The Impact of Opioids on Chronic Pain: Clinical Research and Career Training in Spinal Cord fMRI and Brain Reward Systems

 描述(申请人提供)：尽管阿片类药物被广泛用于治疗纤维肌痛(FM)引起的慢性疼痛，但阿片类药物对中枢神经系统(CNS)活动以及对奖励行为和临床结果的影响尚未确定这一适应症。目前的证据有力地表明，大脑和脊髓活动的改变有助于FM症状的慢性化，而阿片类药物已知会在中枢神经系统活动中产生类似的变化。因此，中心假设是阿片类药物加剧了FM患者中枢神经系统现有的疼痛和奖赏过程的变化。为了验证这一假设，该提案包括临床神经成像研究项目和一个全面的培训计划，凯瑟琳·马图奇博士将在斯坦福大学专家导师、顾问和合作者(肖恩·麦基博士、布莱恩·克努森博士、朱迪·特拉夫顿博士和加里·格洛弗博士)的指导下进行培训。在K99指导培训阶段(1-2年；AIMS 1-2)，Martucci博士将使用脑和脊髓功能磁共振成像(FMRI)进行一项临床研究研究，以衡量服用阿片类药物的FM患者和不服用阿片类药物的FM患者之间的差异。目的1确定阿片类药物对FM疼痛程度和脊髓活动的影响。目标2将确定阿片类药物对大脑奖励系统和FM中奖励行为的影响。这一阶段将包括高级中枢神经成像分析、大脑奖励过程、阿片类药物治疗、临床研究、高级统计和负责任的研究行为方面的培训计划。它还将包括通过斯坦福大学的授课课程和现有导师提供的实验室管理、指导和教学方面的培训。在R00独立研究阶段(3年至5年；目标3)，Martucci博士将对FM患者进行一项纵向临床研究，包括阿片类药物依赖和阿片类药物天真，以确定FM中疼痛、症状和中枢神经系统活动随时间的变化。最初指导的K99培训阶段的项目和培训将有效地为Martucci博士指导为稍后的独立R00阶段提出的项目做好准备。总之，这些项目将提供一个更完整的阿片类药物对FM的影响的图景，并将填补在开阿片类药物处方时发生的神经生物学变化的内在风险以及行为和心理改变的关键知识空白。这项建议要求支持Martucci博士接受额外的培训，以提高和扩大她目前在疼痛处理和慢性疼痛研究的神经生物学方面的研究生和博士后研究专业知识水平。这将使她能够成功过渡到一名由R01资助的独立教职员工级别的首席研究员，并实现她的长期目标，即建立一个专注于慢性疼痛的神经和行为改变的独立研究实验室。

 DESCRIPTION (provided by applicant): Although opioids are widely prescribed for chronic pain due to fibromyalgia (FM), the effects of opioid medications on the activity of the central nervous system (CNS) and on reward behavior and clinical outcomes have not been determined for this indication. Current evidence strongly suggests that altered activity in the brain and spinal cord contributes to the chronicity of FM symptoms, and opioids are known to produce similar changes in CNS activity. Thus, the central hypothesis is that opioids exacerbate existing alterations in pain and reward processes in the CNS in individuals with FM. To test this hypothesis, the proposal includes clinical neuroimaging research projects and a comprehensive training plan that Dr. Katherine Martucci, Ph.D., will conduct under the guidance of expert mentors, advisors and collaborators at Stanford University (Drs. Sean Mackey, Brian Knutson, Jodie Trafton, and Gary Glover). During the K99 mentored training phase (Years 1-2; Aims 1 & 2), Dr. Martucci will conduct a clinical research study using brain and spinal cord functional magnetic resonance imaging (fMRI) to measure differences between individuals with FM who take opioids and individuals with FM who do not. Aim 1 will determine the effect of opioids on levels of pain and spinal cord activity in FM. Aim 2 will determine the effect of opioids on the brain's reward systems and reward behavior in FM. This phase will include a training program in advanced CNS neuroimaging analysis, brain reward processes, opioid therapy, clinical research, advanced statistics, and responsible research conduct. It will also include training in lab management, mentoring, and teaching through didactic courses at Stanford University and from established mentors. During the R00 independent research phase (Years 3-5; Aim 3), Dr. Martucci will conduct a longitudinal clinical study of individuals with FM, both opioid-dependent and opioid-naïve, to determine changes in pain, symptoms, and CNS activity in FM over time. The projects and training of the initial mentored K99 training phase will effectively prepare Dr. Martucci to conduct the projects proposed for the later independent R00 phase. Together, these projects will provide a more complete picture of the effects of opioid medications in FM and will fill the critical knowledge gaps of inherent risks of neurobiological changes and altered behavior and psychology that occur when prescribing opioids. This proposal requests support for Dr. Martucci to receive additional training in order to enhance and expand her current level of graduate and postdoctoral research expertise in neurobiology of pain processing and chronic pain research. This will enable her to successfully transition to an independent R01-funded, faculty- level principal investigator and to achieve her long-term goal of establishing an independent research lab focused on neurological and behavioral alterations in chronic pain.