Non invasive vagal nerve stimulation in opioid use disorders

阿片成瘾是一种流行比例的主要危机，药物过量现在是 美国的意外死亡事件。阿片类药物使用障碍(ODS)的治疗包括 对阿片受体的影响，如丁丙诺啡，但对许多患者来说是有限的。纳曲酮是一种 阿片类拮抗剂，最近的研究表明其疗效与丁丙诺啡相当。起爆 然而，长效纳曲酮的治疗需要大约七天的禁食期 当患者出现强烈的戒断症状并有复发风险时，可能会导致 与服药过量有关的死亡。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 脑区包括腹侧纹状体(伏隔核)和内侧前额叶皮质(前部)的系统 扣带回)在阿片成瘾、渴求和复发中起着重要作用，炎症的增加也是如此。这 该项目将评估一种神经调节形式，包括对迷走神经的非侵入性电刺激 这可能在纳曲酮开始长期用药前的阿片类药物戒断期间起到有用的作用 阻断去甲肾上腺素、交感神经和炎症反应并增强外周功能的治疗 调节药物渴求区域(腹侧纹状体、前部)的副交感神经和中枢脑功能 扣带状)。无创迷走神经刺激(NVNS)对应激反应影响的初步研究 创伤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，增强副交感神经功能，减少炎症 反应(IL-6或IL-6)，并增强中枢大脑对压力的反应(前扣带回)。我们现在 建议将这项技术应用于ODS患者的治疗。使用建模进行验证后 以及最佳给药参数的确定，我们将使用这些参数来评估NVNS的效果 与假刺激相比，阿片类药物渴求、外周自主神经、心血管、炎症和大脑 高分辨率正电子发射断层扫描(HR-PET)测量的功能反应 最近治疗的ODS患者的药物提示视频中的放射性标记水。基于这一结果 研究后，我们将进入UH3阶段，这将涉及一项关于NVNS的随机、假对照试验 ODS患者在阿片类药物停药一到两周后进行渴求评估， 脑功能和脑多巴胺能功能的HR-PET成像及外周功能评估 自主神经、心血管和炎症反应与NVNS或SHAM的联合应用。 我们推测，NVNS将减少阿片类药物的渴求和炎症，外周自主神经和 心血管反应和增强大脑反应(前扣带回功能和多巴胺功能 腹侧纹状体)，并促进ODS患者成功转换为长效纳曲酮。

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.