized medication contained 4.4 percent delta-9-tetrahydrocannabinol and 4.9 percent cannabidiol and was administered three times daily. Pain was assessed with visual analog scale and Brief Pain Inventory. Planned study enrollment was not reached; however, these findings suggest that a larger trial with longer follow-up in individuals with chronic pain is indicated.

●Chronic pain (general population) – Clinical studies are limited and conflicting. Several meta-analyses of randomized trials in populations with a variety of types of pain have shown trends toward better pain control with the addition of cannabinoids, especially for neuropathic pain [101]. (See 'Chronic pain' below.)

Most of the data regarding cannabinoids for pain come from individuals with cancer. Information about available agents, dosing, and adverse effects is presented separately. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Cannabis and cannabinoids'.)

Ketamine — Use of ketamine as an adjunct for pain management is discussed separately. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Ketamine for acute pain not responsive to opioids'.)

CHRONIC PAIN

Prevalence — Chronic pain is experienced by a large percentage of individuals with SCD, as described in two studies from 2010 and 2008:

●The 2010 Multicenter Study of Hydroxyurea (MSH) collected data from pain diaries for 299 adults with SCD who had at least three painful episodes per year prior to enrollment [102]. These diaries revealed analgesic use on a median of 35 percent of days (range, 0 to 99 percent) and oral opioid use (eg, oxycodone, codeine) over a two-week period in 60 percent of individuals.

●The 2008 Pain in Sickle Cell Epidemiology Study (PiSCES) prospectively evaluated pain in 232 adults with SCD using pain diaries for six months; of these, 29 percent reported pain on >95 days [103].

Assessment for the cause and characteristics of the pain — Not all chronic pain is due to vaso-occlusion.

It is important to identify other causes of pain that may require different therapies in order to use the most effective and appropriate interventions as well as to avoid toxicities of chronic opioid use when chronic opioids are not optimal therapy.

Assessment is similar to acute pain, with evaluation for other complications of SCD, medication side effects, and other possible contributing conditions. (See "Evaluation of acute pain in sickle cell disease".)

Examples of other types of pain that may require other interventions include the following:

●Orthopedic pain due to avascular necrosis (AVN), compression fractures, arthropathies, which may be treated surgically. (See "Acute and chronic bone complications of sickle cell disease", section on 'Management of avascular necrosis'.)

●Acute vaso-occlusive pain associated with onset of menstrual cycle pain, which can be treated with hormonal therapies or nonsteroidal antiinflammatory drugs (NSAIDs) [104]. (See "Primary dysmenorrhea in adolescents" and "Dysmenorrhea in adult females: Clinical features and diagnosis" and "Dysmenorrhea in adult females: Treatment".)

●Coexisting conditions including depression, post-traumatic stress disorder (PTSD), social dysfunction, substance use disorders, and/or other mental health issues, especially for individuals with frequent emergency department visits for chronic pain [9]. (See "Screening for depression in adults" and "Overview of prevention and treatment for pediatric depression" and "Posttraumatic stress disorder in adults: Treatment overview" and "Posttraumatic stress disorder in children and adolescents: Treatment overview".)

Management of chronic pain — Mechanisms differ from acute pain and may include central sensitization and hyperalgesia, among others [105]. Chronic pain in SCD differs from chronic pain in other settings (eg, cancer pain) in that in SCD chronic pain is typically interspersed with episodic and chaotic waxing and waning acute pain. SCD-associated pain is also likely to have a larger component of neuropathic pain, peripheral and central sensitization to pain, and opioid hyperalgesia. The purpose of pain control is to maximize functioning and quality of life over decades, rather than to provide shorter-term palliative care.

Individuals with SCD may have to navigate a greater number of providers unfamiliar with their condition and may face a higher degree of provider misperceptions about the existence and intensity of pain than individuals with cancer. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Provider misperceptions that interfere with the assessment' and 'Therapeutic relationship' above.)

Management is individualized according to the causes, intensity, and duration of pain and values and concerns of the individual and their clinician (table 1). Some individuals may prefer to avoid chronic medications, whereas those with pain on the majority of days may require daily opioids. Some may benefit from deep tissue massage [7].

Management is conducted at home for most individuals.

●Disease-modifying therapies – Disease-modifying therapies discussed above can generally be continued during hospitalizations. They should be reviewed and adjusted (or initiated) once the individual has recovered from an acute pain episode or other acute hospitalization. (See 'Overall recommendations/summary' above.)

●Opioids – Opioid management in individuals with SCD is complex for many reasons. A good therapeutic relationship and input from clinicians with expertise in chronic pain management and the special needs of individuals with SCD is needed, in which opioids can be managed collaboratively with shared decision making. (See 'Therapeutic relationship' above.)

The prevalence of opioid use disorder in individuals with SCD is similar to or less common than other populations; however, individuals with SCD who develop an opioid use disorder have special care requirements that must balance the management of the opioid use disorder along with the need for ongoing evaluation and treatment of severe pain, which may have several causes including vaso-occlusive pain and other conditions that require other types of treatments.

