Genetics and Pain Severity in Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01441141
Recruitment Status : Completed
First Posted : September 27, 2011
Last Update Posted : April 4, 2018
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:


- 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.


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


  • 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.


  • 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.

Condition or disease
Genotype Pain Sickle Cell Anemia Vaso-Occlusive Pain Crisis

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.


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
Actual Enrollment : 67 participants
Observational Model: Case-Control
Time Perspective: Retrospective
Official Title: Exploratory Studies of Psychophysical Pain Phenotyping and Genetic Variability in Sickle Cell Disease
Study Start Date : September 7, 2011

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. To determine if thresholds for pain perception are lower in SCD than in non-SCD controls.

Secondary Outcome Measures :
  1. 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.
  2. To determine if variants in the GCH1 gene alter thresholds for pain perception in sickle cell disease.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01441141

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Swee Lay Thein, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT01441141     History of Changes
Other Study ID Numbers: 110252
First Posted: September 27, 2011    Key Record Dates
Last Update Posted: April 4, 2018
Last Verified: March 16, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Pain Sensitivity
Quantitative Sensory Testing (QST)
Genetic Variation
Sickle Cell Anemia

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn