Abstinence and Drug Withdrawal: Innovative Translational Methods for Neonates

摘要/摘要 胎儿药物暴露是一个全国性的问题。全国近5%的孕妇暴露了她们的 胎儿对宫内药物(非法和处方药)的反应。新生儿禁欲综合征(NAS)指的是多个 停药引起的系统障碍和神经行为失调/婴儿S 已经养成了耐受性和身体依赖性。需要研究和治疗NAS的新方法 因为尽管有目前的干预措施，NAS婴儿通常需要长时间的住院和药物治疗 治疗中枢、自主神经、血管运动和胃肠道不稳定，这也可能导致不良 神经行为结果。越来越多的研究表明感官刺激的重要性，尤其是 触觉刺激，促进大脑正常发育和功能稳定。有证据表明 不可察觉的类噪音振动(随机共振)可以在不稳定的生物中引起稳定性 系统。这一建议的基本假设是，新生儿NAS的特征是生理性的 反映戒毒严重程度和戒毒过程中病理生理不稳定性的障碍 新生儿可以通过随机的振动-触觉刺激来稳定下来。40名NAS(阿片类药物暴露)新生儿将 参加加州大学马萨诸塞州纪念医疗中心的一项严格的短期研究，以检查以下两个目标： 目的1.通过密集测量量化戒毒生理信号的不稳定性 在NAS婴儿中。生理信号的变化和相互关系，如呼吸、心脏不稳定 节拍和温度，以及过度运动，将使用非线性计算信号进行量化 分析(点过程和小波)以探索生理不稳定性是否可以指示NAS的严重程度和 预测戒断症状的发生/缓解。这样的信息将有助于促进药理学 新生儿禁欲和停药的管理。目的2.检验随机因素的有效性， 振动触觉刺激增强NAS患儿生理稳定性及缓解 戒毒症状。受试者将作为他们自己的对照来检验这一假设， 振动-触觉扰动冲击不稳定的神经回路，减少NAS的进行性传播 从皮质下(脑干)到皮质结构的应激性，以呼吸、心脏过度变化为特征 速度、温度和随后的运动激增。随机振动条件(特别设计 在泡沫中嵌入机械执行器的床垫；30-60赫兹，均方根幅度0.1 mm)将与 控制期以测试刺激是否：1)通过减少心肺功能的不稳定性改善心肺控制 心跳(例如，心动过缓、心动过速)和呼吸，包括周期性呼吸暂停事件的减少 呼吸和呼吸急促；2)抑制睡眠干扰，表现为减少过度的身体运动； 3)缓解以改进的NAS临床评估分数为指标的戒断症状。调查结果来自 这一建议将阐明随机的、振动触觉刺激是否具有作为辅助治疗的潜力。 NAS用于改善心肺控制和减少睡眠中断(以过量 NAS婴儿的运动)。未来更严格的前瞻性研究可能最终有助于阐明潜在的 NAS涉及的机制，导致改进的治疗干预措施，以减少严重程度和持续时间 停药与标准护理相辅相成，从而改善发病率和减少住院 以及NAS婴儿的医疗费用。

SUMMARY/ABSTRACT Fetal drug exposure is a nationwide problem. Nearly five percent of pregnant women nationwide expose their unborn child to drugs in utero (illicit and prescription). Neonatal Abstinence Syndrome (NAS) refers to multi- system disturbances and dysregulated neurobehaviors caused by discontinuation of drug/s to which an infant has developed tolerance and physical dependence. Novel approaches to study and treat NAS are needed because despite current interventions NAS infants often require prolonged hospitalization and pharmacological treatment for central, autonomic, vasomotor and gastrointestinal instabilities, which may contribute also to poor neurobehavioral outcomes. Growing research suggests the importance of sensory stimulation, particularly tactile stimulation for enhancing normal brain development and stability of function. There is evidence that unperceivable noise-like vibrations (stochastic resonance) can provoke stability in destabilized biological systems. The underlying hypothesis of this proposal is that NAS in newborns is characterized by physiological disturbances that reflect drug-withdrawal severity and that pathophysiological instabilities in drug-withdrawing neonates can be stabilized by stochastic, vibro-tactile stimuli. Forty NAS (opiate-exposed) neonates will participate in a rigorous, short-term study at UMass Memorial Healthcare to examine the following two aims: Aim 1. Quantify via intensive measurement the instabilities of physiological signals of drug withdrawal in NAS infants. Changes and relationships among physiological signals, e.g., instability of respiration, heart beat and temperature, and excessive movement, will be quantified using non-linear computational signal analyses (point process and wavelet) to explore whether physiological instabilities can index NAS severity and predict onset/offset of withdrawal symptoms. Such information would help facilitate pharmacological management of abstinence and drug withdrawal in neonates. Aim 2. Examine the efficacy of stochastic, vibro-tactile stimulation for enhancing physiological stability in NAS infants and alleviating the symptoms of drug withdrawal. Subjects will serve as their own control to test the hypothesis that stochastic, vibro-tactile perturbations impinge upon destabilized neural circuits and reduce the progressive spread of NAS irritability from subcortical (brainstem) to cortical structure, marked by excessive changes in respiration, heart rate, temperature and subsequent upsurge in movement. Conditions of stochastic vibration (specially designed mattress with mechanical actuators embedded in foam; 30-60Hz, RMS amplitude 0.1mm) will be compared to control periods to test whether stimulation: 1) Improves cardio-respiratory control by reducing instability of heart beat (e.g., bradycardia, tachycardia) and respiration, including decreasing incidents of apnea, periodic breathing and tachypnea; 2) Inhibits sleep disruption as marked by reduction of excessive body movements; and 3) Relieves withdrawal symptoms indexed by improved NAS clinical assessment scores. Findings from this proposal will elucidate whether stochastic, vibro-tactile stimulation has potential as an adjuvant treatment of NAS for improving cardio-respiratory control and reducing sleep disruption (indexed by excessive movement) in NAS infants. A more rigorous future prospective study may ultimately help elucidate underlying mechanisms involved in NAS, lead to improved therapeutic interventions for reducing severity and duration of drug withdrawal complementary to standard care, and thereby improve morbidity and reduce hospitalization and medical costs among NAS infants.