HCV and Pain in Substance Users With and Without HIV

描述(由申请者提供)：此申请是为波士顿大学医学院普通内科助理教授朱迪思·徐博士颁发的以患者为导向的研究职业发展奖(K23)，她正在确立自己作为丙型肝炎病毒(丙型肝炎病毒)相关结果的研究员的地位。这项研究计划既扩展了她之前在丙型肝炎病毒方面的工作，又让她作为一名专注于药物使用者的疼痛研究人员，朝着一个新的方向发展。该奖项将为徐博士提供必要的支持，以实现以下目标：1)发展患有丙型肝炎病毒和艾滋病毒等慢性病毒感染的药物使用者的慢性疼痛病因学方面的专业知识；2)发表将导致改善药物使用者疼痛治疗的研究；以及3)通过获得R01证书过渡到一名独立资助的研究人员。全面的培训计划包括正式的课程作业，以及疼痛测量和实验疼痛模型的“动手”培训。徐博士的主要导师将是杰弗里·萨梅特博士，他是药物使用和慢性病毒感染领域的知名研究员。她将接受领先的转化性疼痛研究专家毛建仁博士和资深初级研究员兼临床心理学家罗伯特·爱德华兹博士的额外指导。疼痛是药物使用者的主要问题，需要更好地了解其病因，以改善临床护理。目前有有限的研究来确定丙型肝炎病毒和艾滋病毒等病毒感染如何影响慢性疼痛和疼痛状况的风险。徐博士将探索与丙型肝炎病毒有关的新假设：1)在实验条件下对疼痛过敏，2)临床疼痛。为了探索这些假说，徐博士将对单一感染丙型肝炎病毒、感染艾滋病毒/丙型肝炎病毒的阿片类药物成瘾者和未感染的阿片类药物成瘾者进行一项实验性的横断面研究，比较实验疼痛反应和自我报告的临床疼痛。她将收集120名服用丁丙诺啡或美沙酮的阿片依赖患者：40名丙型肝炎病毒+/艾滋病毒-，40名丙型肝炎病毒+/艾滋病毒+和40名丙型肝炎病毒/艾滋病毒-对照。参与者将接受以下实验测试：1)冷加压试验以评估冷疼痛耐受性，2)机械刺激以测试机械痛阈值，3)重复针刺以评估时间总和。这项研究还将使用经过验证的量表收集关于疼痛和疼痛相关变量的数据，如“简要疼痛清单”，以及从外周血样本中测量促炎症和抗炎细胞因子(肿瘤坏死因子-1、白细胞介素2、白细胞介素6、白细胞介素2、白细胞介素10和白细胞介素4)。她将进行适当的统计测试，以评估感染丙型肝炎病毒的阿片成瘾者(单独感染丙型肝炎病毒或丙型肝炎病毒+/艾滋病毒+)是否有不同的实验性疼痛反应(较低的疼痛耐受性/阈值和更多的时间总和)和较高的自我报告的慢性疼痛的患病率，并探索炎症细胞因子是否介导了丙型肝炎病毒和疼痛之间已发现的联系。这项研究将有助于我们了解药物使用者疼痛的原因，并将塑造未来的研究，以测试新的方法(可能包括抗丙型肝炎病毒治疗)，以预防和治疗这一脆弱的患者群体的疼痛。 公共卫生相关性：疼痛是现任和前任药物使用者的常见问题，他们中的许多人感染了艾滋病毒和丙型肝炎病毒。需要更好地了解疼痛的病因，以便有效地预防和治疗有药物使用问题的患者的慢性疼痛。这项研究解决了一个简单(但相对未被探索)的问题：慢性病毒感染如何导致患者对疼痛的脆弱性？此外，它还通过研究炎症细胞因子在形成疼痛反应中的作用，开始探索丙型肝炎病毒背景下疼痛过敏的潜在机制。这项研究的结果可能直接惠及有药物使用和疼痛历史的患者，1)为他们的疼痛提供解释，2)导致疼痛治疗的改进，包括抗丙型肝炎病毒治疗或抗细胞因子药物(如戊二酸茶碱)。此外，它还将告知临床医生和政策制定者，他们在权衡预防传播的治疗和干预措施的成本/收益时，必须考虑丙型肝炎病毒感染的长期后果。

DESCRIPTION (provided by applicant): This application is for a Patient-Oriented Research Career Development Award (K23) for Dr. Judith Tsui, an Assistant Professor in General Internal Medicine at Boston University School of Medicine, who is establishing herself as an investigator in hepatitis C virus (HCV) related outcomes. The research plan both extends her prior work in HCV, and allows her to grow in a new direction as a pain researcher focusing on substance users. The award will provide Dr. Tsui with the support necessary to accomplish the following goals: 1) develop expertise in the etiology of chronic pain in substance users with chronic viral infections like HCV and HIV; 2) publish research that will lead to improved treatments for pain among substance users; and 3) transition into an independently funded researcher by obtaining an R01. The comprehensive training plan includes formal coursework, as well as "hands-on" training in pain measurement and experimental pain models. Dr. Tsui's primary mentor will be Dr. Jeffrey Samet, an established investigator in the fields of substance use and chronic viral infections. She will receive additional mentoring from Dr. Jianren Mao, a leading translational pain researcher, and Dr. Robert Edwards, an accomplished junior investigator and clinical psychologist. Pain is a major problem among substance users, and a better understanding of its etiology is needed to improve clinical care. There