Genetics and Pain Severity in Sickle Cell Disease
Genetics and Pain Severity in Sickle Cell Disease
Background:

 - Pain is the most common symptom of sickle cell disease. Episodes of severe sickle cell pain
 are known as "crises." High rates of pain crises are associated with a higher risk of early
 death. Some people with sickle cell disease have many severe pain crises while others
 experience fewer crises. This difference in pain crisis may be caused by sensitivity to pain.
 People with high sensitivity to pain may have more pain crises. Many factors, including a
 person's genetic makeup, determine sensitivity to pain. Comparing genetic information from
 people with sickle cell disease and healthy volunteers may provide more information on pain
 and sickle cell disease.

 Objectives:

 - To study genetics and pain sensitivity in sickle cell disease.

 Eligibility:

 -  African or African American individuals at least 18 years of age with sickle cell
 disease.

 -  Healthy African or African American volunteers at least 18 years of age.

 Design:

 -  Participants will be screened with a medical history and physical exam. They will also
 provide blood and urine samples.

 -  Participants will have the following tests:

 -  Quantitative sensory testing to measure sensitivity to pressure, heat, cold, and
 mechanical pain.

 -  EndoPat test to measure blood vessel function and reaction.

 -  Questionnaires about mood, evidence of depression, pain, quality of sleep, and sleep
 disturbances.

 -  Measures of daily pain, whether or not related to sickle cell disease.

 -  After the first visit, those in the study will have monthly study visits for 6 months.
 The above tests will be repeated at these visits.
Sickle cell disease (SCD) is the most common genetic disease in the United States inherited
 as an autosomal recessive disorder, where approximately 70,000 individuals have sickle cell
 disease. Acute painful vaso-occlusive crisis (VOCs) is one of the common complications of SCD
 that influences overall survival (Platt, Thorington et al. 1991). Pain, is also the most
 common cause of SCD morbidity, which has a negative impact on quality of life of these
 individuals and their families. There is significant inter-individual variation in the
 frequency and course of severe VOCs that result in hospital based treatment, the reasons for
 which have not been clearly elucidated. Vaso-occlusion of irreversibly sickle red cells
 within the microcirculation is believed to be the proximate cause of painful VOCs, however it
 is likely that other non-SCD related factors affecting pain perception and sensitivity to
 pain will also contribute to individuals susceptibility to pain and therefore contribute to
 the observed inter-individual variability in the course of VOC. Early identification of
 individuals who are at high risk for developing severe pain related morbidity and chronic
 pain syndromes is crucial since early multimodal interventions might have the potential to
 minimize both the morbidity and mortality associated with VOCs.

 <TAB>

 Patients with SCD are hypothesized to have lower nitric oxide (NO) bioavailability due to NO
 scavenging by cell free hemoglobin released into plasma during red cell hemolysis. NO
 deficiency has been identified as a key factor in development vascular dysfunction in SCD. NO
 has also recently been identified as a key mediator in processing nociceptive signals and
 modulation of pain in non-SCD models. Thus, low NO is associated with lower pain perception
 (Meller, Dykstra et al. 1992; Tegeder, Costigan et al. 2006). GTP cyclohydrolase (GCH1) is
 the rate-limiting enzyme for synthesis of an essential cofactor for both NO production and
 metabolism of aromatic amino acids, namely tetrahydrobiopterin (BH4). Therefore it is
 hypothesized that genetic variants in the GCH1 gene will affect BH4 levels and which will
 have a secondary impact on vascular dysfunction and sensitivity to pain in SCD.

 The primary goal of this protocol is to establish patterns of sensitivity to experimental
 pain among subjects with SCD compared to healthy African American controls. In addition, an
 exploratory analysis will determine if increased sensitivity to experimental pain correlates
 with the frequency and intensity of clinical pain in those with SCD. Once an expected pattern
 of experimental pain phenotypes are established for a cohort with SCD, we will then further
 explore the role of GCH1 genetic variants in experimental pain perception and vascular
 function. If successful, a longer term secondary objective is to establish a sufficiently
 large patient cohort with experimental pain phenotypes for future exploratory genetic studies
 to investigate the role of other loci that might influence sensitivity to experimental pain
 and vascular function in SCD.
-  ELIGIBILITY CRITERIA FOR ALL PARTICIPANTS:

 All study participants must be of self-described African or African American ancestry. They
 will be at least 18 years old and must be able to provide informed, written consent for
 participation.

 INCLUSION CRITERIA:

 Inclusion Criteria for Sickle Cell Patients

 1. Diagnosis of sickle cell disease (documentation of SS, SC, S beta + thalassemia, S
 beta + thalassemia by electrophoresis is required).

 2. If taking chronic analgesics (NSAID, acetaminophen) or opioids, study subjects should
 be on a stable dose for 4 weeks prior to recruitment.

 Inclusion Criteria for Control Subjects

 1. Hemoglobin AA genotype by HPLC or hemoglobin electrophoresis.

 2. General good health defined as the absence of untreated major medical conditions (e.g.
 uncontrolled systemic hypertension, etc.).

 EXCLUSION CRITERIA:

 Exclusion Criteria for Sickle Cell Patients

 1. History of severe vaso-occlusive pain crisis resulting in either evaluation in an
 emergency department or admission to a hospital during the two weeks prior to study
 enrollment.

 2. Acute pain at the time of enrollment defined as spontaneous recent onset pain with a
 self rated score of 6 or higher on a scale of 0-10. (This is acute pain not the pain
 that subjects function at on a daily basis.)

 Exclusion Criteria for Control Subjects

 1. Acute pain or injury at enrollment or a recent history of chronic pain (daily pain
 reported for at least 6 months) in the past 3 years.

 2. Major medical/psychiatric illness known to cause pain.

 3. Sickle cell trait.