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

阿片使用障碍(ODS)的治疗包括影响阿片受体的药物，如 丁丙诺啡，但许多患者的使用受到限制，其他人反对用丁丙诺啡治疗成瘾 具有阿片类激动剂特性的药物。纳曲酮是一种阿片类拮抗剂，更容易被 许多患者，最近的研究表明它在疗效上是相同的。开始使用长效药物治疗 然而，纳曲酮需要大约七天的禁食期，在此期间，患者会遭受痛苦。 来自强烈的戒断症状，有复发的风险，可能导致与过量服药有关的死亡。阿片类药物 对去甲肾上腺素和交感神经系统有抑制作用，许多症状 撤资是由这些系统的反弹激活推动的。脑区的多巴胺能系统，包括 腹侧纹状体(伏隔核)和内侧前额叶皮质(前扣带回)在 阿片成瘾、渴求和复发，以及炎症的增加。该项目将评估一种形式的 涉及非侵入性电刺激迷走神经的神经调节可能起到有用的作用 纳曲酮长期阻断治疗前阿片类药物戒断期间 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 中枢在调节药物渴求的区域(腹侧纹状体、前扣带回)起作用。我们的预赛 无创迷走神经刺激对创伤人体应激反应影响的研究资料 创伤后应激障碍(PTSD)受试者和患者显示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(白介素6或白介素6)， 并增强中央大脑(前扣带回)对压力的反应。我们现在建议将这项技术应用于 到ODS患者的治疗上。在使用建模和确定最优 给药参数，我们将使用这些参数来评估nVNS和假刺激对阿片类药物的影响 渴求、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)和放射性标记水到药物线索的视频 最近治疗的ODS患者。根据这项研究的结果，我们将继续进行UH3 阶段，该阶段将涉及一项随机、假对照试验，用于在一至五年期间对ODS患者进行NVNS 阿片类药物停药两周后评估渴求，双侧脑HR-PET成像 功能和大脑多巴胺能功能，以及外周自主神经、心血管和 炎症反应与NVNS或Sham的联合应用。我们假设NVNS会 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(前扣带回功能和腹侧纹状体的多巴胺功能)，并促进 在ODS患者中成功转换为长效纳曲酮。

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.