Non-Invasive Vagal Nerve Stimulation in Patients with Opioid Use Disorders

阿片类药物成瘾是流行病比例的一个主要危机，药物过量现在是阿片类药物成瘾的主要原因。 意外死亡在美国。阿片类药物使用障碍（OUD）的治疗包括以下药物： 这些药物对阿片受体如丁丙诺啡有影响，但对许多患者来说，获得这些药物是有限的。纳洛酮是一种 阿片类拮抗剂，在最近的研究中已显示其疗效与丁丙诺啡相当。启动 然而，使用长效纳洛酮治疗需要大约7天的禁欲期， 此时患者会出现强烈的戒断症状，并有复发的风险， 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 许多戒断症状是由这些系统的反弹激活驱动的。多巴胺能 大脑区域中的系统，包括腹侧纹状体（核纹状体）和内侧前额叶皮层（前 扣带回）在阿片类药物成瘾、渴望和复发中起重要作用，炎症增加也是如此。这 该项目将评估一种神经调节形式，包括迷走神经的非侵入性电刺激 在开始长期纳洛酮治疗前的阿片类戒断期间， 治疗阻断去甲肾上腺素、交感神经和炎症反应，并增强外周 调节药物渴求的区域（腹侧纹状体、前额叶、后额叶）中的副交感神经和中枢脑功能 扣带）。我们关于非侵入性迷走神经刺激（nVNS）对应激影响的初步数据 受过创伤的人类受试者和创伤后应激障碍（PTSD）患者的反应表明， nVNS可靠地阻断外周交感神经并增强副交感神经功能，减少炎症反应， 反应（白细胞介素-6，或IL-6），并增强中枢脑反应（前扣带回）的压力。我们现在 建议将这项技术应用于治疗OUD患者。使用建模进行验证后 并确定最佳给药参数，我们将使用这些参数来评估nVNS的效果 与假刺激对阿片类药物渴求、外周自主神经、心血管、炎症和大脑的影响相比， 使用高分辨率正电子发射断层扫描（HR-PET）测量功能反应， 放射性标记的水与最近接受治疗的OUD患者的药物线索视频。根据这一结果， 研究中，我们将进行UH 3阶段，这将涉及一个随机，假对照试验的nVNS， OUD患者在阿片类药物戒断1 - 2周期间，随后评估渴望， 脑功能和脑多巴胺能功能的HR-PET成像，以及外周 与施用nVNS或假手术联合的自主神经、心血管和炎症反应。 我们假设nVNS将减少阿片类药物的渴求和炎症，外周自主神经， 心血管反应和增强大脑反应（前扣带功能和多巴胺功能， 腹侧纹状体），并促进OUD患者成功转化为长效纳洛酮。

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.