Roles of Pharmacists in the Management of Sickle Cell Disease in Adults: A Narrative Review

Abstract

Background: Sickle cell disease (SCD) is an autosomal, recessive, genetic condition of the sickle cell genes. It affects about 100 000 people in the United States where an estimated 1 out of every 365 black children and 1 out of every 13 black children will be born with SCD and sickle cell trait, respectively. Severe and unpredictable pain crisis are the leading cause of emergency department visit for adult patients with SCD and account for 90% of inpatient hospitalizations and 85% of all acute medical care, as well as high usage of medical resources. The care of patients with SCD is complex and requires a multidisciplinary approach. With a few pharmacotherapeutic options to reduce SCD complications and pain episodes, the role of pharmacists in the medication management is unclear. This article aims to outline the potential role of pharmacists in SCD management. Data sources: The authors searched Medline, PubMed, EMBASE, and Scopus from January 1, 1990 to August 31, 2022, for primary literature that assessed the role of pharmacists in managing patients with SCD. Results: The authors identified relevant studies and summarized the role of pharmacists in SCD management. Conclusions: Access to comprehensive health care is essential to ensure that patients with SCD have decreased hospitalizations and good health-related quality of life. Pharmacists are an integral part of the multidisciplinary health-care team and can help patients with SCD navigate the complexities of health care. Pharmacists are medication experts who are positioned to ensure comprehensive care in the acute and chronic SCD management.

Overview of Sickle Cell Disease

Sickle cell disease (SCD) is an autosomal, recessive, genetic hemoglobinopathy that affects about 100 000 people in the United States.^{1 -3} Globally, SCD primarily affects individuals from sub-Saharan Africa, India, Saudi Arabia, and Mediterranean countries, such as Italy, Turkey, and Greece. ³ In addition, SCD affects individuals from the Spanish-speaking regions of Central America, Caribbean, and South America. ³ In the United States, an estimated one out of every 365 black children will be born with SCD and one out of every 13 black children will be born with sickle cell trait. ³ The four main sickle cell genotypes in the United States are HbSS, HbSC, HbSβ⁺-thalassemia, and HbSβ⁰-thalassemia.^4,5 Patients with the HbSS and HbSβ⁰-thalassemia genotypes have a more severe course of clinical and hematologic symptoms, whereas patients with HbSC and HbSβ⁺-thalassemia have a less severe course.^{4 -6}

Sickle cell disease results from the substitution of an amino acid from glutamic acid to valine at the sixth position on the beta-globin chain of adult hemoglobin (HbA).^2,7 The genetic mutation leads to polymerization of the hemoglobin molecule and alters the red blood cell (RBC) shape, density, membrane, adhesion, and ability to deform, and causes the sickling of erythrocytes. ⁷ Dehydration increases the likelihood of erythrocytes sickling and becoming rigid. ⁷ The increased presence of selectins (adhesion molecules) leads to a higher rate of adhesion, which increases the formation of heterocellular aggregates, causing small vessel occlusion resulting in local hypoxia.^2,7 The process releases a continuous cycle of increased HbS formation, which releases inflammatory mediators and free radicals that contribute to reperfusion injury. ⁷ Hemoglobin also attaches to nitric oxide (NO), a potent vasodilator that releases oxygen, ⁷ and this causes complications of SCD.

Some of the clinical signs and symptoms of HbSS include chronic anemia, scleral icterus, arthralgia, fatigue, hematuria, anorexia, weakness, pallor, abdominal pain, and enlargement of the liver, heart, and spleen.^4,5 Most patients with SCD begin to show signs and symptoms of the disease around 5 months of age. ² There are many complications of SCD, which can often worsen with increasing age and involve any organ system in the body.^2,8 Regardless of age, patients with SCD experience acute complications, including vaso-occlusive crisis (VOC), acute chest syndrome (ACS), splenic sequestration, priapism in males, stroke, hepatobiliary complications, acute renal failure, and ocular disorders. ⁸ As patients advance in age, they will start to manifest chronic complications, such as diastolic heart dysfunction, leg ulcers, pulmonary hypertension (PH), end-stage renal disease, albuminuria, venous thromboembolism, and avascular necrosis.^8,9

About 90% of hospitalizations are due to severe and unpredictable pain crises, accounting for 85% of all acute medical care and a high usage of medical resources.^10,11 The annual economic burden of SCD on the patient and health care system costs an estimated $2.98 billion.^12,13 Blacks from low-income communities who are living with SCD account for most SCD-related hospitalizations. ¹² This economic determinant of health frequently manifests as poor SCD medication adherence, high treatment discontinuation rates, and possibly higher rates of opioid utilization. ¹⁴

