Proof of concept study to treat negative affect in chronic low back pain

本提案响应了RFA-NS-19-029，以满足更好的循证疼痛治疗需求， 患有慢性腰痛（CLBP）的患者，同时患有负性情感障碍，如严重的 具有焦虑特征的抑郁症。伴抑郁或焦虑障碍的CLBP亚组 （通常被称为高负面影响）是大约20-30%的50万成人与CLBP在这一地区。 国家这个亚组对疼痛治疗特别难治，迫切需要更好的非药物治疗。 阿片类药物，全面的疼痛治疗方案。CLBP患者和高水平的负面情绪（NA） 遭受更高程度的疼痛，残疾和功能更差。由于这些因素，它们被规定为 阿片类药物更频繁，滥用阿片类药物的比例更高（40-60%的不依从率）， 与通过服用额外的阿片类药物来自我治疗抑郁和焦虑有关。疼痛管理不佳， 高NA患者的部分原因是缺乏更有效的循证治疗方案，以改善 疼痛，抑郁，焦虑和功能，并防止阿片类药物滥用。我们在单独的RCT中显示， 抗抑郁药（AD）或“基于恐惧回避的物理治疗”改善的高NA CLBP患者 疼痛功能抑郁和焦虑在本提案中，我们还将提供数据，显示该组合 抗抑郁药+恐惧回避PT比单独的每种治疗或对照条件更有效。 此外，我们还测试了一种增强型恐惧回避康复方案（EFAR），以改善 结果进一步，我们发现它比常规护理更有效。解决CLBP未满足的需求 对于高负性情绪的患者，我们建议在随机试验中测试AD+EFAR的组合是否 比单独使用每种治疗更有效地改善疼痛，功能，抑郁症，并防止阿片类药物滥用（3- 300例受试者）。为了更好地识别对干预成分（AD或EFAR）的反应者，我们将 采用适应性设计，使每种治疗的无应答者重新随机接受另一种治疗 治疗这种药物治疗+行为治疗的多模式组合方法在该领域是新颖的 并有可能改变目前的治疗模式。我们还将展示社区实践 环境也准备迅速实现这一转变。主要结果是衡量 疼痛和自我报告的功能（联合反应）有临床意义的变化，以及50%的比率 与基线相比，4个月时抑郁症状改善（抑郁反应）。我们跟踪结果 总共8个月。主要次要结局是每个治疗组中药物滥用的比例。 其他次要结局包括睡眠质量、活动水平、焦虑、渴望和阿片类药物的变化 次给药结束我们的预期结果将提供高质量的证据，支持AD+EFAR联合使用， 高NA的CLBP患者的流行组。我们还将确定哪些表型亚组 患者可能仅对AD或EFAR有最佳反应。

This proposal responds to RFA-NS-19-029 to address the need for better evidence-based pain treatment for patients with chronic low back pain (CLBP) who have co-occurring negative affective disorders, such as major depression with anxious features. The CLBP subgroup with comorbid depression or anxiety disorders (commonly termed, high negative affect) is approximately 20-30% of the 50 million adults with CLBP in this country. This subgroup is particularly refractory to pain treatment and is in desperate need of better non- opioid, comprehensive pain treatment options. Patients with CLBP and high levels of negative affect (NA) suffer higher levels of pain and have worse disability and function. Due to these factors they are prescribed opioids more frequently and misuse opioids at a much greater rate (40-60% rates of non-adherence), which is related to self-medication of depression and anxiety by taking extra opioids. Poor pain management in patients with high NA is due in part to a lack of more effective evidenced-based treatment options to improve pain, depression, anxiety, and function, and prevent opioid misuse. We have shown in separate RCTs in CLBP patients with high NA that antidepressants (AD) or “fear avoidance based physical therapy” improve pain, function, depression, and anxiety. In this proposal we will also present data showing that the combination of antidepressants + fear avoidance PT is more efficacious than each treatment alone or a control condition. Moreover, we have also tested an enhanced fear avoidance rehabilitation protocol (EFAR) to improve outcomes further, and we found it more effective than usual care. To address the unmet needs of CLBP patients with high negative affect, we propose to test in a randomized trial if the combination of AD+EFAR is more effective than each treatment alone to improve pain, function, depression, and prevent opioid misuse (3- arms, in 300 subjects). To better identify responders to components of the intervention (AD or EFAR), we will use an adaptive design whereby non-responders to each treatment are re-randomized to receive the other treatment. This multimodal, combination approach of pharmacotherapy +behavioral therapy is novel to the field and has the potential to shift current treatment paradigms. We will also show that the community practice environment is poised to make this shift rapidly as well. The primary outcomes are a measure of combined clinically meaningful changes in pain and self-reported function (Combined Response), and the rate of 50% improvement in depression symptoms (Depression Response) at 4 months vs. baseline. We track outcomes for a total of 8 months. The main secondary outcome is the proportion of drug misuse in each treatment group. Additional secondary outcomes include changes in sleep quality, activity levels, anxiety, craving, and opioid dose. Our anticipated findings will provide high quality evidence supporting the combined use of AD+EFAR in the prevalent group of CLBP patients with high NA. We will also identify which phenotypic subgroups of patients may best respond to just AD or EFAR alone.