Nitric Oxide and Sickle Cell Pain

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
Service.

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.

- INCLUSION CRITERIA FOR SICKLE CELL SUBJECTS:

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

INCLUSION CRITERIA FOR MATCHED CONTROLS:

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

EXCLUSION CRITERIA FOR ALL STUDY PARTICIPANTS:

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

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