A study by Haywood and colleagues evaluated patients with SCD who were receiving care at the emergency department (ED). ¹⁵ The researchers found that black patients with SCD had up to 25% longer wait times than patients without SCD although the patients with SCD had a higher triage status. ¹⁵ This study concluded that Black patients with SCD had a higher likelihood of experiencing this inequality. ¹⁵ A study by Linton and colleagues addressed this gap by developing an emergency severity index (ESI) clinical decision tool that would allow patients with SCD to be appropriately triaged by nurses in the ED. ¹⁶ The results from the study showed that patients with SCD who had an ESI score of 2 or higher in the intervention group were triaged at a higher rate compared with the control group (64.95% vs 35.05%, P < 0.003). ¹⁶ This study has paved the way for ED staff to receive advanced education and training leading to improved care. Furthermore, the National Heart, Lung, and Blood Institute (NHLBI) guidelines has recommended that patients with SCD should be assigned an ESI score of 2 on a 5-point scale, with 1 being the most urgent and 5 being the least urgent. ¹⁷ This ESI assignment will allow patients with SCD to receive timely medical interventions.

General Management Strategies of SCD

The general management of adults living with SCD incorporates drug therapy and blood transfusions, according to the NHLBI treatment guidelines. ¹⁷ Allogeneic hematopoietic stem cell transplantation is a management strategy for a small subset of patients with severe SCD complications such as stroke. ¹⁸ To date in the United States, there are four FDA-approved drugs to help prevent complications associated with SCD. ¹⁹ The current FDA-approved medication therapies do not address the underlying causes of SCD nor completely resolve the clinical manifestations of SCD. ²⁰ The FDA first approved hydroxyurea (Droxia, Siklos) in 1998 for SCD. ²¹ The second FDA-approved drug was L-glutamine (Endari) ²² in July 2017; both voxelotor (Oxbryta) ²³ and crizanlizumab (Adakveo) ²⁴ were approved in November 2019.

Hydroxyurea is FDA-approved to reduce the frequency of VOCs and the need for transfusions. ²¹ Its proposed mechanism of action in SCD is to increase the fetal hemoglobin levels in RBCs, making them less likely to sickle. ²⁵ It also decreases neutrophils and increases NO while decreasing adhesion of RBCs to the endothelium. ²⁵ The generic hydroxyurea, Droxia, is available as capsules, whereas Siklos is available as tablets. ²¹ Endari is FDA-approved for patients with SCD who are 5 years of age and older. ²² Its mechanism of action is unknown but its proposed mechanism in SCD is through its antioxidant properties. ²² It helps increase nicotinamide adenine dinucleotide (NAD+) redox potential by increasing the availability of reduced glutathione in sickled RBCs. ²⁶ Endari is available as a 5-gm oral powder packet, whereas the generic options are available as capsule, tablets, oral powder for solution, and oral powder for suspension. ²² Voxelotor is FDA-approved for patients with SCD who are 12 years of age and older. ²³ It works by stabilizing HbS in their oxygenated forms, inhibiting HbS polymerization, and leading to less vaso-occlusion. ²⁷ It is available as tablets and oral tablets for suspension. ²³ Crizanlizumab-tmca (Adakveo) is FDA-approved to reduce the frequency of VOCs in patients with SCD who are 16 years of age and older. ²⁴ It is a humanized monoclonal antibody that works by binding to platelet (P)-selectin (adhesion molecule) and blocking the interaction with P-selectin glycoprotein ligand 1 (PSGL-1). ²⁴ It is administered intravenously based on body weight. ²⁴

Pharmacist’s Role in the General Management of SCD

Pharmacists are integral members of the multidisciplinary health care team and can help patients with SCD navigate the complexities of the US health care system. They are accessible health care professionals who are equipped to manage patients with chronic conditions and provide medication therapy management (MTM). ²⁸ The clinical services offered by pharmacists include but are not limited to medication/dose changes, lifestyle change education, medical condition and treatment education, treatment recommendations, follow-ups, adherence assessment, and referral to other health care providers. ²⁸ The effectiveness of pharmacist-led chronic disease management has been well-documented with conditions, such as diabetes, dyslipidemia, hypertension, heart failure, pain, and SCD.^{29 -37}

