SPPM Annual Meeting Reviews
A New Look at Pain in Sickle Cell Disease
By Timothy W. Casias, MD
Department of Anesthesiology
School of Medicine and Public Health
University of Wisconsin
Madison, Wisconsin
and Lisgelia Santana, MD, FAAP
Director, Pain Medicine
Nemours Children's Hospital
Orlando, Florida
During the first part of the lecture of sickle cell disease, we had the opportunity to listen to a wonderful patient with sickle cell disease in which she highlighted her journey with this disease. We appreciated all of the insight that she brought.
After her talk, Dr. Benjamin Lee from Texas Children’s Hospital talked with us about the challenges in the treatment of sickle cell pain. The lecture started out talking about epidemiology and genetics, and about the different types of sickle cell disease and the DNA differences that cause a red blood cell to sickle. Not surprisingly, life expectancy has increased in people with sickle cell disease as it has gone from the 1970s to 2000s.
In the United States, about 100,000 people have sickle cell disease and about 1:365 African American births and 1:16,300 Hispanic American births have sickle cell disease. About 1:13 African American births have the incidence of sickle cell trait. This is about three times Huntington’s disease, Cystic Fibrosis, Muscular Dystrophy, and Hemophilia. In the United States, the disease tends to be more focused in the South and East. Vaso Occlusive Crisis (VOC) are the primary cause of hospitalizations, yet the majority are unreported. About 80% of these are treated at home, 86% are hospitalized sometime over five years, and 95% of hospitalizations in patients with sickle cell disease are for VOC pain.
Unfortunately, survival decreases with more than four VOC’s per year. As a consequence, nearly 60% of children miss more than three days of school, 17% of missed workdays are due to VOC and 24% of caregivers miss more than two days of work or school. Also, not surprisingly, there are cognitive and psychological effects in which 20% have deficits in IQ scores, 30% are diagnosed with depression and 10% have anxiety.
The costs to the health care system and patients is also staggering in which 197,000 ER visits were due to VOC per year (nearly two visits per patient) and the disease related hospital admission rate is four times higher than those with congestive heart failure and 13 times higher than those with HIV. The average cost of treating a patient with sickle cell disease to age 45 is estimated to be about $1 million (>$10,000 annually for children and >$30,000 annually for adults). This adds up to about $1 billion total annual health care costs for all patient costs. Dr. Lee then went to talk about health care outcomes and disparities and what causes them. Over the next 30-40 years we will see an increase in the number of minorities to the point that people of color will be 54% of the population. This is an issue because there is a difference in quality of health care outcomes between non-minority and minority patients. This lead to an Institute of Medicine report in 2003.
There is also a racial bias in pain assessment and treatment recommendations. This means that the standard of care is likely contingent on race and ethnicity. African American patients are less likely to be given pain medications and if they are, it is likely to be given in smaller quantities. There was also a study which looked at 4.2 million pediatric encounters for abdominal pain and black and low income children had increased risk of perforated appendicitis and hospital admission. Dr. Lee then presented a couple of studies that looked at implicit racial/ethnic bias in healthcare providers using the implicit association test, which found bias present. He then went on to talk about describing perceived racial bias among youth with sickle cell disease, in which all participants reported at least one incident of racial bias.
One of the issues that gets worse in all specialties is that as children become adults, care becomes harder to obtain This is especially true in sickle cell disease, where patients are more likely to have increased VOC pain episodes, ED visits, hospitalizations and mortality.
There was a sickle cell access to care summit held in September, 2018 which recommended a dedicated SCD clinic or day clinic within existing hospital medical centers, develop network with local providers (broaden access), establish structured program for transition and leverage existing infrastructure.
Dr. Bill Zemsky described how the basic science about sickle cell disease and vasodilation has changed over the last 30 years, and how it is more than just the sickled cell that causes damage, but the endothelium as well. We know that the amount of pain for these patients increases with age and that 29% of adults have pain greater than 95% of the days. This can be caused by many different inputs including central sensitization from multiple vasoocclusive events, opioid induced hyperalgesia and mood stress and sleep disorders. Qualitative sensory testing shows that people with worse disease end up having more central sensitization. Functional MRI shows similar findings, in which there is at least some pain that is centrally sensitized and that those with high pain phenotype seem to have more sensitization. Unfortunately, there are no evidence-based therapies for chronic pain in sickle cell disease, but a lot of techniques that are used for other chronic pain conditions can be used for sickle cell chronic pain as well. One of the first priorities should be to decrease opioid usage, as this can lead to hypersensitivity. Bone marrow therapy can be curative, and the pain eventually remits. Gene therapies are promising but have a long way from widespread availability.
Hydroxyurea helps by multiple mechanisms of action including fetal hemoglobin induction, lower neutrophil counts, reduced hemolysis, and nitric oxide release. Glutamine is now FDA approved and reduces oxidative stress of sickled RBC and decreases endothelial adhesion. Crizanlizumab is an anti P selectin monoclonal antibody which is administered as a monthly infusion. Rivapansel is a E and partially P selectin inhibitor that can be used in the acute setting which has been shown to decrease opioid usage by 83%. Voxeletor increases HgB affinity for oxygen and blocks polymerization, which is an oral once a day therapy and at high doses there is some evidence of decreased vasoocclusive crisis.
