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

阿片类药物使用障碍（OUD）的治疗包括对阿片类受体有影响的药物，例如 丁丙诺啡，但获得是有限的，许多患者和其他人反对治疗成瘾与 具有阿片类激动剂特性的药物。纳洛酮是一种阿片类拮抗剂， 许多患者，最近的研究表明它在疗效上是等效的。开始长效 然而，纳洛酮需要大约七天的禁欲期，在此期间， 从强烈的戒断症状与复发的风险，可导致过量相关的死亡。阿片 对去甲肾上腺素和交感神经系统有抑制作用， 撤回是由这些系统的反弹激活驱动的。大脑中的多巴胺能系统， 腹侧纹状体（背侧核）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，以及炎症的增加。该项目将评估一种形式的 涉及迷走神经的非侵入性电刺激的神经调节 在开始长期纳洛酮治疗之前的阿片类戒断期间， 去甲肾上腺素、交感神经和炎症反应，并增强外周副交感神经和 调节药物渴求区域的中枢脑功能（腹侧纹状体、前扣带回）。我们的初步 非侵入性迷走神经刺激（nVNS）对创伤患者应激反应影响的数据 受试者和创伤后应激障碍（PTSD）患者显示，nVNS可靠地阻断外周 交感神经和增强副交感神经功能，减少炎症反应（白细胞介素-6或IL-6）， 并增强中枢脑对压力的反应（前扣带）。我们现在建议将这项技术 to the treatment治疗of patients患者with OUD OUD.在使用建模和确定最佳 给药参数，我们将使用这些参数来评估nVNS与假刺激对阿片类药物 渴望，外周自主神经，心血管，炎症和脑功能反应， 高分辨率正电子发射断层扫描（HR-PET）和放射性标记水的药物线索的视频， 最近治疗过的OUD患者。根据这项研究的结果，我们将继续进行UH 3 阶段，这将涉及一项随机，假对照试验nVNS患者OUD在1至 阿片类药物戒断两周，然后评估渴求，双侧大脑的HR-PET成像 功能和脑多巴胺能功能，以及外周自主神经，心血管和 炎症反应与nVNS或假手术联合给药。我们假设nVNS将 减少阿片类药物的渴求和炎症，外周自主神经和心血管反应，并增强 大脑反应（前扣带功能和腹侧纹状体的多巴胺功能），并促进 在OUD患者中成功转换为长效纳洛酮。

Treatment of Opioid Use Disorders (OUDs) includes medications with effects on opioid receptors such as buprenorphine, but access is limited for many patients and others are opposed to treating addictions with medications that have opioid agonist properties. Naltrexone is an opioid antagonist that is more acceptable for many patients, and recent studies show it to be equivalent in efficacy. 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.