Pain, Opioids And Pro-Inflammatory Immune Responses

描述（由申请人提供）：分别地，急性疼痛和阿片样物质施用已显示各自诱导全身促炎反应，理论上使患者处于炎症疾病的风险中或加剧炎症疾病（即，心脏病、糖尿病、关节炎）。令人惊讶的是，当疼痛和阿片类药物给药同时发生时，这些炎症反应的表达是未知的，这是患有急性疼痛并服用阿片类镇痛药的患者的常见临床病例。一个加性模型可以预测，在两者都存在的情况下，促炎过程会增加，但疼痛得到充分治疗的患者的健康状况会更好。疼痛和阿片类药物对免疫功能的综合影响可能特别复杂的患者人群估计有520万12岁或以上的美国人滥用处方阿片类药物。这些个体不仅由于其作为“成瘾者”的状态而处于不良疼痛管理的风险中，而且有良好的临床前证据表明，他们的慢性阿片类药物使用带来全身炎症的一般状态，从而使患者对急性阿片类药物和疼痛的组合产生独特或增强的炎症反应。为了有效地最大限度地提高这组在没有疼痛的情况下自行服用处方阿片类药物的患者的健康结果，临床医生需要更全面地了解他们持续使用阿片类药物对炎症结果的影响。为了更好地了解一般阿片类药物治疗急性疼痛的健康影响，特别是在滥用处方阿片类药物的患者中，将在每种药物的充分表征的样品中检查急性疼痛和阿片类药物给药的主要和相互作用效应的炎症反应。具体而言，我们将评估炎症和细胞因子的反应：（1）实验性（冷加压）疼痛;（2）急性阿片类药物（IV芬太尼1 mcg/kg）激发;和（3）阿片类药物给药的组合（IV芬太尼1 mcg/kg），随后在健康对照受试者中进行冷加压疼痛（n=22，11名女性）和接受丁丙诺啡治疗的年龄和性别匹配的处方阿片类药物滥用者（n=22，11名女性）。将在3小时的时间段内跟踪促炎（IL-6、IL-12、TNF 1）和抗炎（IL-4、IL-10）活性的标志物以及促炎细胞因子表达的核转录因子（NF-κ B），以捕获阿片类镇痛活性的持续时间以及第二信使产生的变化。拟议的研究在评估疼痛和阿片类镇痛背景下的免疫反应方面是独特的，在纳入炎症标志物和相关分子信号传导途径方面具有创新性，并且值得注意的是纳入了弱势患者人群，处方阿片类药物滥用者。这项工作将提供关于急性疼痛，阿片类药物给药和阿片类药物慢性自我给药的炎症效应如何相互作用的有价值和新颖的人类数据，从而对阿片类药物疼痛的安全有效管理具有明确的临床意义。 公共卫生相关性：单独地，急性疼痛和阿片样物质施用各自诱导全身促炎反应，理论上使患者处于炎性疾病的风险中或使炎性疾病恶化（即，心脏病、糖尿病、关节炎）。然而，令人惊讶的是，当它们同时发生时，例如在疼痛和服用阿片类镇痛药的患者的常见情况下，这些药物的炎症作用基本上是未知的。此外，在没有疼痛的情况下滥用处方阿片类药物的个体中这种相互作用的性质尚未得到研究。为了更好地了解急性和慢性阿片类药物在有和没有疼痛的人中的炎症作用，将在健康对照和寻求治疗的处方阿片类药物滥用者中检查促炎免疫标志物。

DESCRIPTION (provided by applicant): Separately, acute pain and opioid administration have each been shown to induce a systemic pro-inflammatory response, theoretically putting the patient at risk for, or exacerbating, diseases of inflammation (i.e., heart disease, diabetes, arthritis). Surprisingly, unknown is the expression of these inflammatory responses when pain and opioid administration co-occur, as is the common clinical case of a patient with acute pain and taking opioid analgesics. An additive model would predict that pro-inflammatory processes are increased in the presence of both, yet better health outcomes for patients whose pain is adequately treated suggests otherwise. A patient population for whom the combined effects of pain and opioids on immune function are likely to be particularly complex are the estimated 5.2 million Americans aged 12 or older who abuse prescription opioids. Not only are these individuals at risk for poor pain management due to their status as an "addict", but there is good preclinical evidence to suggest that their chronic opioid use brings with it a general state of systemic inflammation, and thus setting the patient up for a unique or enhanced inflammatory response to the combination of acute opioids and pain. To effectively maximize health outcomes in this group of patients who self-administer prescription opioids in the absence of pain, clinicians need a more comprehensive understanding of the effects of their ongoing opioid use on inflammatory outcomes. To better understand the health implications of treating acute pain with opioids in general, and in patients who abuse prescription opioids in particular, inflammatory responses to the main and interaction effects of acute pain and opioid administration will be examined in well-characterized samples of each. Specifically, we will evaluate the inflammatory and cytokine responses to: (1) experimental (cold-pressor) pain; (2) an acute opioid (IV fentanyl 1mcg/kg) challenge; and (3) the combination of opioid administration (IV fentanyl 1mcg/kg) followed by cold-pressor pain, in healthy control subjects (n=22, 11 female) and age- and gender-matched prescription opioid abusers in buprenorphine treatment (n=22, 11 female). Markers of pro-inflammatory (IL-6, IL-12, TNF1) and anti-inflammatory (IL-4, IL-10) activity, as well as a nuclear transcription factor for pro- inflammatory cytokine expression ( NF-kb), will be followed over a 3hr time period to capture the duration of opioid analgesic activity, as well as second-messenger generated changes. The proposed study is unique in evaluating immune responses in the context of pain and opioid analgesia, innovative in the inclusion of inflammatory markers and relevant molecular signaling pathways, and noteworthy in including a vulnerable population of patients, prescription opioid abusers. This work will provide valuable and novel human data on how the inflammatory effects of acute pain, opioid administration, and chronic self-administration of opioids interact, and thus have clear clinical implications for the safe and effective management of pain with opioids. PUBLIC HEALTH RELEVANCE: Separately, acute pain and opioid administration each induce a systemic pro-inflammatory response, theoretically putting the patient at risk for, or exacerbating, inflammatory disease (i.e., heart disease, diabetes, arthritis). Yet, surprisingly, the inflammatory effects of these when they co-occur, such as in the common situation of the patient in pain and taking opioid analgesics, are essentially unknown. Further, the nature of this interaction in those individuals who abuse prescription opioids in the absence of pain has not been examined. In an effort to better understand the inflammatory effects of acute and chronic opioids in persons with and without pain, pro-inflammatory immune markers will be examined in healthy controls and treatment- seeking prescription opioid abusers.