As noted in a communication from the Centers for Disease Control (CDC), unique considerations in SCD can change the balance of risks and benefits of opioids, and guidance on opioid use for the general population should not be extrapolated to individuals with SCD; SCD-specific guidance related to treatment of pain is more appropriate [106]. Appropriate analgesics for those who require them include long-acting oral morphine, oxycodone, and/or methadone (table 4) [107]. Methadone may have advantages over other opioids due to opioid agonism in combination with N-methyl-D-aspartate (NMDA) antagonism and monoamine uptake inhibition [108].

Attempts should be made to taper opioids in outpatients once their pain has been controlled and the preventive therapies described above have been maximized. In some cases, addressing the root cause of chronic pain syndromes such as orthopedic complications or post-traumatic stress disorder can lessen or even eliminate the need for opioids. A multidisciplinary approach is advisable, along with close communication with the patient about the tapering plan.

Opioids can have other long-term risks besides opioid use disorder, including developmental and hormonal changes in children and gastrointestinal effects. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Opioid side effects'.)

●Buprenorphine – Over one-fourth of adults with SCD require daily opioid therapy. This often impairs the quality of life and is linked to central sensitization, risk of depression, and opioid side effects. In addition, some patients have become tolerant to opioid benefits, and some have developed opioid use disorder, although this is rare. Investigation of alternatives to standard opioids in chronic pain syndromes is a priority.

Buprenorphine is a potential alternative to chronic opioid use in selected patients managed by clinicians experienced with the drug [109]. It is a high affinity partial mu-opioid receptor agonist and kappa opioid receptor antagonist approved for treating both opioid use disorder and chronic pain [16].

Limited studies describing the use of buprenorphine in people with SCD are encouraging. Limited reports in people with SCD suggest it may improve quality of life and daily functioning and may reduce emergency room visits. Common side effects can include potential precipitation of withdrawal symptoms, QTc prolongation, headaches, nausea, and constipation. Prospective studies evaluating safety, efficacy, and appropriate candidates are needed [109-112].

●Pain plan – The use of an individualized care plan can help manage and coordinate care for chronic pain and acute pain exacerbations. (See 'Adjunctive interventions' above and 'Individualized care plan' above.)

●Treatment of depression – Depression is common in individuals with chronic pain and is underdiagnosed in individuals with SCD. Antidepressants such as duloxetine and other serotonin and norepinephrine reuptake inhibitors (SNRIs) may be beneficial as part of a comprehensive pain management program. Monitoring the drug's benefit with Brief Pain Inventory (BPI) or other assessment tools should be included in the plan, along with a discussion about the risk associated with therapy, including counseling about avoiding abrupt stopping. (See "Unipolar depression in adults: Assessment and diagnosis" and "Unipolar major depression in adults: Choosing initial treatment".)

Given the complexity of managing depression in individuals taking opioids, the benefit is likely to be enhanced if there is co-management with a primary care provider familiar with cognitive behavior and pharmacologic therapy for the treatment of depression. (See "Unipolar depression in adult primary care patients and general medical illness: Evidence for the efficacy of initial treatments".)

●Therapies for neuropathic pain – Those with a neuropathic component to their pain (see "Acute vaso-occlusive pain management in sickle cell disease", section on 'Clinical assessment of pain') may benefit from the addition of medications directed at neuropathic pain, although these do not take the place of opioid analgesics or preventive therapies [113]. Methadone may be efficacious due to NMDA antagonism [114,115]. Close attention must be paid to the QT interval on the electrocardiogram because of the risk of QT prolongation by methadone, especially at high doses. Additional information on assessing and treating neuropathic pain is presented separately. (See "Use of opioids in the management of chronic non-cancer pain" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Pharmacologic therapy for neuropathic pain, or nociplastic or centralized pain'.)

Refractory pain: Role of regular transfusions — A period of regular transfusions may be effective in some individuals to break the cycle of refractory/chronic pain or frequent pain episodes that are not controlled with analgesics or hydroxyurea or as a temporizing measure while the individual is being evaluated for (or treated with) therapies that may take time to become effective. Transfusions are thought to work by lowering the percentage of sickle hemoglobin and preventing vaso-occlusion. Thus, this approach is most likely to be effective in individuals with chronic or frequent vaso-occlusive pain and less likely to be effective in those whose pain is predominantly due to other causes (eg, compression fractures, neuropathic pain).

When used for this indication, transfusions may be given for a defined period of time (eg, six months) with close assessment and monitoring to determine whether they are effective. Simple transfusions and phlebotomy may be used to maintain the hemoglobin S below 50 percent. If this is ineffective or associated with significant iron overload, red blood cell exchange transfusion may be substituted [9]. Details are discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sickle cell disease (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Context for prevention – Vaso-occlusive pain is the most common reason for individuals with sickle cell disease (SCD) to seek medical attention. Pain interferes with quality of life and is challenging to manage. Implementing the best approach to reduce future vaso-occlusive pain events and manage chronic pain requires a good therapeutic relationship with trust and communication. Management often benefits from an individualized care plan to which patients, family members, other caregivers, emergency department personnel, and all other involved clinicians have access. (See 'Components of successful management' above.)

