Clonidine Treatment for Neonatal Abstinence Syndrome

描述（由申请人提供）：在美国，每年有多达20,000名婴儿出生在阿片类药物（“麻醉剂”）成瘾的母亲手中。和他们的母亲一样，这些婴儿也依赖阿片类药物。出生后，婴儿被从阿片类药物来源中移除，导致这些婴儿出现戒断综合征。新生儿戒断症状包括呕吐、腹泻、喂养不良、心动过速、高血压、出汗、躁动、失眠、易怒、震颤、耳鸣、生长不良的嗜食和酸中毒、可逆性神经系统异常，甚至癫痫发作。这种复杂的体征和症状被称为新生儿戒断综合征（NAS）。目前的标准治疗方案是重新使用阿片类药物，然后缓慢减量，因此需要延长住院时间，从数周到数月不等。可口定是一种非麻醉性中枢α 2-肾上腺素能受体激动剂，可阻断交感神经系统过度兴奋的作用，是成人阿片类药物戒断的批准治疗药物。我们目前有一个医生赞助的IND（#63,781）来研究可乐定作为阿片类药物治疗NAS的辅助疗法的效果。本提案将验证可乐定和阿片类药物联合治疗的假设：1)安全有效，2)减少阿片类药物的使用，3)缩短治疗和住院时间。这将在一项随机、安慰剂对照的双盲临床试验中完成，该试验比较了稀释的鸦片酊剂（DTO）与安慰剂（对照）和DTO与可乐定的联合。其他子研究包括确定1)DTO和可乐定在入组队列中的药代动力学和药效学，2)通过评估6个月和12个月时Bayley婴儿发育量表（BSID）的发育结果进一步进行安全性评估。药代动力学将通过测定可乐定和吗啡的血清浓度和分析分布量、消除半衰期和清除率来确定。

DESCRIPTION (provided by applicant): In the United States, as many as 20,000 babies a year are born to opioid ("narcotic") addicted mothers. Like their mothers, these infants are opioid dependent. Following birth, the infant is removed from its opioid source, inducing a withdrawal syndrome in these infants. Withdrawal symptoms in newborns include vomiting, diarrhea, poor feeding, tachycardia, hypertension, diaphoresis, restlessness, insomnia, irritability, tremors, clonus, hyperphagia with poor growth and acidosis, reversible neurologic abnormalities, and even seizures. This complex of signs and symptoms is referred to as neonatal abstinence syndrome (NAS). Reinstitution of opioids followed by a slow tapering protocol is currently the standard of care, necessitating prolonged hospitalization from weeks to months. Clonidine is a non-narcotic central alpha2-adrenergic receptor agonist that blocks the effects of over-excitation of the sympathetic nervous system and is an approved treatment for opioid withdrawal in adults. We currently have a physician sponsored IND (#63,781) to study the effect of clonidine as adjunct therapy to opioids for the treatment of NAS. This proposal will test the hypothesis that combination therapy of clonidine and opioids is 1) safe and efficacious, 2) allows reduced amount of opioid drug use, and 3) results in shorter time of treatment and hospitalization. This will be accomplished in a randomized, placebo controlled double blind clinical trial comparing diluted tincture of opium (DTO) combined with a placebo (control) vs. DTO combined with clonidine. Additional sub-studies include determination of 1) pharmacokinetics and pharmacodynamics of DTO and clonidine in the enrolled cohort and 2) further safety evaluation by evaluating developmental outcome on the Bayley Scale of Infant Development (BSID) at 6 and 12 months of age. Pharmacokinetics will be determined by measuring serum concentrations of clonidine and morphine and analyzing volume of distribution, elimination half-life and clearance. These results will have important clinical implications and may change the standards of care not only for management of infants with severe NAS, but also for the management of infants and children, after long-term iatrogenic opioid exposure for instance following prolonged analgesia for mechanical ventilation or multiple operations.