Pain in SCD-Many mechanisms and mysteries.

Pain is the most common complication experienced by individuals living with sickle cell disease (SCD). While episodes of acute pain, also known as vaso-occlusive crises, are the hallmark of the disease, chronic pain is prevalent in SCD and is associated with many comorbidities. We review current understanding of pain in SCD across the lifespan, integrating definitions, mechanistic categories, and management within biologic, psychosocial, and environmental contexts. Acute vaso-occlusive pain, which emerges as early as infancy, evolves from intermittent nociceptive events driven by multicellular vaso-occlusion, hemolysis, inflammation, and ischemia-reperfusion injury. Chronic pain, which commonly emerges in adolescence and increases with age, reflects heterogeneous nociceptive, neuropathic, and nociplastic mechanisms shaped by SCD-related complications, psychological comorbidities, and social stressors. Chronic pain also contributes to the pathogenesis of acute pain through sensitization processes. Evaluation of mechanisms using tools such as quantitative sensory testing and functional neuroimaging supports hyperexcitability within the peripheral and central nervous system, which is likely important in the development and maintenance of chronic pain. Therapeutically, most guidelines to manage SCD pain are limited by low-certainty evidence; nonetheless, multimodal strategies emphasize timely individualized opioids with nonopioid and nonpharmacologic adjuncts, which are most effective when delivered within multidisciplinary, patient-centered care models. We propose that an individualized whole-person care approach guided by patient-report and biomarker-based framework is key in delineating mechanisms and advancing mechanistic interventions to address pain and related morbidities in SCD.