Immunological mechanisms underlying acupuncture analgesia in patients with sickle cell disease

Project Summary Pain in sickle cell disease (SCD) is a major lifelong complication that disproportionately affects Black and African American people. Clinically, SCD presents in two distinct phases: the steady-state phase associated with chronic pain, and the vaso-occlusive crisis (VOC) phase characterized by severe pain which requires high doses of opioids and is associated with increased risk of overdose and death, opioid-induced hyperalgesia, and lowered quality of life (QoL). Mechanistic studies directly addressing the pathophysiological mechanisms of transition from steady-state to VOC are notably limited. Recent studies suggest that the progression of VOC is linked to abnormal vasoconstriction resulting from dysfunction of the autonomic nervous system (ANS). There is an urgent need to gain a fundamental understanding of the pathophysiology underlying the transition from pain to VOC and to develop evidence-based, effective, and safe therapies for managing pain in SCD patients. Preliminary results from our completed trial (ClinicalTrials.gov Identifier: NCT05045820) suggest that verum acupuncture treatment improved patient-reported pain, QoL, and reduce opioid requirements and the number of patientreported VOC. However, our understanding of the pathophysiology of SCD and VOC, and the mechanisms by which acupuncture ameliorates clinical symptoms of SCD, remains very limited. Our recent findings revealed a complex interplay among dysregulated inflammatory mediators and autoantibodies, and their relationship with VOC, pain, and sensory sensitivity at baseline in SCD patients. Subsequently, we observed that the reduced inflammatory markers and improvements of VOC/QoL/opioid requirement outcomes significantly differ between the verum and sham treatment groups. Leveraging a new clinical trial, we propose to specifically examine the inflammatory/immune biomarkers related with the onset and progression of VOC and their modulation by acupuncture through three Aims. Aim 1: Characterize variation in inflammatory/immune profiles in SCD patients as they progress to VOC. Aim 2: Determine the effect of acupuncture on inflammatory/immune patterns. Aim 3: Investigate the anti-inflammatory mechanisms of acupuncture. Persistent disparities in healthcare access faced by African Americans are widely recognized and have clear links to unfavorable health outcomes. If successful, the proposed studies have the potential to unveil novel mechanistic targets for effectively managing VOC and advance our understanding of the mechanisms underlying acupuncture analgesia.