Nitric Oxide and Sickle Cell Pain

Conditions:Chronic Pain, Anemia
Therapuetic Areas:Hematology, Musculoskeletal
Age Range:18 - Any
Start Date:June 17, 2011
End Date:December 5, 2013

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Biochemical and Genetic Mechanisms for Etiology of Sickle Cell Pain


- Sickle cell disease often causes crises, with episodes of pain. Many people with sickle
cell disease also have pain between crises. Inflammation is an important part of sickle cell
pain. It may be related to levels of nitric oxide. Nitric oxide is a gas in the body that
helps relax blood vessels and may be related to the pain from sickle cell disease.
Researchers want to study the relationship between blood levels of nitric oxide and pain in
people with sickle cell disease. Researchers also want to study how certain genes express
themselves related to sickle cell pain.


- To collect blood samples and other genetic expression information to study sickle cell
pain and its relation to nitric oxide levels in the blood.


- People at least 18 years of age who have sickle cell disease.

- Healthy volunteers at least 18 years of age.


- This study requires a screening visit and four study visits scheduled 1 week apart.
Each visit will last about 1 hour.

- Participants will be screened with a medical history and physical exam. They will
complete questionnaires about pain levels (if any). They will also provide blood
samples for genetic and other testing.

- Participants will have a breath test to see how much nitric oxide they exhale. They
will also have a test of their ability to detect small changes in temperature and

- Participants will keep a diary to record daily pain levels and pain medicines taken.
They will write down what they eat to track foods that contain nitrates (such as meats
like ham and bacon and vegetables like beets and spinach).

- At each of the four study visit, participants will bring the pain diary, provide blood
samples, and have breath nitric oxide tests.

Sickle cell disease is a systemic disorder whose proximate cause is a mutation in the
beta-globin chain of hemoglobin. Although it is characterized by differing degrees and
patterns of clinical manifestations, its major features include severe episodes of pain. The
sickle cell pain crisis is one of the most typical characteristics of this disease and pain
associated with crisis is reported to be more intense than other types of clinical pain by
those with sickle cell disease and displays both nociceptive and neuropathic qualities. Pain
in sickle cell disease is more widely experienced and poorly managed than previously
considered. In one community sample, more than 50 percent of the patients reported
experiencing pain on more than half the days of the study period. Painful crisis consist of
pain experienced in different areas of the body, typically in the extremities, back, abdomen
and chest and some studies suggest that patients experience prodromal or pre-crisis phases
of their pain, some of which last up to 24 hours before developing the typical features of a
pain crisis. The nature of pain experience in patients with sickle cell disease is not well
documented nor are the mechanisms of sickle cell pain well understood.

Objectives: The first objective of the study is to characterize genetic expression data of
sickle cell disease and matched controls at weekly time points over a 4 week period. The
second objective is to measure levels of exhaled Nitric Oxide (eNO) and other biomarkers in
sickle cell patients and in matched controls over the same time points. The third objective
is to evaluate experimental pain perception in both groups.

Population: By stratifying patients by pain level, this study will recruit sickle cell
patients with a range of symptom severity (N=45) and sex-, race-, ethnicity and age-matched
controls (N=45) without sickle cell trait from the NIH Patient Recruitment and Referral

Design: This is a prospective, exploratory study of steady state and acute pain phase in
sickle cell patients. Participants will undergo evaluations (eNO and blood collection)
during weekly clinic visits and keep a pain diary for 4 weeks after the first visit. All
participants will also undergo one session of quantitative sensory testing.

Importance: The purpose of this study is to improve the understanding of the biochemical and
molecular genetic mechanisms associated with sickle cell pain by characterizing the
transcriptome of sickle cell disease during steady state and pain phases. It is hypothesized
that analysis of the transcriptome will result in a panel of biomarkers that correlate with
the severity level of pain and perhaps signal the onset of a painful episode. The successful
elucidation of these relationships may identify novel targets for intervention leading to
attenuation of sickle cell pain, improved treatment and less impact on quality of life and
functional status.


All subjects with sickle cell disease will be eligible for enrollment in this study if
they meet all of the following criteria:

18 years of age or older

Diagnosis of sickle cell disease (electrophoretic or HPLC documentation of hemoglobin S
only phenotype is required)

No vaso-occlusive crisis during the previous two weeks

Medically stable

Can speak and understand English to complete assessments and scales


All volunteer matched control study participants will be eligible for enrollment on this
study if they meet all the following criteria:

18 years of age or older

Non-sickle cell trait or disease

Medically healthy based upon the history and physical exam and screening blood analyses

No chronic pain condition.

Can speak and understand English to complete assessments and scales

Ethnicity, age (within 5 years), and sex matched to that of sickle cell subjects already
enrolled on study


Study participants will be excluded from the study if he/she has one or more of the

Inability to provide his/her own informed consent.

Drug or alcohol dependence/abuse within the past 5 years

Cigarette smoking or the use of any tobacco products within two years

Use of tranquilizers, steroids, non-steroidal anti-inflammatory agents three or more times
per week.

Clinically significant medical condition that will confound the analysis of factors
associated with sickle cell pain, such as:

- Chronic inflammatory disease (i.e. rheumatoid arthritis, systemic lupus
erythematosus, cirrhosis)

- Diabetes mellitus

- Uncontrolled hypertension

- Known malignancies
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9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, MD
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