Sickle Cell Disease and Pain

My first patient with sickle cell disease (SCD) was an 8-month-old infant experiencing an acute pain episode. I learned about SCD in the 1980s during a pediatric nursing course in college. SCD is an inherited disorder that causes the formation of abnormal hemoglobin and affects about 100,000 people in the United States. More than 90% of those affected are non-Hispanic Black, or one out of every 365 African Americans, and roughly 3%-9% are Latino or Hispanic. SCD also affects patients with Southern European, Middle Eastern or Asian Indian backgrounds. In the 1970s, SCD was considered a pediatric illness, because less than 50% of children diagnosed at that time survived to adulthood. Today, more than 95% of children diagnosed with SCD reach adulthood due to several advancements in treatment. But despite the improved survival to adulthood, SCD continues to reduce life expectancy by several decades.

The public has a renewed interest in SCD because of the U.S. Food and Drug Administration's (FDA's) recent approval of two gene therapies that could potentially cure the disease. However, healthcare providers specializing in SCD and researchers, as well as children and adults diagnosed with SCD and their families, have significant concerns that the high cost of these therapies will influence access for a population that already experiences many healthcare disparities. As a nurse scientist, I gained valuable expertise working directly with people with SCD. As a result of my work, I became an advocate for this population, collaborating with SCD specialty providers, researchers and other healthcare providers.

In this blog, I will answer the most common questions about SCD that I've received from healthcare providers and the public. I will also share insights from people diagnosed with SCD about how we deliver care and provide some recommendations on how we as nurses can advocate for this population.

What causes SCD?

The term SCD includes several inherited hemoglobinopathies. The most common type of SCD is sickle cell anemia, but other genotypes include hemoglobin SCD and hemoglobin sickle-beta-thalassemia (beta-thalassemia positive or beta-thalassemia negative). SCD causes red blood cell (RBC) sickling when hemoglobin molecules are exposed to low or no oxygen.

• Often, the initiating event is unknown and unpredictable, but it can be caused by cold environments, dehydration, physical exertion, pain and illness, including infections.

Why does SCD reduce life expectancy?

• SCD causes systemic complications such as profound anemia and life-threatening conditions such as acute chest syndrome, the most common cause of death in these patients.
• Organ damage from recurrent blood sickling and end-organ hypoperfusion leads to conditions such as retinopathy, strokes and kidney disease that become chronic or life-threatening.
• Pain, the hallmark symptom of SCD, begins in childhood, occurs more frequently and intensifies as people age. People with SCD report daily pain that can exacerbate and become debilitating, requiring emergency treatment to prevent conditions such as acute chest syndrome that are life-threatening.
• Up to 5% of people diagnosed with SCD can have three to10 episodes of severe pain every year.

SCD Pain

SCD pain is complex and multifactorial. It involves changes to RBC morphology that cause the cells to change to a sickle shape, adhering to and damaging the endothelial wall of the blood vessel and damaging the endothelium.

• Sickled cells clump with leukocytes and platelets, worsening blood flow, causing RBC lysis, and further blocking perfusion to extremities and end organs, leading to a cycle of worsening hypoxemia, more pain and RBC sickling.
• Acute pain episodes, usually from vaso-occlusive crisis (VOC), result in reduced oxygenation or infarction-reperfusion injuries, accompanied by inflammatory responses.
• VOC has been reported in the literature numerous times and is a frequent cause of acute care visits. But people with SCD often experience pain that is unrelated to VOC.
• Chronic SCD pain is generally caused by extended hyperalgesia (increased sensitivity or extreme response to pain after numerous episodes of VOC) and central sensitization, but the underlying mechanisms are poorly understood.
• Acute SCD pain is severe and recurrent, requiring management with opioids, and patients with chronic pain also may require opioids to manage it.
• SCD pain is associated with poor health-related quality of life.
• Increased frequency of hospitalizations for SCD pain is a predictor of early mortality.

SCD Pain: Trust the Patient

People with SCD experience complex pain that is multidimensional. SCD pain mechanisms include inflammatory, peripheral/nociceptive, peripheral neuropathic/sensitization, central neuropathic/sensitization and/or centralized pain that may occur simultaneously in the same person.

