Opioid selection and the risk of serious infections in older adults

描述（由申请人提供）：有大量证据表明阿片类镇痛药的使用会损害免疫系统反应，长期以来人们一直担心这些影响会增加严重的、潜在危及生命的感染的风险。在动物模型和人类受试者中进行的体内研究表明，阿片类药物影响免疫功能的替代标志物，这些标志物对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，免疫功能受到明显的剂量依赖性抑制，以及动物模型中严重感染风险的剂量依赖性增加，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，感染的风险也在增加。目前有许多阿片类镇痛药可用，但并非所有都具有相同的免疫抑制特性。动物模型研究表明，以吗啡的化学结构为参照，具有C3和C6羟基的阿片类药物（如吗啡）具有最强的免疫抑制作用，而单独在C3位点修饰（如可待因）可降低免疫抑制作用，在C6位点取代羰基（如氢吗啡酮）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易受伤害的老年人选择镇痛药至关重要。此外，阿片类药物的免疫抑制作用是剂量依赖性的，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类药物代谢的常用药物可以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的研究，具体目的如下：1)检验新使用者严重感染风险的假设

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.