Targeting novel mechanisms of pain in sickle cell disease

Abstract

Patients with sickle cell disease (SCD) suffer from intense pain that can start during infancy and increase in severity throughout life, leading to hospitalization and poor quality of life. A unique feature of SCD is vaso-occlusive crises (VOCs) characterized by episodic, recurrent, and unpredictable episodes of acute pain. Microvascular obstruction during a VOC leads to impaired oxygen supply to the periphery and ischemia reperfusion injury, inflammation, oxidative stress, and endothelial dysfunction, all of which may perpetuate a noxious microenvironment leading to pain. In addition to episodic acute pain, patients with SCD also report chronic pain. Current treatment of moderate to severe pain in SCD is mostly reliant upon opioids; however, long-term use of opioids is associated with multiple side effects. This review presents up-to-date developments in our understanding of the pathobiology of pain in SCD. To help focus future research efforts, major gaps in knowledge are identified regarding how sickle pathobiology evokes pain, pathways specific to chronic and acute sickle pain, perception-based targets of “top-down” mechanisms originating from the brain and neuromodulation, and how pain affects the sickle microenvironment and pathophysiology. This review also describes mechanism-based targets that may help develop novel therapeutic and/or preventive strategies to ameliorate pain in SCD.

Mast cell‐neural interactions contribute to pain and itch

“…This process occurs in chronic pain conditions such as SCD. [40][41][42] Brain neuroimaging also demonstrated the existence of central sensitization in patients with SCD. 41,43 Mast cells are also present in the meninges and different regions of the brain including thalamus and are known to influence blood-brain barrier permeability.…”

“…Most evidence is based on studies using a transgenic mouse model of SCD, HbSS-BERK expressing human sickle hemoglobin exclusively, and presenting characteristics of pain similar to those observed clinically. 42,119,120 These sickle mice show extensive mast cell degranulation directly affecting nerve bundles and blood vessels in the skin (Figures 3 and 4). In the The spread of mast cell extracellular extensions also suggests the presence of extracellular traps.…”

“…Vascular occlusion is caused by sickle RBCs obstructing blood flow leading to impaired oxygen supply and nutrients to the organs, vascular dysfunction, ischemia/reperfusion injury, inflammation, and end organ damage. 42,115,128 Ischemia/reperfusion injury stimulates mast cell degranulation. 129 VOC pain is associated with ischemia/reperfusion injury in SCD, and we simulated VOClike pain following hypoxia/reoxygenation in sickle mice.…”

Advances in the Treatment of Sickle Cell Disease

“…The management of SCD is limited by many unanswered clinical questions and challenges, such as (1) treatment options for patients with SCD who are pregnant, 135 (2) the ethical dilemmas posed by the current state of HSCT 136,137 and gene therapy, especially for asymptomatic patients and (3) optimum pain management in a population faced with lifelong episodes of acute and chronic pain that evolves with age and is exacerbated by socioeconomic stressors and age. 138,139 Ironically, painda substantial and bedeviling problem for patients, their families, and their physicians alikedis, with few exceptions, 140 seldom specifically targeted in therapeutic trials.…”

Repurposing pyridoxamine for therapeutic intervention of intravascular cell-cell interactions in mouse models of sickle cell disease

“…Drugs targeting the activation and adhesion of leukocytes and platelets, coagulation, and inflammation are being tested in clinical studies for preventing and treating VOC-mediated pain crises in SCD patients. 1,51 As leading drugs, rivipansel and crizanlizumab are reported to reduce time to resolution of VOC events and requirement for opioid analgesia in SCD patients in recent phase II studies. 9,10 However, complete inhibition of leukocyte-EC contacts might disrupt the innate immune response.…”