Non invasive vagal nerve stimulation in opioid use disorders

阿片类药物使用障碍中的无创迷走神经刺激

• 批准号: 10376890
• 负责人: James Douglas Bremner
• 金额: $ 9.1万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376890
• 关键词: Abstinence; Adverse reactions; Anterior; Area; Brain; Brain region; Buprenorphine; Cardiac; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Chest; Cues; Data; Devices; Dopamine; Dose; Drug usage; Electric Stimulation; Epidemic; Family; Health Services Accessibility; Imagery; Inflammation; Inflammatory; Inflammatory Response; Injectable; Interleukin-6; Intervention; Knowledge; Lead; Machine Learning; Measures; Medial; Methods; Modeling; Movement; Naltrexone; Neck; Nerve; Norepinephrine; Nucleus Accumbens; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Antagonist; Opioid Receptor; Opioid agonist; Outcome; Outcomes Research; Overdose; Patients; Peripheral; Pharmaceutical Preparations; Phase; Photoplethysmography; Physiological; Physiology; Pilot Projects; Play; Positron; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prefrontal Cortex; Property; Radiolabeled; Randomized; Relapse; Resistance; Resolution; Respiration; Rewards; Role; Sampling; Stress; Sympathetic Nervous System; Symptoms; System; Technology; Time; United States; Vagus nerve structure; Validation; Vasomotor; Ventral Striatum; Visual; Water; Withdrawal; Withdrawal Symptom; addiction; analog; base; biological adaptation to stress; craving; drug craving; human subject; implantation; neuroregulation; opioid use disorder; opioid withdrawal; overdose death; relapse patients; relapse risk; response; response biomarker; tomography; transmission process; treatment response; vagus nerve stimulation; vasoconstriction

Opioid addiction is a major crisis of epidemic proportions and drug overdose is now the leading cause of accidental death in the United States. Treatment of Opioid Use Disorders (OUDs) includes medications with effects on opioid receptors such as buprenorphine, but access is limited for many patients. Naltrexone is an opioid antagonist that has been shown in recent studies to be equivalent in efficacy to buprenorphine. Initiation of treatment with long-acting naltrexone, however, requires a period of abstinence of about seven days during which time patients suffer from intense symptoms of withdrawal with a risk of relapse that can lead to overdose-related death. Opioids have an inhibitory effect on norepinephrine and the sympathetic nervous system, and many symptoms of withdrawal are driven by rebound activation of these systems. Dopaminergic systems in brain areas including ventral striatum (nucleus accumbens) and medial prefrontal cortex (anterior cingulate) play an important role in opioid addiction, craving and relapse, as do increases in inflammation. This project will assess a form of neuromodulation involving non-invasive electrical stimulation of the vagus nerve that may play a useful role during the period of opioid withdrawal before the initiation of long-term naltrexone treatment in blocking norepinephrine, sympathetic, and inflammatory responses and enhancing peripheral parasympathetic and central brain function in areas modulating drug craving (ventral striatum, anterior cingulate). Our preliminary data on the effects of non-invasive Vagal Nerve Stimulation (nVNS) on stress response in traumatized human subjects and patients with posttraumatic stress disorder (PTSD) show that nVNS reliably blocks peripheral sympathetic and enhances parasympathetic function, reduces inflammatory responses (interleukin-6, or IL-6), and enhances central brain responses (anterior cingulate) to stress. We now propose to apply this technology to the treatment of patients with OUDs. Following verification using modelling and determination of optimal dosing parameters, we will use these parameters to assess effects of nVNS versus sham stimulation on opioid craving, peripheral autonomic, cardiovascular, inflammatory, and brain functional responses measured with High-Resolution Positron Emission Tomography (HR-PET) and radiolabeled water to videos of drug cues in recently treated patients with OUDs. Based on the outcome of this research, we will proceed to the UH3 phase, which will involve a randomized, sham-controlled trial of nVNS in patients with OUDs during the one to two week period of opioid withdrawal followed by assessment of craving, HR-PET imaging of both brain function and brain dopaminergic function, and assessment of peripheral autonomic, cardiovascular and inflammatory responses in conjunction with administration of nVNS or sham. We hypothesize that nVNS will reduce opioid craving and inflammatory, peripheral autonomic and cardiovascular responses and enhance brain responses (anterior cingulate function and dopamine function in ventral striatum), and promote successful conversion to long-acting naltrexone, in patients with OUDs.

阿片类药物成瘾是流行比例的重大危机，药物过量现在是 美国意外死亡。阿片类药物使用障碍（OUDS）的治疗包括 对丁丙诺啡等阿片类药物受体的影响，但对于许多患者而言，访问受到限制。纳曲酮是一个 在最近的研究中已表明的阿片类拮抗剂在丁丙诺啡的疗效方面是等效的。引发 然而，用长效纳曲酮进行治疗需要一段时间的禁欲。 患者在哪个时候遭受严重戒断症状，​​复发的风险可能导致 过量相关的死亡。阿片类药物对去甲肾上腺素和交感神经有抑制作用 系统和许多戒断症状都是由这些系统的反弹激活驱动的。多巴胺能 大脑区域的系统，包括腹侧纹状体（伏隔核）和内侧前额叶皮层（前部皮层） 扣带）在阿片类药物成瘾，渴望和复发中起重要作用，炎症的增加也是如此。这 项目将评估一种神经调节形式，涉及迷走神经的非侵入性电刺激 在长期纳曲酮启动之前，这可能在阿片类药物提取期间起有用 阻断去甲肾上腺素，交感神经和炎症反应的治疗 调节药物渴望的区域中的副交感神经和中央脑功能（腹侧纹状体，前部 扣带）。我们关于非侵入性迷走神经刺激（NVN）对压力的影响的初步数据 受伤的人类受试者和创伤后应激障碍（PTSD）的反应表明， NVN可靠地阻止外周交感神经并增强副交感神经功能，减少炎症 反应（白介素-6或IL-6），并增强了压力的中央大脑反应（前扣带回）。我们现在 建议将该技术应用于OUD患者的治疗。使用建模进行验证 并确定最佳剂量参数，我们将使用这些参数来评估NVN的效果 对阿片类药物渴望，周围自主神经，心血管，炎症和大脑的假手术刺激 用高分辨率正电子发射断层扫描（HR-PET）和 在最近接受过OUDS患者的药物线索视频中，放射标记的水。基于此结果 研究，我们将进入UH3阶段，该阶段将涉及NVN的随机，假对照试验 在一到两周的阿片类药物戒断期内，OUDS患者，然后评估渴望， 脑功能和脑多巴胺能功能的HR-PET成像，并评估周围 自主，心血管和炎症反应与NVN或假施用结合。 我们假设NVN将减少阿片类药物的渴望和炎症，周围自主神经和 心血管反应并增强大脑反应（前扣带回功能和多巴胺功能 腹侧纹状体），并促进了OUD患者的成功转化为长效纳曲酮。