Opioid selection and the risk of serious infections in older adults

描述(申请人提供)：有大量证据表明，使用阿片类止痛剂会损害免疫系统的反应，长期以来，人们一直担心这些影响会增加严重的、可能危及生命的感染的风险。在动物模型和人类受试者中的活体研究表明，阿片类药物影响免疫功能的替代标记物，这些免疫功能标记物对于预防严重感染至关重要，如白细胞迁移和吞噬。尽管研究表明，在动物模型和人类中，免疫功能受到显著的剂量依赖性抑制，动物模型中严重感染的风险也随着剂量的增加而增加，但这些发现在人类中的临床相关性尚不清楚。这些担忧与老年人尤其相关，他们通常受到疼痛的影响，感染风险增加。目前有许多阿片类止痛药可用，但并不是所有的都具有相同的免疫抑制特性。在动物模型中的研究表明，以吗啡的化学结构为参照，C3和C6上都带有羟基的阿片类药物(如吗啡)具有最强的免疫抑制作用，而仅在C3上修饰(如可待因)可减少免疫抑制，而C6上的羰基取代(如氢吗啡)可消除免疫抑制作用。确定那些最不可能增加严重感染风险的阿片类药物，对于为脆弱的老年人选择止痛药至关重要。此外，阿片类药物的免疫抑制作用具有剂量依赖性，对于几种阿片类药物，体内数据表明，同时使用阿片类药物和其他抑制阿片代谢的常用药物可显著增加阿片类药物的血清浓度。我们建议对老年人进行一系列研究，具体目的如下：1)测试新使用者严重感染风险的假设 可待因(代谢为吗啡)比具有类似止痛特性的其他阿片类药物的新使用者更大；2)测试假设，即新使用吗啡的人比新使用具有类似止痛特性的其他阿片类药物的人严重感染的风险更大；以及3)测试同时使用羟考酮或美沙酮及其代谢的强抑制剂会增加与此类使用相关的严重感染风险的假设 没有新陈代谢抑制剂。拟议的研究将使用回溯性队列研究设计和田纳西州医疗补助的数据，比较与使用选定阿片类药物相关的严重感染发生率，同时控制相关基线和随时间变化的协变量的影响。我们的研究团队拥有成功完成拟议项目所需的经验和专业知识。拟议的研究旨在对疼痛治疗领域产生重大影响，促进我们对阿片类止痛药对严重感染风险的影响的了解，并为老年人的临床护理提供信息。

DESCRIPTION (provided by applicant): There is substantial evidence that opioid analgesic use impairs immune system responses and there has been a long-standing concern that these effects increase the risk of serious, potentially life-threatening infections. In vivo studies in animal models and human subjects have demonstrated that opioids affect surrogate markers of immune functions that are crucial for prevention of serious infections, such as white cell migration and phagocytosis. Although studies have demonstrated significant dose-dependent suppression of immunological functions in animal models and humans as well as a dose-dependent increase in the risk of serious infections in animal models, the clinical relevance of these findings in humans remains unclear. These concerns are particularly relevant for older adults, who are commonly affected by pain and are at increased risk for infections. A number of opioid analgesics are currently available, but not all have the same immunosuppressive properties. Studies in animal models suggest that, taking the chemical structure of morphine as reference, opioids with hydroxyl groups at both C3 and C6 (e.g. morphine), have the strongest immunosuppressive effects, whereas modification at C3 alone (e.g. codeine) reduces immunosuppression, and substitution of a carbonyl group at C6 (e.g. hydromorphone) eliminates the immunosuppressive effects. Identifying those opioids that are the least likely to increase the risk of serious infections will be crucial to inform the selection of analgesics for vulnerable older adults. Furthermore, the immunosuppressive effects of opioids are dose-dependent and for several opioids, in vivo data suggest that concurrent use of opioids and other commonly used medications that inhibit opioid metabolism could markedly increase the serum concentration of opioids. We propose to conduct a series of studies of older adults with the following specific aims: 1) Test the hypothesis that the risk of serious infections in new users of codeine (which is metabolized to morphine) is greater than in new users of other opioids with comparable analgesic properties; 2) Test the hypothesis that the risk of serious infections in new users of morphine is greater than in new users of other opioids with comparable analgesic properties; and, 3) Test the hypothesis that concurrent use of oxycodone or methadone and strong inhibitors of their metabolism increases the risk of serious infections relative to such use without metabolic inhibitors. The proposed studies will use a retrospective cohort study design and data from Tennessee Medicaid, to compare the incidence of serious infections associated with the use of selected opioids while controlling for the effect of relevant baseline and time-varying covariates. Our research team has the combination of experience and expertise needed to successfully complete the proposed projects. The proposed studies are designed to have a high impact on the field of pain therapeutics, advance our understanding of the effects of opioid analgesics on the risk of serious infections and inform the clinical care of older adults.