●Value of prevention – Vaso-occlusive pain is common in SCD, and all individuals require an adequate assessment for pain and an opportunity to discuss all potential options that are available. These include medical therapies discussed herein, as well as chronic transfusions and hematopoietic cell transplantation. The risks and benefits of these therapies should be discussed in individuals with hemoglobin SS disease (Hb SS) and Hb S-beta⁰-thalassemia, even before they develop vaso-occlusive pain, as well as any other individuals with SCD who have frequent vaso-occlusive pain episodes. (See 'Importance of prevention' above.)

●Choice of medication – New medications have become available that can reduce vaso-occlusive pain by modifying the pathogenesis of SCD-associated vaso-occlusion by several mechanisms. An approach to deciding when to add another medication is summarized above and illustrated in the algorithm (algorithm 1). (See 'Choice of medication' above.)

•Hydroxyurea – Hydroxyurea should be the first therapy initiated for individuals with SCD. It has the longest experience for efficacy in reducing vaso-occlusive pain and other complications and the most mature safety data (table 3). It has been demonstrated to improve survival. Many individuals who would benefit are not treated with hydroxyurea, and many who are treated with hydroxyurea are not receiving the optimal dose. (See 'Hydroxyurea' above.)

When medical therapy is indicated for vaso-occlusive pain prevention in infants ≥9 months, children adolescents, or adults, we recommend appropriately-dosed hydroxyurea over other disease-modifying therapies (Grade 1B). We also suggest hydroxyurea in infants with Hb SS or Hb S-beta⁰-thalassemia who are symptomatic with pain (Grade 2B). The decision to start hydroxyurea is illustrated in the algorithm (algorithm 2).

Hydroxyurea should be discontinued in advance of attempted conception (six months for males and three months for females) and should not be used during pregnancy or breastfeeding.

Supporting evidence for hydroxyurea and dosing and adverse effects are presented separately. (See "Hydroxyurea use in sickle cell disease".)

•L-glutamine, voxelotor, crizanlizumab – For individuals who continue to have pain despite optimally dosed hydroxyurea or who cannot take hydroxyurea, other options include pharmaceutical-grade L-glutamine (glutamine; alters redox state of red blood cells [RBCs]), voxelotor (reduces sickle hemoglobin polymerization), and crizanlizumab (anti-P-selectin). L-glutamine and crizanlizumab are preferred for additional pain relief; voxelotor reduces hemolysis and may improve global functioning and fatigue. Other advantages and concerns are summarized in the table (table 2). The decision to add another agent and the choice among these therapies are individualized with shared decision-making that incorporates the age of the patient (for children), values and preferences related to ease of administration, and other burdens and adverse effects. (See 'Options if hydroxyurea is not tolerated or ineffective in individuals with Hb SS or Hb S-Beta(0)-thalassemia' above.)

●Nonpharmacologic interventions – A number of interventions can reduce pain frequency or intensity. Attention to reducing triggers for pain and overall health maintenance that addresses optimal sleep, nutrition, psychosocial support, and other needs are important adjuncts to medical therapy. (See 'Adjunctive interventions' above.)

●Chronic pain evaluation – Chronic pain is experienced by a large percentage of individuals with SCD. Not all chronic pain is due to vaso-occlusion, and it is important to identify other causes of pain that may require different therapies, including orthopedic complications (avascular necrosis, compression fractures, arthropathy), menstrual cycle pain, psychiatric disorders, and others. (See 'Chronic pain' above and 'Assessment for the cause and characteristics of the pain' above.)

●Chronic pain management – Chronic pain in SCD differs from chronic pain in other settings such as cancer pain, in that in SCD, chronic pain is typically interspersed with episodic and chaotic waxing and waning acute pain. Management is individualized according to the causes, intensity, and duration of pain and values and concerns of the individual and their clinician (table 1). It is important to provide adequate opioids as well as to avoid unnecessary opioid escalation and to taper opioids when appropriate. The prevalence of opioid use disorder is less common than in other populations but brings special considerations related to SCD when it occurs. (See 'Management of chronic pain' above.)

●Role of transfusions – A period of regular transfusions may be effective in some individuals to break the cycle of refractory/chronic pain or frequent pain episodes that are not controlled with analgesics or hydroxyurea. (See 'Refractory pain: Role of regular transfusions' above and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

●Acute pain evaluation and management – Separate topic reviews discuss the evaluation of acute pain and the management of acute vaso-occlusive pain in individuals with SCD. (See "Evaluation of acute pain in sickle cell disease" and "Acute vaso-occlusive pain management in sickle cell disease".)