The role of the pharmacist is particularly important when managing patients with SCD. Sickle cell disease management is comprehensive and complex, and it requires a multidisciplinary approach. A model for managing adult patients with SCD was proposed by Kanter and colleagues to incorporate appropriate care and reduce health disparities. ³⁸ This model was created from a workshop to train health care professionals, such as advanced care nurse practitioners, physician assistants, social workers, and pharmacists, on caring for patients with SCD. ³⁸ It proposes having dedicated clinical space and shared clinical staff who provide collaborative care through a specialized medical home in urban, suburban, and rural areas. ³⁸ In this model, the pharmacist can review patients’ medications and conduct medication reconciliation during transitions of care following hospital admission or discharge, and subsequent ambulatory care clinic follow-up after a VOC event. The pharmacist is key in providing additional information to the insurance company to help streamline prior authorizations for SCD-modifying therapies and opioids. Voxelotor and L-glutamine are dispensed through specialty pharmacies. Patients on these agents require a trial of 90 consecutive days with hydroxyurea prior to receiving approval. The pharmacist can coordinate care by finding accessible and affordable medications and providing patient counseling for better medication adherence. The pharmacist provides medication management and evaluates and monitors drug therapy for safety and effectiveness.

A study by Barton and colleagues evaluated a pharmacist-led initiative for the use of hydroxyurea in patients with SCD in a multidisciplinary tertiary clinic. ³⁵ They found that the average hydroxyurea dose administered after 6 months of use was significantly higher in the pharmacist cohort (19.1 vs 22.2, P = 0.038). ³⁵ Results also showed that the pharmacist-led group had fewer acute care visits (20 vs 6, P = 0.01) when compared with the traditional group. ³⁵ The pharmacist group was found to be more likely to review hydroxyurea therapy for dose assessment after completion of laboratory visits. ³⁵ A study by Han and colleagues found a significant correlation between pharmacist encounters and an improved rate of hydroxyurea dose escalation for patients with SCD (odds ratio [OR] 1.48, 95% CI 1.07-2.05, P = 0.02). ³⁶ The encounter with the pharmacist also showed improved screening for sickle cell retinopathy (OR 1.16, 95% CI 1.00-1.35, P = 0.05) and microalbuminuria (OR 2.14, 95% CI 1.17-1.62, P < 0.001). ³⁶

A study by Yager and colleagues was conducted to evaluate the impact of a pharmacist-led sickle cell clinic on the frequency of hydroxyurea dose adjustments, pharmacist interventions, and change in health care utilization. ³⁷ The results from the study showed a significant decrease in hospital admissions (50% vs 29.6%, P < 0.002) when they compared it from 3 months prior to their first appointment with the pharmacist to 3 months after a 6-month follow-up with the pharmacist. ³⁷

Acute and Chronic Pain in SCD

Patients with SCD experience acute, chronic, and/or acute-on-chronic pain due to VOC, ACS, or avascular necrosis. ³⁹ An acute pain crisis is defined as a complication of microcirculation obstruction by sickle hemoglobin–containing RBCs, resulting in inflammation, ischemia, and subsequent tissue damage. ³⁹ Conversely, ongoing pain that appears on most days during at least a 6-month period in either a single or multiple locations is classified as chronic pain. ³⁹ Chronic SCD pain can be triggered without identifiable factors due to central or peripheral sensitization or with identifiable factors, such as avascular necrosis, VOC, and leg ulcers. ³⁹ The gold standard for pain assessment and diagnosis is patient self-reporting of symptoms. ⁴⁰ Currently, there are no reliable and feasible diagnostic tests to confirm the presence of pain due to SCD except for pain due to avascular necrosis or leg ulcer, which can be seen on physical examination. ⁴⁰ However, there are some unidimensional pain assessment tools utilized to assess the pain intensity for patients with SCD and include the Numeric Rating Scale (pain ratings from 0 to 10) and Visual Analog Scale, which are for patients 8 years of age and older, whereas the Bieri Faces Pain Scale is for patients who are 3 years of age and older.^{41 -44} Nevertheless, due to the limited robustness of the unidimensional tools, multidimensional tools that assess the impact of patients’ pain on their daily activities are preferred in SCD. ⁴¹ These include the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-ME) for patients 18 years of age and older and Pediatric Quality of Life Inventory SCD (PedsQL SCD) for patients who are 2 to 18 years of age.^{41,45 -47} It is important to note that sickle cell pain in general is hard to classify due to individual variability in the severity of the pain.

