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.

随着近几年现代经皮周围神经刺激 (PNS) 系统的出现，PNS 在治疗难治性慢性神经病理性疼痛 (CNP) 中的应用呈指数级增长，并报告有疗效。 PNS 通过靠近目标周围神经的皮下电极输送电流。尽管有重大的技术创新，三七总皂苷究竟如何调节疼痛处理仍然未知。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，具有独特的资格来胜任这个有凝聚力的项目。我们的提案直接针对 HEAL RFA-NS-23-003，以优化 PNS 作为非成瘾性 CNP 治疗方法。我们的主要假设是，PNS 会减少对电脉冲的异位放电反应，从而导致初级感觉传入潜伏期增加、镇痛和中枢敏化降低。我们的总体目标是确定 PNS 疼痛缓解的中枢和周围神经系统机制，并描述治疗反应的生物心理社会预测因素。我们建议对 134 名下肢 CNP-PI 患者进行机械随机对照试验，随机接受稳定的常规医疗治疗 (CMM) 或 CMM 与 PNS 联合治疗 (PNS+CMM)。所有参与者都将接受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 个月时进行定量感觉测试 (QST)，并在 6 个月时对植入 PNS 的患者进行额外的 QST 测试。 S1R 在慢性疼痛中的局部表达允许外周疼痛发生器的可视化，我们开发了一种新型 PET 放射性示踪剂，对与局部受体密度和疼痛症状相关的 S1R 具有高度选择性。 78 名患者（每组 39 名）将在基线时接受 [18F]FTC-146 PET/MRI 下肢检查，并在 3 个月时接受 [18F]FTC-146 PET/CT 检查。我们将描述治疗与参与者属性和基线 QST 疼痛敏感性测量的相互作用，以预测治疗反应；检查抑郁症和身体机能作为治疗反应的中介因素；比较治疗期间的纵向疼痛、抑郁症状、疼痛灾难性、身体功能和 QST 轨迹，比较稳定植入后对 PNS 的急性 QST 反应，并确定外周影像标记是否与基线疼痛和治疗反应相关。该项目将为精准 PNS 治疗提供信息，识别 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。 PNS 诱导的 CNS 修复的证明可能会导致 CNP 治疗过程中神经刺激时间（即较早与较晚）的重大范式转变。 CNP-PI 的诊断成像生物标志物和 PNS 治疗的预测/反应成像生物标志物的鉴定将显着推进 CNP 的诊断成像方法。