The Multifaceted Nature of Pain in Sickle Cell Disease: From Molecular Mechanisms to Emerging Therapeutic Frontiers

Sickle cell disease (SCD) is an inherited haemoglobinopathy resulting from a single point mutation in the β-globin gene, leading to the polymerization of deoxygenated haemoglobin and the formation of sickled erythrocytes. This multisystem disorder is characterized by recurrent acute and chronic pain, which remains its most common and debilitating complication, significantly impacting morbidity, mortality, and quality of life. This review provides a comprehensive overview of the evolving understanding of pain pathophysiology in SCD, moving beyond the traditional nociceptive and inflammatory models to encompass neuropathic mechanisms and central sensitization. We explore the complex cellular and molecular mediators of vaso-occlusive crises (VOC), including the critical roles of activated neutrophils, platelets, endothelial adhesion molecules (notably selectins), mast cells, and inflammatory cytokines. The review further examines the mechanisms underlying chronic pain syndromes and neuropathic pain, highlighting the roles of peripheral and central sensitization, as well as neurogenic inflammation. Current pharmacological management strategies are discussed, including the use of opioids, NSAIDs, antidepressants, and anticonvulsants, alongside their benefits and limitations. We also evaluate established disease-modifying therapies such as hydroxyurea, L-glutamine, and crizanlizumab. Finally, this review delves into emerging therapeutic frontiers, including novel HbF-inducing agents (e.g., decitabine, HDAC and LSD1 inhibitors, IMiDs), anti-adhesion and anti-inflammatory molecules, nutritional supplements, and curative gene therapies. A comprehensive, multimodal, and individualized approach that targets the multifaceted mechanisms of pain is essential for improving outcomes in SCD.