The 2020 guidelines for sickle cell management of acute and chronic pain by the American Society of Hematology (ASH) recommends using an individualized approach. ⁴⁸ The approach consists of pharmacological and nonpharmacological approaches as there is no one-size-fits-all treatment for pain management due to SCD. ⁴⁸ The guidelines emphasize that treatment of acute SCD pain in the acute care setting should be initiated using a standardized protocol, which includes pain medication within 1 hour of the patient’s arrival to the hospital ED. ⁴⁸ Currently, opioids are the mainstay of therapy for the management of acute SCD pain. ⁴⁸ The most recent Centers for Disease Control and Prevention (CDC) opioid guidelines recommend evaluating the use of opioids as a first-line option for chronic pain. ⁴⁹ However, the CDC stated that these guidelines will not be applied to patients who have SCD-related pain, palliative care, and cancer pain. ⁴⁹ Nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen can also be used as part of multimodal analgesia. ⁴⁸ All NSAIDs are associated with potential side effects, including nephrotoxicity, gastrointestinal bleeding, and liver injury. Therefore, they should be used with caution, especially in patients with sickle cell nephropathy. ⁴⁸ The NSAID use should be at the lowest effective dose and at shorter durations. ⁴⁸ To minimize the use of NSAIDs and avoid the risk of addiction from full agonist opioids, buprenorphine has emerged as a possible alternative for the treatment of chronic pain from SCD-related VOCs. ⁵⁰

Buprenorphine is recommended due to its high opioid receptor affinity, partial mu-opioid receptor agonism, longer duration of action, lower risk of addiction, withdrawal, and developing tolerance when compared with full strong mu receptor agonism agents. ⁵⁰ A study by David and colleagues reported that patients on chronic, high-dose opioid therapy with inadequate response had successful transition to sublingual buprenorphine. ⁵¹ The conversion strategy was done through a multidisciplinary team and performed under careful monitoring for the risk of withdrawal symptoms; the converted patients experienced minimal adverse effects. ⁵¹ According to the researchers, only a few patients reverted back to using strong opioids. ⁵¹

Pharmacist’s Role in the Management of Acute and Chronic Pain in SCD

It is important for pharmacists taking care of patients with SCD to appreciate the types and pathophysiology of pain as this can impact drug therapy. To ameliorate the opioid crisis and national opioid shortages, pharmacists in acute care, ED, community pharmacies, and ambulatory care settings can provide care by removing barriers to access for these patients. Moreover, many pharmacists, as part of medication safety committees, are involved in creating opioid management protocols in the ED and acute care settings. In addition, pharmacists often have a stronger presence in the ED where they work with medication history technicians to decrease medication errors and wait times for patients. ⁵² In the ED, medication history technicians can take a comprehensive history from patients after being triaged. This includes obtaining information from the prescription drug monitoring program (PDMP) database, previous hospital admission opioid needs, a patient’s account of how much breakthrough medication they were taking prior to the ED visit, and the best opioid regimen that previously worked for the patient. ⁵³ The findings obtained by the technician are then documented in the electronic health record (EHR) for physicians and pharmacists to select and optimize the most appropriate opioid regimen for the patient. ⁵³

Pharmacists are regularly consulted to dose patient-controlled analgesia during hospital admissions. This involves monitoring the continuous rates of the opioid being administered, the demand doses the patient requests versus the demand doses the patient is actually receiving based on the lockout period as well as naloxone need and vital signs to ensure the patient is not going into respiratory depression from high-dose opioid use. ⁵³ Patients with SCD on opioids should also be screened for other medical comorbidities that can interfere with their treatment, such as those with sleep apnea, opioid use disorder, constipation, and depression. ⁵³

Currently, the FDA drug shortage website lists injectable formulations of fentanyl, hydromorphone, morphine, and remifentanil as the opioids in short supply. ⁵⁴ Pharmacists can be proactive by educating hospital staff to be more conservative with these particular opioids and reserving the opioid supply for patients with severe pain conditions including SCD. Pharmacists can pull data to trend sickle cell patient population in their specific health care system and anticipate surges especially in the upcoming winter season when VOC triggers are higher. Pharmacists can provide alternatives to opioids when they are in short supply, with considerations for medication cost, insurance coverage, dosage form, and patient comorbidities. ⁵³

