Neurosteroids as Novel Therapeutic Agents for Chronic Pain in OEF/OIF Veterans

描述 慢性疼痛症状在持久自由行动/伊拉克自由行动（OEF/OIF）退伍军人中非常常见，超过50%的OEF/OIF退伍军人在部署返回后报告慢性疼痛症状（腰痛是最常见的报告）。不幸的是，疼痛的药物管理往往是次优的，许多OEF/OIF退伍军人经历持续和未缓解的疼痛症状和/或疼痛药物无法忍受的副作用。例如，目前的药物如阿片类药物通常用于治疗慢性疼痛症状，但麻醉性镇痛药可能具有严重的副作用风险，如呼吸抑制、成瘾、镇静和与其他药物的潜在致命相互作用。因此，迫切需要开发用于慢性疼痛障碍的有效、安全和非习惯形成的新药理学治疗。啮齿动物模型中的广泛临床前数据和OEF/OIF退伍军人的临床结果表明，神经类固醇可能是治疗OEF/OIF退伍军人疼痛疾病的有前景的治疗方法。神经类固醇是在人脑中富集的内源性分子，并且可以立即用于临床试验， 因为它们在美国作为膳食补充剂可在非处方药中获得。因此，神经类固醇干预可能代表OEF/OIF退伍军人慢性疼痛症状管理的重要新领导。 基于我们在OEF/OIF退伍军人中的初步数据和来自多个研究小组的啮齿动物数据，证明了神经类固醇的镇痛作用，我们的第一个目标是在90名患有慢性腰痛的OEF/OIF退伍军人中进行随机对照试验（RCT），以调查神经类固醇双烯醇酮是否能有效缓解该队列的疼痛症状。这将是一项为期4周的随机、双盲、安慰剂对照研究，研究前有一周的疼痛评估期和一周的安慰剂导入期。我们假设，用双烯醇酮治疗将显着减少自我报告的背痛，并改善OEF/OIF退伍军人的功能结果。我们的第二个目标是确定血清中神经类固醇水平是否可以作为自我报告疼痛和神经类固醇干预反应的预测因子。 因此，我们假设，增加神经甾体治疗后与阿替诺龙将预测治疗反应，在我们以前的试点随机对照试验在退伍军人与创伤后应激障碍，精神分裂症和轻度TBI的初步数据所建议的。我们的第三个探索性目标是确定是否有初步证据表明参与神经类固醇合成的酶的常见遗传变异，神经类固醇的血清浓度和对神经类固醇干预的治疗反应之间存在关联。 重要性：该项目可能为患有慢性疼痛疾病的OEF/OIF退伍军人提供一种新的治疗方法，该方法安全，不形成习惯，价格低廉，耐受性良好，并改善功能结局和生活质量。 它还可以识别治疗反应的候选生物标志物，可能为患有疼痛疾病的退伍军人提供有效的个性化治疗。 公共卫生相关性： 目前缺乏安全有效的药物用于治疗慢性腰痛，这种疾病影响了大量OEF/OIF退伍军人，并经常伴有PTSD和其他共病症状。如果作为可增强或恢复内源性别孕烯醇酮水平的前体负载策略，阿替烯醇酮可导致症状减轻，则阿替烯醇酮可代表用于这些症状领域的有效、安全、耐受性良好、立即可获得且廉价的治疗，可能导致患有慢性疼痛障碍的OEF/OIF退伍军人的功能结果和生活质量改善。

DESCRIPTION Chronic pain symptoms are extremely common among Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans, and more than 50% of OEF/OIF Veterans report chronic pain symptoms upon return from deployment (low back pain being the most commonly reported). Unfortunately, pharmacological management of pain is frequently suboptimal, and many OEF/OIF Veterans experience persistent and unalleviated pain symptoms and/or intolerable side effects from pain medications. For example, current medications such as opiates are commonly used to treat chronic pain symptoms, but narcotic analgesics can have serious side effect risks such as respiratory depression, addiction, sedation, and potentially lethal interactions with other drugs. There is thus an acute and urgent need for the development of effective, safe, and non-habit-forming new pharmacological treatments for chronic pain disorders. Extensive preclinical data in rodent models and clinical findings in OEF/OIF Veterans suggest that neurosteroids may be promising therapeutic approaches for the treatment of pain disorders in OEF/OIF Veterans. Neurosteroids are endogenous molecules that are enriched in human brain and are immediately accessible for translation to clinical trials, as they are available over-the-counter as dietary supplements in the U.S. Neurosteroid interventions may thus represent an important new lead for the management of chronic pain symptoms in OEF/OIF Veterans. Based on our preliminary data in OEF/OIF Veterans and rodent data from multiple research groups demonstrating the analgesic actions of neurosteroids, our first objective is to conduct a randomized controlled trial (RCT) in 90 OEF/OIF Veterans with chronic low back pain to investigate if the neurosteroid pregnenolone is effective in alleviating pain symptoms in this cohort. This will be a 4-week, randomized, double-blind, placebo-controlled study, preceded by a one-week pain assessment period and a one-week placebo lead-in period. We hypothesize that treatment with pregnenolone will significantly reduce self-reported back pain and improve functional outcomes in OEF/OIF Veterans. Our second objective is to determine whether neurosteroid levels in serum can have utility as predictors of self-reported pain and response to neurosteroid intervention. We thus hypothesize that increases in neurosteroids post-treatment with pregnenolone will predict therapeutic response, as suggested by preliminary data in our prior pilot RCTs in Veterans with PTSD, schizophrenia, and mild TBI. Our third and exploratory objective is to determine if there is preliminary evidence for an association between common genetic variations in the enzymes involved in neurosteroid synthesis, serum concentrations of neurosteroids, and treatment response to a neurosteroid intervention. Significance: This project could lead to a novel therapeutic for OEF/OIF Veterans with chronic pain disorders that is safe, non-habit-forming, inexpensive, well-tolerated, and improves functional outcome and quality of life. It could also identify candidate biomarkers for therapeutic response, potentially leading to efficacious personalized treatments for Veterans with pain conditions. PUBLIC HEALTH RELEVANCE: There is currently a paucity of safe and effective agents for the treatment of chronic low back pain, a disorder that impacts large numbers of OEF/OIF Veterans and is frequently accompanied by PTSD and other comorbid symptoms. If pregnenolone, as a precursor loading strategy that can enhance or restore endogenous levels of allopregnanolone, can result in symptom reduction, pregnenolone could represent an effective, safe, well- tolerated, immediately accessible, and inexpensive treatment for these symptom domains, potentially leading to improved functional outcome and quality of life in OEF/OIF Veterans with chronic pain disorders.