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

 描述（由申请人提供）：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，但尚未确定阿片类药物对中枢神经系统（CNS）活动以及奖励行为和临床结局的影响。目前的证据有力地表明，大脑和脊髓中的活动改变有助于FM症状的慢性化，并且已知阿片类药物在CNS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CNS中疼痛和奖励过程的现有改变。为了验证这一假设，该提案包括临床神经影像学研究项目和全面的培训计划，凯瑟琳马图奇博士，博士，将在斯坦福大学的专家导师、顾问和合作者（Sean Mackey、Brian Knutson、Jodie Trafton和加里格洛弗博士）的指导下进行。在K99指导培训阶段（第1-2年;目标1和2），Martucci博士将使用大脑和脊髓功能磁共振成像（fMRI）进行临床研究，以测量服用阿片类药物的FM患者与不服用阿片类药物的FM患者之间的差异。目的1将确定阿片类药物对FM疼痛和脊髓活动水平的影响。目标2将确定阿片类药物对FM中大脑奖励系统和奖励行为的影响。该阶段将包括高级CNS神经影像分析，大脑奖励过程，阿片类药物治疗，临床研究，高级统计学和负责任的研究行为的培训计划。它还将包括实验室管理培训，指导，并通过斯坦福大学的教学课程和既定的导师进行教学。在R 00独立研究阶段（第3-5年;目标3），Martucci博士将对FM患者进行纵向临床研究，包括阿片类药物依赖者和阿片类药物初治者，以确定FM患者的疼痛、症状和CNS活动随时间的变化。初始辅导K99培训阶段的项目和培训将有效地为Martucci博士进行后期独立R 00阶段的项目做好准备。总之，这些项目将提供阿片类药物在FM中的作用的更完整的图片，并将填补神经生物学变化的固有风险的关键知识空白，以及处方阿片类药物时发生的行为和心理改变。该提案要求支持Martucci博士接受额外培训，以提高和扩大她目前在疼痛处理和慢性疼痛研究神经生物学方面的研究生和博士后研究专业知识水平。这将使她能够成功地过渡到一个独立的R 01资助，教师级的首席研究员，并实现她的长期目标，建立一个独立的研究实验室，专注于慢性疼痛的神经和行为改变。

 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.