Genetics and Pain Severity in Sickle Cell Disease

Tracking Information
First Submitted Date	September 24, 2011
First Posted Date	September 27, 2011
Last Update Posted Date	April 4, 2018
Study Start Date	September 7, 2011
Primary Completion Date	Not Provided
Current Primary Outcome Measures; (submitted: May 23, 2013)	To determine if thresholds for pain perception are lower in SCD than in non-SCD controls.
Original Primary Outcome Measures	Not Provided
Change History	Complete list of historical versions of study NCT01441141 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures; (submitted: June 13, 2014)	To determine if SCD subjects with higher GCH1 activity have 1) lower pain perception thresholds, 2) a higher prevalence of pain/VOC, 3) altered vascular reactivity and 4) more frequent pain co-morbidities) compared to subjects who lack this.; To determine if variants in the GCH1 gene alter thresholds for pain perception in sickle cell disease.
Original Secondary Outcome Measures	Not Provided
Current Other Outcome Measures	Not Provided
Original Other Outcome Measures	Not Provided
Descriptive Information
Brief Title	Genetics and Pain Severity in Sickle Cell Disease
Official Title	Exploratory Studies of Psychophysical Pain Phenotyping and Genetic Variability in Sickle Cell Disease
Brief Summary	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.
Detailed Description	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.
Study Type	Observational
Study Design	Observational Model: Case-Control; Time Perspective: Retrospective
Target Follow-Up Duration	Not Provided
Biospecimen	Not Provided
Sampling Method	Not Provided
Study Population	Not Provided
Condition	Genotype; Pain; Sickle Cell Anemia; Vaso-Occlusive Pain Crisis
Intervention	Not Provided
Study Groups/Cohorts	Not Provided
Publications *	Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, Orringer EP. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol. 2006 Jul;134(1):109-15.; Bookman EB, Langehorne AA, Eckfeldt JH, Glass KC, Jarvik GP, Klag M, Koski G, Motulsky A, Wilfond B, Manolio TA, Fabsitz RR, Luepker RV; NHLBI Working Group. Reporting genetic results in research studies: summary and recommendations of an NHLBI working group. Am J Med Genet A. 2006 May 15;140(10):1033-40.; Campbell CM, Kronfli T, Buenaver LF, Smith MT, Berna C, Haythornthwaite JA, Edwards RR. Situational versus dispositional measurement of catastrophizing: associations with pain responses in multiple samples. J Pain. 2010 May;11(5):443-453.e2. doi: 10.1016/j.jpain.2009.08.009.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status	Completed
Actual Enrollment; (submitted: July 23, 2016)	67
Original Estimated Enrollment; (submitted: September 24, 2011)	60
Study Completion Date	Not Provided
Primary Completion Date	Not Provided
Eligibility Criteria	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; Diagnosis of sickle cell disease (documentation of SS, SC, S beta + thalassemia, S beta + thalassemia by electrophoresis is required).; 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; Hemoglobin AA genotype by HPLC or hemoglobin electrophoresis.; 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; 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.; 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; 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.; Major medical/psychiatric illness known to cause pain.; Sickle cell trait.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 99 Years (Adult, Senior)
Accepts Healthy Volunteers	Yes
Contacts	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries	United States
Removed Location Countries
Administrative Information
NCT Number	NCT01441141
Other Study ID Numbers	110252; 11-H-0252
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor	National Heart, Lung, and Blood Institute (NHLBI)
Collaborators	Not Provided
Investigators	Principal Investigator: Swee Lay Thein, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account	National Institutes of Health Clinical Center (CC)
Verification Date	March 16, 2018