Editorial: Current Treatment Strategies and Integrative Medicine for Management of Pain in Sickle Cell Disease

Kimberlei A Richardson^1*Gabrielle Lynn McLemore²Keesha Powell-Roach³Kalpna Gupta⁴

• ¹Department of Pharmacology, Howard University College of Medicine, Washington,, DC, United States
• ²Department of Biology, Morgan State University, School of Computer, Mathematics, and Natural Sciences, Baltimore, United States
• ³School of Nursing, Rutgers University, New Brunswick, United States
• ⁴Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, United States

This editorial is an introduction to a series of articles in a special issue of Frontiers in Pain Research Journal entitled, “Current Treatment Strategies and Integrative Medicine for Management of Pain in Sickle Cell Disease.” Sickle cell disease (SCD) is a globally prevalent, inheritable disorder characterized by rigid, abnormally shaped red blood cells that can lead to vaso-occlusive crises, hemolysis, other complications, and pain. The acute and chronic pain experienced by individuals with SCD is often reported as a debilitating symptom that profoundly impacts their quality of life. Despite numerous efforts to develop more effective treatments, there is still great difficulty in the management of pain in this population. This compilation of five articles underscores the potential of integrative and precision medicine approaches to advance pain management, while revealing the biological, clinical, and systemic components shaping SCD pain experiences and treatment outcomes. In this editorial, the major findings from the various authors have been summarized and placed within a broader context while also highlighting challenges that still lie ahead for the management and treatment of chronic pain in SCD. Conventional pain management in SCD has routinely depended on opioids, despite their high addiction potential. Non-opioid, integrative medicine strategies show promise as potentially safe and efficacious alternatives for managing SCD pain, but the lack of evidence-based and guideline-recommended strategies for implementing such therapies hinder their widespread use. A critical review of these strategies by Smith, et al., 2023 highlights that the full implementation of pharmacological/biobehavioral pain strategies targeting mechanistic pain pathways is challenging due to limited knowledge, and inadequate resources including financial and personnel support. The authors recommend personalized medicine, pharmacogenomics, and IMS as potential strategies for managing SCD pain, updated Melzack's Neuromatrix pain model, and present a framework for classifying SCD pain subphenotypes and mechanisms, selecting personalized multimodal treatment strategies, and identifying research gaps for potential exploration. The authors contend that precision medicine and integrative health offer a cogent research approach for multimodal, individualized strategies to diagnose and treat acute/chronic SCD pain. Building upon the established knowledge from integrative medicine, further advancements in metabolic interventions have demonstrated the potential to enhance patient outcomes. SCD disrupts oxygen transport and is characterized by oxidative stress and endothelial dysfunction, often exacerbated by hemolysis-induced L-arginine depletion. L-arginine is essential for nitric oxide synthesis, which regulates vascular health and oxidative stress. Recent findings from Christian et al., 2024 in Kinshasa, Democratic Republic of Congo, demonstrate the impact of arginine supplementation on lactate dehydrogenase levels, a key marker of hemolysis, in a retrospective cohort of 31 patients with SCD across three different treatment phases. These results highlight the potential of L-arginine supplementation to mitigate hemolysis-related complications in SCD since significant reductions in hemolysis-related complications were observed when arginine was combined with hydroxyurea therapy. While arginine supplementation targets physiological mechanisms, other approaches, such as Traditional Chinese Medicine (TCM), incorporate a holistic perspective that addresses both physical and systemic aspects of SCD care.Wang and colleagues, 2023 sought to integrate TCM principles to guide the use of acupuncture and other alternative strategies, in treating comorbidities related to SCD care. The use of TCM diagnoses introduces a culturally resonant and holistic dimension by categorizing SCD pathologies into syndromes such as Qi and blood deficiency, stagnation, or mixed presentations. Based on these pathologies, patients with SCD were sorted into three different TCM Syndrome groups: Deficiency, Stagnation, and Equal. The groups did not differ on quantitative sensory testing, but differences were observed in the frequency of vaso-occlusive crisis and opioid consumption, and patients' pain profiles. Patients in the stagnation group exhibited heightened pain, interference and nociplastic pain, while the deficiency group faced profound chronic pain and comorbidities. These findings provide a novel clinical relevance for TCM diagnoses and highlight the potential of TCM-based diagnostics to inform personalized acupuncture and integrative therapies, not only for SCD, but for other clinical populations with complex pathologies. The focus on holistic approaches that are critical to long-term patient outcomes extends to identifying and mitigating the skeletal/bone complications associated with SCD. Bone pain is one of the most pervasive and debilitating complications of SCD, significantly affecting quality of life. The review by Gollamudi et al., 2023 provides a comprehensive overview of the mechanisms driving bone complications in SCD, drawing parallels with findings from non-SCD models to elucidate common pathways. By exploring the dynamic interactions between the skeletal and peripheral nervous systems, this review underscores the importance of understanding the nuances of these processes to develop effective, targeted therapies. Furthermore, it highlights the need for rigorous research to address gaps in our knowledge about the roles of stress erythropoiesis, avascular necrosis, and inflammation in SCD bone complications. As we move toward innovative approaches, this work aims to inform future basic and translational research that can ultimately reduce the burden of bone pain and improve outcomes for individuals living with SCD. As bone related complications highlight the interplay of systemic and cellular mechanisms, genetic research provides deeper insights into individual variability in SCD pain experiences.Genetic variation has long been hypothesized to influence individual pain perception and severity. Despite this, the relationship between single nucleotide polymorphisms (SNPs) and SCD-related pain remains underexplored, leaving significant gaps in our understanding and limiting the potential for precision medicine approaches. This systematic review by Gehling et al., 2023 synthesizes two decades of scientific literature examining the association between SNPs and SCD-related pain outcomes. There are significant gaps in understanding chronic pain phenotypes and their genetic basis. The evidence reviewed in this study points to the potential of genetic variation as a contributor to both acute and chronic pain phenotypes in SCD. However, the field remains in its infancy, with a need for replication, larger sample sizes, and expanded research on chronic pain. The insights from the studies included in this series converge on a central theme: the necessity of individualized, comprehensive, and integrative approaches to SCD pain management. A holistic framework that includes pharmacogenomics and TCM diagnostics to address molecular drivers of bone pain and hemolysis is essential. Moreover, systemic barriers such as resource constraints and inequities in healthcare access must be addressed to ensure that these advancements benefit every patient. An improvement in patient outcomes and quality of life can be achieved through the integration of diverse therapeutic strategies and a comprehensive, patient-centered approach.