Prescribed opioid induced brain damage in chronic pain patients

边缘系统具有许多关键功能，包括行为和记忆的调节。也许 在记忆处理过程中，没有任何边缘系统结构比海马体发挥更重要的作用。 拟议研究的科学基础表明，海马体和联合区是 暴露在阿片类药物中的风险值得注意的是，阿片类药物经常被大量使用，包括急性和慢性使用。 慢性，并在许多临床情况下，导致目前的流行与阿片类药物成瘾，过量， 失忆症的报告支持拟议研究的科学基础的具体报告来自： (1)动物中令人信服的可重复数据和人类中的一致观察结果表明阿片类药物 激活边缘系统，产生高代谢，急性细胞损伤，海马记忆丧失 萎缩 (2)癫痫患者中阿片类药物诱导的近中海马癫痫样活动与颅内电极。 (3)在阿片类药物过量（OD）背景下发生遗忘综合征的患者病例报告， MRI显示双侧大脑半球完全弥散加权高信号和体积丢失。值得注意的是，一些 报告描述了OD患者没有相关的缺氧，但有健忘症和MRI改变。 (4)据报道，慢性疼痛患者会出现认知缺陷。目前尚不清楚这是否 与阿片类药物过量患者的情况相似，这是拟议研究的动力。 我们的总体假设是，长期服用高剂量阿片类药物的慢性疼痛患者 海马损伤和相关的神经认知功能障碍。因此，我们预测， 患者的海马体积较小，在神经心理学测试中表现更差， 与不使用阿片类药物的慢性疼痛患者相比，使用MRI成像和 神经心理学测试，本提案的具体目的是在这些患者群体中测试假设 长期服用高剂量阿片类药物的慢性疼痛患者： 1. MRI显示海马体积较小。 2.在记忆力和相关的神经心理学测试中表现更差 海马功能 如果这些高风险但高影响的假设得到证实，从而转化为充分的临床前观察， 我们将揭示阿片类药物使用对人类认知功能的一种以前未知的影响， 与数百万接受处方阿片类药物的人、有阿片类药物滥用史的人相关， 围手术期、围重症监护期或受伤后接受阿片类药物治疗的患者。因此，这将表明 具有潜在重大医学、社会和经济影响的新发现。

The limbic system serves a number of critical functions, including regulation of behavior and memory. Perhaps no limbic structure plays a more critical role in memory processing than the hippocampus. The scientific foundation of the proposed research indicates that the hippocampus and association areas are at risk when exposed to opioids. Notably opioids often are used in large quantities, both acutely and chronically, and in many clinical contexts, leading to the current epidemic with opioid addiction, overdose, and reports of amnesia. Specific reports supporting the scientific foundations for the proposed research arise from: (1) Compelling reproducible data in animals and congruent observations in humans indicating that opioids activate the limbic system, producing hypermetabolism, acute cell injury, and memory loss with hippocampal atrophy. (2) Opioid-induced mesial hippocampal epileptiform activity with intracranial electrodes in epileptic humans. (3) Case reports of patients developing an amnestic syndrome in the setting of opioid overdose (OD) with complete diffusion-weighted hyperintensity and volume loss of both hippocampi on MRI. Notably, some reports describe OD patients without associated hypoxia, but with amnesia and MRI changes. (4) Chronic pain patients have been reported to develop cognitive deficits. It is currently unknown whether this is similar to that seen in patients presenting with opioid OD, the impetus for the proposed research. Our overall hypothesis is that patients with chronic pain who have been on long-term, high-dose opioids develop hippocampal injury and associated neurocognitive dysfunction. Therefore, we predict that these patients will have smaller hippocampal volumes and perform more poorly on neuropsychological tests of memory than matched chronic pain patients who do not use opioids. Using a combination of MRI imaging and neuropsychological testing, the specific aims of this proposal are to test the hypotheses in these patient groups that humans with chronic pain on long-term, high-dose opioids: 1. Will demonstrate smaller hippocampal volumes by MRI. 2. Will perform more poorly on neuropsychological tests of memory and associated hippocampal functions. If these high-risk but high-impact hypotheses are confirmed, thus translating ample preclinical observations, we will have revealed a previously unknown effect of opioid use on human cognitive function which could be relevant to millions of humans receiving prescription opioids, people with a history of opioid abuse, and patients who receive opioids perioperatively, peri-intensive care, or after injury. As such this would indicate a new discovery with potentially major medical, social, and economic impact.