Vasoocclusive episodes (VOE;painful crises) are a well-known hallmark of sickle cell disease (SCD) and are responsible for the vast majority of health care encounters. There is significant heterogeneity in the frequency of VOE (acute pain) among these patients. SCD patients also experience chronic pain due to complications such as avascular necrosis and leg ulcers. While some of this heterogeneity can be explained by well known genetic modifiers, such as the hemoglobin F, there is a large number of patients in whom there is a lack of a clear-cut explanation for this variation. Opioids form an important component of the management of acute and chronic pain in patients with SCD. Chronic opioid use, sometimes associated with dependence and addiction in a subset of patients, may pose difficult management problems. This coupled with a general lack of adequate knowledge of the management of pain and the fear of addiction often results in under-treatment of painful conditions. The Mu opioid receptor (OPRM1) is the primary site of action of endogenous opioid peptides and opioid analgesics. Recent data indicate that polymorphisms in the OPRM1 gene as well as other genes (COMT, PTGS1, PTGS2, SLC6A4, SCN9A) are associated with differences in pain threshold and narcotic requirements. This study will test the hypothesis that variations in these genes act as genetic modifiers influencing pain frequency, intensity, threshold, opioid usage and dose requirement, as well as opioid dependency. This will be achieved by 1) a prospective analysis of frequency of VOE, pain diaries, and total opioid usage, 2) a prospective data collection consisting of frequency of hospitalizations with VOE, narcotic usage during a hospitalized VOE, evolution of pain scores, and length of hospital stay and correlation of these data with genetic variation in the aforementioned genes, and 3) an experimental component of testing pain threshold with a pressure pain algometer. It is anticipated that genetic correlates of pain frequency and opioid dose requirements will be determined and will lead to individualization of the management of pain in patients with SCD.

Public Health Relevance

This project addresses pain and its management in patients with sickle cell. These patients suffer from acute and chronic pain, which requires the use of narcotics. The inter-individual variation in pain perception and response to treatment is often misconstrued as drug seeking/addiction by providers. By identifying the genetic basis of this variation, we may improve the care and eliminate the disparities for these patients.

National Institute of Health (NIH)
National Institute on Minority Health and Health Disparities (NIMHD)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRG1-EMNR-L)
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Georgia Regents University
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Gutsaeva, Diana R; Montero-Huerta, Pedro; Parkerson, James B et al. (2014) Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability. Blood 123:1917-26
Ikuta, Tohru; Thatte, Hemant S; Tang, Jay X et al. (2011) Nitric oxide reduces sickle hemoglobin polymerization: potential role of nitric oxide-induced charge alteration in depolymerization. Arch Biochem Biophys 510:53-61
Gutsaeva, Diana R; Parkerson, James B; Yerigenahally, Shobha D et al. (2011) Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood 117:727-35
Ikuta, Tohru; Adekile, Adekunle D; Gutsaeva, Diana R et al. (2011) The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease. Blood Cells Mol Dis 47:235-42