Mechanisms of Action of Peripheral Nerve Stimulation for the Treatment of Chronic Neuropathic Pain

周围神经刺激治疗慢性神经病理性疼痛的作用机制

• 批准号: 10730521
• 负责人: SANDIP BISWAL
• 金额: $ 652.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730521
• 关键词: Absence of pain sensation; Acute; Address; Afferent Neurons; Analgesics; Animal Model; Animals; Axon; Central Nervous System; Clinical Trials; Dedications; Devices; Diagnostic Imaging; Electric Stimulation; Electrodes; Frequencies; Goals; Human; Implant; Intervention; Ion Channel; Ion Pumps; Ions; Lower Extremity; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediator; Medical; Membrane; Mental Depression; Modeling; Modernization; Nerve; Nociception; Pain; Pain Threshold; Pain management; Participant; Patients; Peripheral; Peripheral Nerve Stimulation; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Phase; Phenotype; Physical Function; Physiologic pulse; Positron-Emission Tomography; Potassium; Prediction of Response to Therapy; Qualifying; Randomized; Refractory; Reporting; Sensory; Signal Transduction; Sodium; System; Testing; Time; Tissues; Treatment Efficacy; Variant; Visualization; arm; biopsychosocial; central pain; central sensitization; chronic neuropathic pain; chronic pain; clinical pain; conditioned pain modulation; conditioning; depressive symptoms; diagnostic biomarker; effective therapy; evidence base; healing; imaging approach; imaging biomarker; implantation; innovation; molecular imaging; nerve injury; novel; opioid misuse; opioid use; pain catastrophizing; pain processing; pain relief; pain sensitivity; pain symptom; painful neuropathy; peripheral pain; pre-clinical; psychologic; radiotracer; randomized trial; receptor density; remote assessment; response; response biomarker; sigma-1 receptor; subcutaneous; tissue injury; transmission process; treatment group; treatment response; trial comparing

With advent of modern, percutaneous peripheral nerve stimulation (PNS) systems in the last few years, there has been exponential use of PNS for the treatment of refractory chronic neuropathic pain (CNP) with reported efficacy. PNS delivers electrical current through subcutaneous electrodes in proximity to a target peripheral nerve. Despite major technical innovations, exactly how PNS modulates pain processing remains unknown. Our interdisciplinary team is uniquely qualified for this cohesive project with deep expertise in PNS implant, pain clinical trials, psychological assessments, quantitative sensory testing (QST), and advanced molecular imaging for pain. Our proposal directly addresses HEAL RFA-NS-23-003 to optimize PNS as a nonaddictive CNP treatment. Our main hypothesis is that PNS induces reduced ectopic firing in response to electrical pulses, with resulting increased latency of primary sensory afferents, analgesia, and decreased central sensitization. Our overall goal is to identify central and peripheral nervous system mechanisms of PNS pain relief and to characterize the biopsychosocial predictors of treatment response. We propose a mechanistic RCT of 134 patients with lower extremity CNP-PI randomized to stable conventional medical management (CMM) or combined CMM and PNS therapy (PNS+CMM). All participants will undergo baseline and monthly remote assessments for up to 1 year. Quantitative sensory testing (QST) will be performed in all participants at baseline, 30 days, and 3 months, with an additional QST session in PNS implanted patients at 6 months. The local expression of S1R in chronic pain allows for visualization of peripheral pain generators, and we have developed a novel PET radiotracer highly selective for the S1R correlating with local receptor density and pain symptoms. 78 patients (39 in each arm) will undergo [18F]FTC-146 PET/ MRI of the lower extremities at baseline and [18F]FTC-146 PET/CT at 3 months. We will characterize treatment interactions with participant attributes and baseline QST pain sensitivity measures in predicting treatment response; examine depression and physical function as mediators of treatment response; compare longitudinal pain, depressive symptom, pain catastrophizing, physical function, and QST trajectories across treatments, compare acute QST responses to PNS after stable implantation, and determine whether peripheral imaging markers correlate with baseline pain and treatment response. This project will inform precision PNS therapy identifying phenotypes of CNP-PI and PNS treatment response and modifiable factors associated with therapeutic response. Demonstration of PNS-induced reconditioning of the CNS may result in significant paradigm shifts regarding the timing of neurostimulation (i.e. earlier vs. later) in the course of CNP treatment. Identification of a diagnostic imaging biomarker of CNP-PI and predictive/response imaging biomarkers of PNS therapy will significantly advance the diagnostic imaging approach to CNP.

近年来，随着现代经皮周围神经刺激(PNS)系统的出现，PNS在难治性慢性神经病理性疼痛(CNP)的治疗中得到了广泛的应用，并取得了较好的疗效。三叉神经节通过目标周围神经附近的皮下电极传递电流。尽管有重大的技术创新，三七总皂甙究竟是如何调节疼痛处理的仍不清楚。我们的跨学科团队在PNS植入、疼痛临床试验、心理评估、定量感觉测试(QST)和先进的疼痛分子成像方面拥有深厚的专业知识，是这一具有凝聚力的项目的唯一合格人选。我们的建议直接针对REAL RFA-NS-23-003，以优化PNS作为一种非成瘾的CNP治疗。我们的主要假设是，三七总皂苷可以减少对电脉冲的异位放电，导致初级感觉传入、镇痛和中枢敏化的潜伏期延长。我们的总体目标是确定PNS疼痛缓解的中枢和外周神经系统机制，并确定治疗反应的生物、心理和社会预测因素。我们提出了一种机械性随机对照试验，将134例下肢CNP-PI患者随机分为稳定的常规内科治疗(CMM)和CMM+PNS联合治疗(PNS+CMM)。所有参与者都将接受为期长达一年的基线和每月远程评估。所有参与者将在基线、30天和3个月进行定量感觉测试(QST)，并在6个月时对植入三叉神经节的患者进行额外的QST测试。S1R在慢性疼痛中的局部表达使外周疼痛产生的可视化成为可能，我们开发了一种新型的PET放射性示踪剂，它与局部受体密度和疼痛症状相关，具有高度的选择性。78例患者(每臂39例)在基线时行[18F]FTC-146PET/MRI检查，3个月后行[18F]FTC-146PET/CT检查。我们将描述治疗与参与者属性的交互作用和预测治疗反应的基线QST疼痛敏感性测量；检查抑郁和身体功能作为治疗反应的中介；比较不同治疗方案的纵向疼痛、抑郁症状、疼痛灾变、身体功能和QST轨迹；比较稳定植入后PNS的急性QST反应，并确定外围成像标记物是否与基线疼痛和治疗反应相关。该项目将为精确的PNS治疗提供信息，确定CNP-PI和PNS治疗反应的表型，以及与治疗反应相关的可修改因素。三七总皂苷诱导的中枢神经系统再适应可能导致在CNP治疗过程中神经刺激的时机(即更早与更晚)的显著范式转变。寻找CNP-PI的诊断影像标志物和PNS治疗的预测/反应影像生物标志物，将大大推进CNP的影像诊断方法。