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NHLBI Topics of Special Interest (TOSI)

HL-133: Phenotypic Characterization of Chronic Pain in Sickle Cell Disease (R01)


The development of sophisticated methodologies to investigate pain phenotypes in subjects with chronic pain in Sickle Cell Disease (SCD). Identification of effective methodologies is an essential step in the development of mechanism-based therapies for pain.

Purpose and Rationale of the Initiative

While the acute vaso-occlusive crisis is the best characterized pain syndrome in children and adults with SCD, more recently it has become apparent that severe chronic pain is also highly prevalent among adults and is a major source of morbidity. In a six month prospective cohort study of 232 subjects 16 years or older, 30% reported severe pain nearly every day, and greater than 50% had pain on more than half of the days. Only 5% of subjects sought medical care for these symptoms. There have been few systematic attempts to characterize chronic pain, and treatment, if administered at all, is empiric and often ineffective. Failure to control pain in SCD has a significant societal impact resulting from the costs of health care utilization — with current yearly estimates of 70,000 to 90,000 hospitalizations, and over 200,000 to 230,000 emergency department visits.

There are multiple possible causes of chronic pain in SCD. The pain phenotype of each individual may represent the cumulative effects of several different processes including central sensitization, peripheral sensitization, post-stroke pain, as well as pain originating in anatomic sites, such as bone disease and skin ulceration, and opioid-induced hyperalgesia.  Careful phenotyping of these subjects will be necessary to an understanding of the role played by each of these processes.

Pain phenotyping utilizes a number of modalities that capture the various dimensions of pain through the use of structured interviews, physical examinations, quantitative sensory testing, functional imaging of the CNS, and genotyping. Specific pain mechanisms, such as neuropathic pain, have been associated with reproducible clusters of descriptive symptoms, anatomic distributions, and characteristic findings on quantitative sensory testing and functional MRI. The careful documentation of the various components of the pain response results in a phenotype characterization of an individual.  Once the pain responses have been identified, treatments tailored to specific mechanisms may be tested. 

The goals of conducting phenotypic studies in subjects with SCD will be to:

  • Define the spectrum of pain mechanisms that may co-exist in individual subjects.
  • Understand the range of pain phenotype heterogeneity in larger cohorts of subjects.
  • Conduct longitudinal studies in children, adolescents, and adults to define the natural history of pain, especially transitioning from recurrent acute pain to chronic pain.
  • Understand the structural and functional changes in the CNS that either lead to or are the result of chronic pain. 

NHLBI has a special interest in applications that propose a multiple PI model where hematologists will collaborate with pain specialists-preferably in institutional settings with established experience in translational pain research. In particular, investigators at centers with CTSA awards will be encouraged to work with the CTSA Pain Researchers Working Group (CPRIG), which has formed a workgroup in SCD to develop cross-institutional collaborative projects. Investigators who have access to institutions that are currently members of one of the two NIH-funded multicenter pain phenotyping studies, the Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) (NIDDK), and the OPPERA: Orofacial Pain: Prospective Evaluation and Risk Assessment (NIDCR) should take advantage of this expertise. Individual projects may place an emphasis on a single evaluative modality (such as neuroimaging or genetics).

Selected Research Examples

Some specific examples may include, but are not limited to:

  • Studies in the transition from acute to chronic pain syndromes in children and adolescents.
  • The relationship of previously stroke and silent cerebral infarcts to the pain phenotype.
  • Prevalence of opioid-induced hyperalgesia in adults with chronic pain.
  • Modulation by genetic determinants of severity in sickle cell disease on pain phenotype.
  • Prevalence of central sensitization in adults with chronic pain.

Submission Dates

Standard receipt dates apply as indicated in the parent RO1 FOA: PA-13-302 Research Project Grant (Parent R01).

Application and Submission Information

Investigators interested in developing applications for these topics are encouraged to submit investigator‐initiated R01 applications under PA-13-302. At the beginning of the title, please include the following characters: HL-. In the first sentence of the abstract, please include the specialized code: HL-133.

Contact Information

Harvey Luksenburg, MD
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Phone: (301) 435-0050



Last Updated: October 2013

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