Mechanisms of pain in sickle cell disease

Abstract

Objectives: The hallmark of sickle cell disease (SCD) is acute and chronic pain, and the pain dominates the clinical characteristics of SCD patients. Although pharmacological treatments of SCD targeting the disease mechanisms have been improved, many SCD patients suffer from pain. To overcome the pain of the disease, there have been renewed requirements to understand the novel molecular mechanisms of the pain in SCD. Methods: We concisely summarized the molecular mechanisms of SCD-related acute and chronic pain, focusing on potential drug targets to treat pain. Results: Acute pain of SCD is caused by vaso-occulusive crisis (VOC), impaired oxygen supply or infarction-reperfusion tissue injuries. In VOC, inflammatory cytokines include tryptase activate nociceptors and transient receptor potential vanilloid type 1. In tissue injury, the secondary inflammatory response is triggered and causes further tissue injuries. Tissue injury generates cytokines and pain mediators including bradykinin, and they activate nociceptive afferent nerves and trigger pain. The main causes of chronic pain are from extended hyperalgesia after a VOC and central sensitization. Neuropathic pain could be due to central or peripheral nerve injury, and protein kinase C might be associated with the pain. In central sensitization, neuroplasticity in the brain and the activation of glial cells may be related with the pain. Discussion: In this review, we summarized the molecular mechanisms of SCD-related acute and chronic pain. The novel treatments targeting the disease mechanisms would interrupt complications of SCD and reduce the pain of the SCD patients.

Distracting Through Procedural Pain and Distress Using Virtual Reality and Guided Imagery in Pediatric, Adolescent, and Young Adult Patients: Randomized Controlled Trial

“…Participants with sickle cell disease responded with a more powerful reduction in anxiety when using VR than GI. While it is unclear why, we know that children and adolescents with sickle cell disease have a different pain trajectory than those with other diseases [ 45 ]. The transition from acute and intermittent vaso-occlusive pain crises in childhood to chronic pain in adolescence is well documented but remains poorly understood [ 46 ].…”

Prevalence of neuropathic pain in adolescents with sickle cell disease: A single‐center experience

“…Not only are patients in this group more likely to have NP during acute pain events, they are also more likely to be treated with opioids, which can trigger mechanisms of opioid hyperalgesia, opioid tolerance, and central sensitization 23–25 . These mechanistic sequelae can contribute to further enhancement of NP pathophysiology 1,11,21,24,26,27 . When NP was evaluated by qualitative sensory testing in 24 children and adolescents at baseline and again during admission for pain, increased cold and mechanical pain sensitivity were found during pain crisis 28 .…”

“…[23][24][25] These mechanistic sequelae can contribute to further enhancement of NP pathophysiology. 1,11,21,24,26,27 When NP was evaluated by qualitative sensory testing in 24 children and adolescents at baseline and again during admission for pain, increased cold and mechanical pain sensitivity were found during pain crisis. 28 Further examination of NP with clinical tools (painDETECT) and qualitative sensory testing evaluations concurrently would contribute to better characterization of NP in adolescents with SCD-related acute and/or chronic NP.…”

Treatment Options That Reduce the Duration of Sickle Cell Vaso-Occlusive Crises: A Systematic Review

“…The subsequent deoxygenation in the RBCs causes them to take a "sickled" shape. These sickled, damaged cells then attach to the endothelial wall, forming a mass with white blood cells and platelets, with the aid of adhesion molecules (P and E-selectin, intercellular adhesion molecule, and basal cell adhesion molecule-lutheran blood group [BCAM/Lu]) [ 3 , 7 ]. The continued ischemia and increased acidity lead to the breakdown of endothelial cells and RBCs, which, in turn, attract monocytes.…”

“…The sickled RBCs then accumulate and cause a blockage in blood vessels (vaso-occlusion), causing a variety of symptoms. The sickled RBCs are also broken down at a higher rate, causing an additional type of anemia (hemolytic) [ 3 ]. Some of the symptoms are sickle cell pain crisis, acute chest syndrome, leg ulcers, strokes, pulmonary emboli, end-organ damage, infections, and many other problems [ 1 , 2 , 4 ].…”