Here are some important facts to consider when assessing pain in patients with SCD:

• There is no blood/diagnostic test that accurately predicts the level of SCD pain.
• There is a great variation in pain phenotypes (how individuals with SCD experience or respond to pain), even in people who have the same SCD genotype (the genetic alteration causing SCD).
• Pain is a subjective experience; it is both sensory and emotional, so people may report pain even when there is no tissue damage or pathophysiological cause (an example of this is phantom limb/phantom pain syndrome).
• An estimated 30%-40% of adolescents and young adults living with SCD experience chronic pain. The factors associated with the transition from acute to chronic SCD pain are poorly understood.

SCD Pain Treatment Guidelines

The American Society of Hematology (ASH) has developed guidelines for the management of acute and chronic pain in adults and children. There are 18 recommendations in their guidelines, and 11 are highlighted here:

Acute Pain Treatment Recommendations

• Rapid assessment (within one hour of emergency department (ED) arrival) and administration of analgesia with frequent reassessments (every 30-60 minutes) for adults and children presenting to an acute care setting with acute pain related to SCD
• A short course of five to seven days of nonsteroidal anti-inflammatory drugs (NSAIDs), in addition to opioids for adults and children, for acute pain management
• Corticosteroids are not recommended to manage acute pain in adults and children diagnosed with SCD.
• For hospitalized adults and children with acute SCD pain, low-dose (subanesthetic) ketamine infusions (in hospitals or inpatient units with appropriate expertise administering the medication) can be used as an adjunct to opioids or when pain is refractory or not being effectively managed with opioids only.
• Regional anesthesia (peripheral or epidural nerve catheter delivered) is the suggested approach for adults and children with localized pain (abdominal, hip, leg) who are not being effectively treated with opioids alone.
• In addition to standard pharmacologic management of acute pain, massage, yoga, transcutaneous electrical nerve stimulation, virtual reality and audiovisual relaxation techniques could be used by adults and children diagnosed with SCD.
• The use of hospital-based SCD-specific acute care facilities (day hospitals and infusion centers with appropriate expertise in managing SCD pain and complications) is recommended over ED-based care, for adults and children with acute pain requiring hospital care.

Recommendations for Managing Chronic Pain

• The use of duloxetine or other serotonin and norepinephrine reuptake inhibitor (SNRI) medications is recommended as an option in the context of comprehensive SCD and management of chronic pain in adults with SCD, with and without identifiable causes, such as avascular necrosis of the bone.
• Consider NSAIDs in the context of comprehensive treatment of patients with SCD and management of chronic pain in adults with SCD that has an identifiable cause such as avascular necrosis of the bone.
• Tricyclic antidepressant medications may be considered as an option in the context of comprehensive SCD pain management for adults with chronic pain due to SCD without another identifiable cause.
• Gabapentinoid medications are recommended as an option for comprehensive SCD and management of chronic pain in adults with SCD without an identifiable cause.
• Consider cognitive behavioral pain management strategies delivered in the context of comprehensive SCD and management of chronic pain in adults and children with SCD.
• Integrative approaches (for example, massage, acupuncture) are recommended as available and as tolerated by the individual patient based on their preference and response, when delivered in the context of comprehensive SCD and management of chronic pain in adults.

SCD and Opioids

A common myth about patients with SCD is that they are at risk for opioid-related death if they are prescribed opioids for pain management. Current evidence does not support the concern that these patients are at high risk for opioid-related deaths.

• One study evaluating deaths due to opioids from 2013-2019 found 0.03% of total opioid-related deaths (77 out of 273,301 recorded opioid-related deaths) were patients who died of an opioid overdose with a diagnosis of SCD.
• Another study conducted to evaluate the total number of deaths due to opioid overdose from 1999-2018 found that 348 of 15,765 people diagnosed with SCD died due to opioids during the time period studied.

