Targeting pain at its source in sickle cell disease

Abstract

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

Acute and Chronic Pain Management in Sickle Cell Disease

“…When compared to treating pain after it has been induced, targeting pain at its source may be the most effective strategy of preventing sickle cell disease suffering. Targeting mast cells with imatinib, Food and drug administration authority-approved medicine, to reduce sickle pathobiology's elicitation of somatosensory processes looks to be a highly promising pharmacotherapeutic technique for preventing and treating sickle cell pain [16]. Aich stated that mast cell and microglial activation, neurogenic inflammation, and leukocyte-derived elastase are all immunomodulatory components of acute and chronic sickle pain that can be used to target and prevent pain genesis.…”

Mechanisms of pain in sickle cell disease

“…Chronic pain is often defined as pain that lasts more than 3 months and is experienced by a large number of SCD patients. 11,13 Although the precise aetiology of chronic pain in SCD still remains unclear, the causes of chronic pain may be from extended hyperalgesia after a VOC, leg ulcers, bone infarction, avascular necrosis, compression fractures, arthropathies, chronic osteomyelitis and central sensitization. 10,12,13,42 Central sensitization.…”

“…103 Stimulating cannabinoid receptors was reported to relieve pain in BERK mice, and vaporized cannabis for chronic pain is under investigation in a double-blind, placebo-controlled clinical trial. 11,37 Non-pharmacological management of pain. In addition to the pharmacological treatments, certain non-pharmacological methods have also been used to manage pain in SCD.…”

“…22,29 Consequently, released inflammatory cytokines including tryptase from mast cells near the site together with lower pH and hypoxia-inducible factor-1 alpha (HIF-1 α ) transcription factor activate nociceptors such as the transient receptor potential vanilloid type 1 (TRPV1). 11,13,23,30 Peripheral nerve endings have various receptors which respond to adenosine triphosphate (ATP) and H + including TRPV1. 31 TRPV1 is one of the key players of pain sensation and is highly expressed in perivascular primary sensory neurons including C and Aδ fibres.…”

“…6,8 The patients possess sickle shaped red blood cells (RBCs), which cause haemolytic anaemia, acute/chronic pain, organ damages or comorbid conditions. [9][10][11] A unique complication of this disease is vaso-occlusive crisis (VOC), which causes episodic or recurrent acute pain, and the patients also suffer from chronic pain. 12,13 Although the precise cause of chronic pain is yet to be discovered, both acute and chronic pain are the hallmark of the disease and dominate the clinical characteristics of SCD patients.…”