Pharmacist’s Role in Decreasing Patient and Health Care Financial Burden

A study by Dole and colleagues evaluated the clinical and financial outcomes of a clinical pharmacist with prescribing authority in New Mexico. ⁵⁵ The outcomes of the study revealed that having a clinical pharmacist consistently reduced patients’ average pain scores. ⁵⁵ This clinic was able to generate $107 550 of revenue by seeing an average of 18 patients per day and saved the health plan about $450 000. ⁵⁵ A retrospective analysis from Poirier et al ³² in 2019 highlighted the benefit of a pharmacy-directed pain management service on institutional opioid use, patient satisfaction scores, and indirect cost savings. The researchers noted that as pharmacist-based consultations increased over a 3-year period, they had a decrease in opioid stewardship interventions during the same period. ³² There were decreases in total institutional opioid use and in high-risk opioid medications, and increases in the use of adjunctive therapy and indirect cost avoidance, ranging from $1.5 to $1.8 million annually. ³²

Pharmacist Role in Reducing Stigma in SCD

Access to comprehensive care is essential for a better health-related quality of life and decreased hospitalizations for individuals with SCD, but adults with SCD have less access when compared with patients with other genetic disorders, such as cystic fibrosis or hemophilia. ⁵⁶ The inequity in comprehensive care services is due to fewer SCD centers, less utilization of SCD centers, and less funding available for SCD.^56,57 These patients are more likely to experience stigma due to multiple factors, such as socioeconomic status, disease status, pain management requiring the use of opioids, delayed growth/puberty, and race.^{58 -62}

A systematic review conducted by Bulgin and colleagues evaluated four domains specific to stigma in patients living with SCD. ⁵⁸ The four domains are “. . . social consequences of stigma . . . effect of stigma on psychological well-being . . . effect of stigma on physiological well-being, and . . . impact of stigma on patient-provider relationships and care-seeking behaviors.” ⁵⁸ The results revealed that these patients have external factors that can contribute toward stigma, such as having family, friends, and health care providers who are uneducated about SCD and its clinical manifestations. ⁵⁸ In addition, patients with SCD can internalize the symptoms of stigma, which can lead to the development of mental health disorders such as depression. ⁵⁸ Citing Haywood et al, ⁶³ Mathur et al, ⁶⁴ and Wakefield et al, ⁶⁵ Bulgin stated that “People with SCD that reported experiencing higher rates of disease and race-based discrimination in healthcare settings also reported greater pain, pain severity, pain burden, and pain interference with functionality, sleep, and daily activities.”

Pharmacist’s Role in Advocacy for Patients With SCD

The national opioid epidemic poses a challenge to pain management for patients with SCD. As a result of the national crisis, opioid prescriptions have become increasingly restricted, heavily monitored, and difficult to obtain from outpatient pharmacies, leading to health disparities for individuals living with pain conditions such as SCD. Individuals with SCD experience increasing barriers to opioid access for their acute and chronic pain management. Pharmacists play a significant role in advocacy to reduce stigmatization about opioid use and dissatisfaction with opioid access among the SCD populations. For pharmacists practicing in the United States, the use of PDMPs can facilitate information sharing about patients’ opioid prescription history without presuming that opioid addiction exists.

A study by Sinha and colleagues reported an increased stigmatization of opioid use in patients with SCD. The stigma affected medical care when the provider focused primarily on reduction of opioid use. ⁶⁶ Furthermore, a study by Ruta and colleagues emphasized the need for developing a collaborative relationship between the patient and the provider to reduce the patient’s dissatisfaction with opioid access. ⁶⁷ A plan should be developed between both the provider and patient to ensure adequate pain control, and this should include the goal of reducing the number of hospitalizations due to SCD-related pain. ⁶⁷ Providers should also communicate with pharmacists practicing in either community pharmacies or managed care to facilitate medication access for these patients.

Other ways that pharmacists can contribute to advocacy for the patients living with SCD include participating in infection control and prevention by ensuring appropriate selection, dosing, and duration of anti-infective agents. By developing trusting relationships with individuals living with SCD, the pharmacist can intervene in SCD care by educating the patients to improve their adherence to medications, vaccinations, and medical treatments. Pharmacists with access to patients’ EHR can review the patient profiles to ensure that the patients are up to date on the approved adult vaccines. Pharmacists can assist in decreasing the health disparities that exist in the rural communities by setting up immunization clinics that can improve access to lifesaving vaccines for rural populations, especially for individuals living with SCD. Within the United States, the CDC has specific vaccine recommendations for asplenic patients, which include individuals living with SCD. Pharmacists should ensure that these SCD populations with asplenia receive the appropriate vaccines for their conditions.

Conclusion

This narrative review demonstrates and enumerates the vital roles that pharmacists can play in the acute and chronic management of SCD. Pharmacists can help optimize SCD patients’ clinical, economic, and humanistic outcomes during transitions of care, MTM services, care coordination, and clinical decision support. Moreover, they can advocate for individuals living with SCD.