Genetics and Pain Severity in Sickle Cell Disease

NCT ID: NCT01441141

Last Updated: 2020-12-10

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 67 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2012-06-17
• Study Completion Date: 2020-12-09

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.

Conditions

Genotype; Pain; Genetic Variation; Quantitative Sensory Testing (QST); GCH1

Keywords

GCH1; Pain Sensitivity; Quantitative Sensory Testing (QST); Genetic Variation; Sickle Cell Anemia

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: OTHER

Study Groups

Arm 1

Subjects with SCD

No interventions assigned to this group

Arm 2

Subjects without SCD

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

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.

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

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.)

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Swee Lay Thein, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Heart, Lung, and Blood Institute (NHLBI)

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

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. doi: 10.1111/j.1365-2141.2006.06110.x.

Reference Type: BACKGROUND

PMID: 16803576 (View on PubMed)

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. doi: 10.1002/ajmg.a.31195.

Reference Type: BACKGROUND

PMID: 16575896 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20439057 (View on PubMed)

Darbari DS, Vaughan KJ, Roskom K, Seamon C, Diaw L, Quinn M, Conrey A, Schechter AN, Haythornthwaite JA, Waclawiw MA, Wallen GR, Belfer I, Taylor JG 6th. Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia. Scand J Pain. 2017 Oct;17:279-286. doi: 10.1016/j.sjpain.2017.08.001. Epub 2017 Sep 30.

Reference Type: DERIVED

PMID: 28969994 (View on PubMed)

Related Links

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2011-H-0252.html

NIH Clinical Center Detailed Web Page

Other Identifiers

11-H-0252

Identifier Type: -

Identifier Source: secondary_id

110252

Identifier Type: -

Identifier Source: org_study_id