is limited research to determine how viral infections such as HCV and HIV impact risk for developing chronic pain and painful conditions. Dr. Tsui will explore the novel hypotheses that HCV is associated with: 1) hypersensitivity to pain under experimental conditions and 2) clinical pain. To explore these hypotheses, Dr. Tsui will conduct an experimental, cross-sectional study of HCV mono- infected, HIV/HCV co-infected, and uninfected opioid addicts that compares experimental pain responses and self-reported clinical pain. She will assemble a cohort of 120 opioid dependent patients on buprenorphine or methadone: 40 HCV+/HIV-, 40 HCV+/HIV+ and 40 HCV-/HIV-controls. Participants will undergo the following experimental testing: 1) the cold-pressor test to assess cold pain tolerance 2) mechanical stimulus to test mechanical pain thresholds and 3) repetitive pinprick to assess for temporal summation. The study will also collect data on pain and pain-related variables using validated scales such as the "Brief Pain Inventory", as well as measurements of pro- and anti-inflammatory cytokines (TNF-1, IL-2, IL-6, IL-2, IL-10 and IL-4) from peripheral blood samples. She will perform appropriate statistical testing to assess whether opioid addicts who are HCV infected (HCV+ alone or HCV+/HIV+) have different experimental pain responses (lower pain tolerance/thresholds and more temporal summation) and a higher prevalence of self-reported chronic pain, and to explore whether inflammatory cytokines mediate found associations between HCV and pain. This research will contribute to our understanding of the causes of pain among substance users, and will shape future studies to test new approaches (possibly including anti-HCV treatment) to prevent and treat pain in this vulnerable patient population. PUBLIC HEALTH RELEVANCE: Pain is a common problem among current and former substance users, many of whom are infected with HIV and HCV. A better understanding of pain etiology is needed in order to effectively prevent and treat chronic pain among patients with substance use problems. This research addresses the simple (yet relatively unexplored) question: how do chronic viral infections contribute to patients' vulnerability to pain? In addition, it begins to explore potential mechanisms for pain hypersensitivity in the setting of HCV by investigating the role of inflammatory cytokines in shaping pain responses. The results of this research may directly benefit patients with a history of substance use and pain by 1) providing an explanation for their pain and 2) leading to improved treatments for pain, including anti-HCV therapy or anti-cytokine medications (such as pentoxyphylline). In addition, it will inform clinicians and policy makers who must consider the long-term consequences of HCV infection when weighing costs/benefits of treatment and interventions to prevent transmission.