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

神经类固醇作为 OEF/OIF 退伍军人慢性疼痛的新型治疗剂

• 批准号: 8990401
• 负责人: JENNIFER C NAYLOR
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990401
• 关键词: Acute; Adverse effects; Aftercare; Allopregnanolone; Analgesics; Back Pain; Biological Markers; Blast Cell; Brain; Candidate Disease Gene; Chest Pain; Chronic low back pain; Clinical; Clinical Data; Clinical Trials; Code; Data; Development; Disease; Double-Blind Method; Enzymes; Freedom; Genetic Variation; Goals; Human; Intervention; Investigation; Lead; Low Back Pain; Mass Spectrum Analysis; Metabolic; Narcotic Analgesics; New Agents; Opiates; Outcome; Pain; Pain Disorder; Pain Measurement; Pain management; Patient Self-Report; Pharmaceutical Preparations; Pharmacological Treatment; Placebos; Post-Traumatic Stress Disorders; Pregnenolone; Quality of life; Randomized; Randomized Controlled Trials; Reporting; Research; Risk; Rodent; Rodent Model; Schizophrenia; Sedation procedure; Serum; Symptoms; Techniques; Testosterone 5-alpha-Reductase; Therapeutic; Therapeutic Agents; Translating; Translations; Traumatic Brain Injury; Ventilatory Depression; Veterans; addiction; base; cholestenone 5 alpha-reductase; chronic pain; clinical effect; cohort; dietary supplements; experience; functional outcomes; improved; innovation; male; mild traumatic brain injury; neurosteroids; novel; novel therapeutics; operation; personalized medicine; placebo controlled study; pre-clinical; public health relevance; response; treatment response

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.

描述 慢性疼痛症状在持久/伊拉克自由行动（OEF/OIF）的手术中极为普遍，而超过50％的OEF/OIF退伍军人报告了部署后恢复后的慢性疼痛症状（低腰痛是最常见的报道）。不幸的是，疼痛的药理学管理通常是次优的，许多OEF/OIF退伍军人经历了持续的，无效的疼痛症状和/或止痛药的无法忍受的副作用。例如，当前的药物（例如阿片类药物）通常用于治疗慢性疼痛症状，但是麻醉镇痛药可能具有严重的副作用风险，例如呼吸抑郁症，成瘾，镇静以及与其他药物的潜在致命相互作用。因此，急需开发有效，安全和非残疾人的慢性疼痛疾病的新药理治疗方法。在OEF/OIF退伍军人中，啮齿动物模型和临床发现中的广泛临床前数据表明，神经类动物可能是治疗OEF/OIF退伍军人疼痛障碍的有前途的治疗方法。神经类固醇是富含人脑的内源分子，可立即进入临床试验， 因此，由于在美国神经类固醇干预措施中作为饮食补充剂可用，因此可能代表了在OEF/OIF退伍军人中管理慢性疼痛症状的重要新领导。 基于我们在OEF/OIF退伍军人中的初步数据以及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个OEF/OIF退伍军人中进行随机对照试验（RCT），以调查慢性腰痛的退伍军人如果神经类固醇可有效缓解该队列中的疼痛症状。这将是一项为期4周的，随机的，双盲的，安慰剂对照的研究，此前为期一周的疼痛评估期和一个为期一周的安慰剂介入期。我们假设怀孕烯醇酮的治疗将显着减轻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的神经固醇水平是否可以作为自我报告的疼痛和对神经类固醇干预的反应的预测指标。 因此，我们假设使用妊娠后治疗后神经类固醇的增加将预测治疗反应，正如我们先前患有PTSD，精神分裂症和轻度TBI的退伍军人的初步数据中的初步数据所暗示的那样。我们的第三个探索性目标是确定是否有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。 意义：该项目可能会导致对具有慢性疼痛障碍的OEF/OIF退伍军人的新型治疗方法，这些疼痛障碍是安全，非抢劫形成，廉价，耐受性良好并改善功能和生活质量的治疗方法。 它还可以识别出治疗反应的候选生物标志物，有可能导致对患有疼痛状况的退伍军人有效的个性化治疗方法。 公共卫生相关性： 目前缺乏治疗慢性腰痛的安全有效药物，这种疾病会影响大量的OEF/OIF退伍军人，并且经常伴有PTSD和其他合并症。如果妊娠烯酮作为一种可以增强或恢复异源性内源水平的前体负荷策略，则可能导致症状减轻，则妊娠可以代表一种有效，安全，耐受性，立即获得，可立即获得的且廉价的治疗这些症状领域，并可能导致潜在地导致慢性疼痛障碍的OEF/OIF退伍军人的功能结果和生活质量改善。