Concept: Research Networks To Promote Innovative Mechanistic and Translational Studies of Sickle Cell Disease Pain

Project Concept Review

Council Date: May 13, 2022

Program Director: Inna Belfer, M.D., Ph.D.

Background

Sickle Cell Disease (SCD) is an understudied lifelong disease impacting an underserved minority population in the United States. Pain is the most common clinical complication of SCD. SCD pain includes severe acute recurrent episodes (or painful crises), persistent nociceptive pain, and chronic neuropathic pain, spanning from childhood through adulthood. Even after curative therapy for SCD, severe chronic pain continues in about 40 percent of individuals. SCD pain significantly and negatively impacts the health and quality of life of SCD patients resulting in high hospitalization rates, missed school and workdays, poor functional and psychological outcomes, and increased mortality rates. Management of SCD pain is complex and often doesn’t address comorbidities and complications.

To better understand the current status and potential future directions of SCD pain research and pain management, NCCIH, in collaboration with the National Heart, Lung, and Blood Institute, led an NIH-wide virtual workshop in July 2021 on “Approaches to Effective Therapeutic Management of Pain for People with Sickle Cell Disease.” While it is well understood that SCD is a genetic disease, with well-known genetic mutations causing various levels of red blood cells sickling and an established understanding of underlying pathophysiology, we currently do not have the same level of understanding regarding pain in SCD patients. Clinically, patients with SCD often describe pain as deep, stabbing, electrical, throbbing, beating, spreading, or feeling like broken glass in the veins. There is enormous heterogeneity in the SCD pain population, as well as within-individual variability in pain phenotypes. In addition, pain trajectory in SCD is unique and complicated. It always starts with an acute pain episode, and the type of pain may change across the lifespan. Most importantly, at the clinical level, SCD pain, both acute and chronic, is a multiorgan problem due to multiple organ damages caused by SCD.  

Many SCD patients report that they experience acute pain in their liver, spleen, kidney, intestine, chest, hands, and genitals. Also, they may have severe headaches and central pain due to strokes. Chronic pain often happens in the gallbladder and legs. Acute pain episodes are caused by vaso-occlusive crises, bone infractions, and multiorgan failure, while chronic pain results from avascular necrosis and bone infractions. Recently, several studies have reported musculoskeletal pain in patients with SCD. This pain is believed to reflect acute and chronic injuries to muscles, joints, and bones.

In contrast to the clear multiorgan pain manifestation at the clinical level for patients with SCD, the underlying basic and mechanistic research on what may be contributing to such multiorgan pain as well as suitable therapeutic targets and interventions strategies to ameliorate the multiorgan pain in SCD patients is largely missing. Currently, most animal studies of SCD pain focus on the skin, not on the organs actually impacted in SCD patients. Furthermore, preclinical and clinical studies of organ damage in SCD patients do not measure pain. Current barriers in SCD pain research include limited opportunities to integrate research across multiple disciplines; limited opportunities to connect SCD pain researchers and experts from other pain fields; limited platforms for dissimilation of knowledge among SCD pain researchers and between researchers, clinicians, and patients; and limited diversity and inclusion of under-represented researchers. To overcome these barriers, NCCIH proposes the development of research networks for SCD pain research.

Purpose of Proposed Initiative

This proposed NCCIH initiative would bring together groups of investigators from different disciplines including hematologists, organ biologists, pain experts, physiologists, neuroscientists, psychologists, geneticists, microbiologists, immunologists, behavioral scientists, and clinicians. Research networks will develop a framework to enable translational and reverse translational studies on SCD pain. Potential outcomes include the development of innovative resources for SCD pain researchers such as humanized animal models; muscle, bone, joint, and visceral SCD pain models; access to human tissues (plasma, feces, DRGs, iPSC cells); and technology for omics, microbiome, and neuroimaging studies on SCD pain. These research networks will provide multidisciplinary cross training (such as intensive workshops, summer institutes, or visiting scholar programs), sponsor scientific meetings and conferences, and develop different platforms for information dissemination. Also, collaborative networks will support small-scale pilot research projects that would enable and/or lay the groundwork for subsequent large-scale targeted projects in the priority areas. 

Priority Areas

The research priorities supported by this concept may include but are not limited to the following:

• Basic/mechanistic and translational research of potential therapeutic targets for complementary and integrative health approaches to SCD pain
• Studies of reverse translation using novel animal models for multiorgan damage in SCD
• Studies of multimodal interventions for acute and/or chronic SCD pain relief (e.g., acupuncture with mindfulness) 
• Identification of genetic/genomic, epigenetic, neuroimmune and microbiome biomarkers predicting the transition from acute to chronic SCD pain as well as its response to complementary and integrative health interventions
• Investigation of the whole person health approach to SCD pain and its comorbidities