Opioid Guidelines and SCD

• The Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids for pain were updated in 2022, clarifying that the recommendations did not apply to people diagnosed with SCD.
• The American Society of Hematology (ASH) guidelines for management of acute and chronic pain in adults and children support the use of opioids to manage acute pain episodes.
• ASH recommends a more nuanced approach to chronic opioid therapy (COT) for adults and children with SCD.
  • For those with recently developed chronic pain, COT is initiated if chronic pain is refractory to multiple other treatment modalities.
  • For those with chronic pain who are functioning well with COT, a shared decision-making approach is suggested, including:
    • Assessment of functioning
    • Prescribing the lowest effective dose
    • Patient education about the avoidance of benzodiazepines, alcohol and other sedating medications
    • Careful monitoring for development of aberrant opioid use and complications (social, behavioral, psychological)
  • For those with chronic pain and receiving COT who are functioning poorly or at high risk of aberrant opioid use or toxicity, continued use of COT is not recommended.

Stigma and Bias

After the 2016 CDC guidelines were released, studies evaluating the impact of the guidelines on people with SCD found significant reductions in opioid prescribing and dispensing and increased VOC-related hospitalizations. People diagnosed with SCD are often stigmatized as "drug seekers," which leads to reduced access to effective and appropriate SCD pain treatment and mistrust between healthcare providers and patients.

Historically, people with SCD have been stigmatized by society and by healthcare providers. People living with SCD and their families report having to educate healthcare providers about the disease. This situation has contributed to mistrust between people/families of people living with SCD and healthcare providers. People diagnosed with SCD often receive disparate care, particularly to manage pain.

• In a survey of ED provider attitudes toward patients with SCD, nurses had higher mean negative attitude scores toward these patients compared with physician providers.
• People with SCD report managing most pain episodes at home and avoid seeking acute care (ED, admission) for pain, with 88% waiting until their pain intensity is an average of 8.7 out of 10.
• People with acute SCD pain presenting to the ED were administered an initial analgesic dose a median of 90 minutes after being triaged, with longer wait times for females.
• When comparing wait times of people presenting to the ED with acute pain, people diagnosed with SCD waited 50% longer to see a physician than patients with long bone fractures.
• People with SCD describe avoiding acute care or using strategies such as "dressing up" before going to seek care as a tactic to have their pain reports taken seriously by healthcare providers.

Innovations in SCD Treatments

In December 2023, the FDA approved two SCD treatments. They are significant breakthroughs with the potential to cure the disease using gene editing. Although the treatments are promising, their long-term effectiveness cost ($2 million-$3 million) have raised concerns about affordability and accessibility.

Nurses can improve SCD care.

Many ways exist to improve care for people with SCD; here are some tips:

• Learn more about SCD, symptoms, complications and the treatments that improve outcomes. Consider attending local or virtual seminars about SCD, which are usually available through a comprehensive sickle cell center.
• Work with a hematologist who cares for people with SCD in your area to develop order sets or other resources, such as individual pain plans that can help manage acute pain episodes.
• Look for policies and resources at your organization to care for people with SCD. Contact SCD patient advocacy groups to discover possible resources to help you support these people.
• Partner with sickle cell centers or SCD community organizations if you don't have policies or resources at your organization to care for these patients.
• Learn about SCD in your community and what resources and places support these people and their families. Reliable sites such as the National Heart, Lung and Blood Institute (NHLBI) have many helpful learning resources. ASH offers free downloadable pocket guides for the management of acute SCD pain episodes.
• Look for existing community advisory boards or partners of those diagnosed with SCD in your area that can review teaching materials and recommend policies and changes for the healthcare environment to improve care.

Strength in Numbers

Although it is considered a rare disease, about 100,000 people have been diagnosed with SCD in the United States. People living with SCD are often the only one in their school, or the only one in their family or community coping with the disease. It can be isolating for the individual and their family. Starting in early childhood, people with SCD must learn to battle pain, fatigue and the life-threatening complications that come with the disease. They are resilient and courageous as they fight the disease every day. They call themselves Sickle Cell Warriors.

These warriors not only battle the disease but the social stigma and biases that come from a lack of knowledge about SCD and symptoms that are almost invisible to the uneducated eye. These warriors need people to walk in solidarity with them, to remove the structural barriers throughout our healthcare systems, to be knowledgeable advocates, and to fight the disease alongside them, because there is strength in numbers. Strength in numbers means that teams of people can be stronger than individuals, that groups of people can empower individuals to fight another day, and they can amplify the voice of a few.

What steps will you take in your unit or organization to advocate for people living with SCD and their families?