Opioid-induced change in pain sensitivity and modulation: Links to opioid misuse

 描述（由申请人提供）：慢性腰痛（CLBP）困扰着多达5000万美国成年人，是残疾的主要原因。目前，阿片类镇痛药是疼痛管理的基石，也是医生为CLBP开出的最常见的药物之一。尽管阿片类药物具有潜在的益处，但由于其潜在的医源性后果，如阿片类药物诱导的痛觉过敏（OIH）和处方阿片类药物滥用（POM）的发生，引起了人们对阿片类药物的主要担忧，这两种药物都有可能损害治疗益处。很明显，并非所有长期服用阿片类药物的患者都会出现这些适应不良反应。我们的初步数据表明，疼痛患者的特定亚组可能更容易发展OIH，以及中枢神经系统（CNS）疼痛调节过程的有害变化。此外，我们的初步数据表明，OIH和阿片类药物引起的疼痛调制的变化可能会增加患者滥用阿片类药物的倾向。考虑到美国目前的阿片类药物处方率，迫切需要更好地了解阿片类药物对中枢神经系统疼痛处理的影响，以及这些感觉变化对阿片类药物滥用或成瘾风险的影响。在这项研究中，我们建议在CLBP患者中进行一项为期4个月的口服阿片类药物的随机对照试验。在这项试验中，每个参与者将在基线时接受定量感觉测试（QST），然后随机接受缓释口服吗啡或匹配的安慰剂。然后，患者将在1、2、3和4个月时接受重复QST。在每个随访时间点，我们将评估疼痛敏感性和调节的变化以及处方阿片类药物滥用。将使用每日电子日记条目来评估治疗功效。我们假设以高水平的负面影响和疼痛灾难化为特征的可识别的患者亚组将处于经历适应不良的阿片类药物诱导的疼痛敏感性变化的最大风险（即，OIH）和疼痛调节，以及处方阿片类药物滥用的可能性增加。总的来说，关于OIH有非常丰富的动物文献（在大鼠中似乎是一种非常稳健的现象），但目前缺乏前瞻性的人类数据。我们希望这项研究的发现是新颖的，及时的，并对阿片类药物疼痛管理领域产生直接影响。确定OIH和POM风险升高的患者亚组应有助于更有效地为个体患者定制治疗方案，并有助于减少慢性疼痛患者长期阿片类药物治疗的潜在严重医源性影响。

 DESCRIPTION (provided by applicant): Chronic low back pain (CLBP) afflicts up to 50 million US adults and is a primary cause of disability. Currently, opioid analgesics are a cornerstone of pain management, and are among the most common medications prescribed by physicians for CLBP. Despite their potential benefits, major concerns have been raised regarding opioids due to their potential iatrogenic consequences, such as the development of opioid-induced hyperalgesia (OIH) and prescription opioid misuse (POM), both of which have the potential to impair treatment benefits. It is clear that not all patients taking long-term opioids will experiene these maladaptive effects. Our preliminary data indicate that specific subgroups of pain patients might be more prone to developing OIH, as well as deleterious shifts in central nervous system (CNS) pain-modulatory processes. Furthermore, our preliminary data suggest that OIH and opioid-induced changes in pain modulation might increase patients' propensity to misuse opioids. Given the current opioid prescribing rates in the U.S., there is an urgent need to better understand effects of opioids on CNS pain processing and, in turn, the effects of those sensory changes on risk for opioid misuse or addiction. In this study, we propose to conduct a 4-month randomized, controlled trial of oral opioids among patients with CLBP. In this trial, each participant will undergo quantitative sensory testing (QST) at baseline, before being randomized to receive either extended-release oral morphine or matched placebo. Patients will then undergo repeat QST at 1, 2, 3, and 4 months. At each of these follow-up time points, we will assess changes in pain sensitivity and modulation, and prescription opioid misuse. Treatment efficacy will be assessed using daily electronic dairy entries We hypothesize that an identifiable subgroup of patients, characterized by high levels of negative affect and pain catastrophizing, will be at the greatest risk for experiencing maladaptive opioid-induced changes in pain sensitivity (i.e., OIH) and pain modulation, as well as an increased likelihood of prescription opioid misuse. Collectively, there is a very strong animal literature on OIH (which seems to be a highly robust phenomenon in rats), but there is currently a paucity of prospective human data. We hope that findings from this research would be novel, timely, and would have direct implications for the field of opioid pain management. Identifying subgroups of patients who are at elevated risk for OIH and POM should facilitate more effective tailoring of treatment regimens to individual patients, and aid in reducing the potentially severe iatrogenic impacts of long-term opioid therapy in patients with chronic pain.