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

该提案响应了RFA-NS-19-029，以解决以下方面的需求：更好的循证疼痛治疗 患有慢性下腰痛(CLBP)的患者，他们有共同发生的负性情感障碍，如严重的 具有焦虑特征的抑郁症。伴有抑郁或焦虑症的CLBP亚组 (通常称为高度负面情绪)约占本地区5000万成人CLBP患者的20%-30% 国家。这一亚群对疼痛治疗特别难治，迫切需要更好的非 阿片类药物，全面的疼痛治疗选择。CLBP和高负性情绪(NA)患者 遭受更高程度的疼痛，残疾和功能更差。由于这些因素，他们被开出了处方 阿片类药物更频繁，滥用阿片类药物的比率要高得多(40%-60%的不依从率)，即 与服用额外的阿片类药物治疗抑郁症和焦虑症有关。疼痛管理不力 高NA患者的部分原因是缺乏更有效的循证治疗方案来改善 疼痛、抑郁、焦虑和功能，防止阿片类药物滥用。我们已经在不同的RCT中显示了 接受抗抑郁药物(AD)或“基于恐惧回避的物理治疗”的高NA CLBP患者改善 疼痛、功能、抑郁和焦虑。在这份提案中，我们还将提供数据显示， 在抗抑郁药物+恐惧回避的情况下，PT比单独治疗或对照条件更有效。 此外，我们还测试了增强的恐惧回避康复方案(EFAR)，以改善 结果进一步，我们发现它比通常的护理更有效。解决CLBP未得到满足的需求 有高负性情绪的患者，我们建议在随机试验中测试AD+EFAR的组合是否 在改善疼痛、功能、抑郁和防止阿片类药物滥用方面比单独治疗更有效(3- 武器，300名受试者)。为了更好地确定干预组件(AD或EFAR)的响应者，我们将 使用自适应设计，其中对每个治疗无效的患者被重新随机化以接受另一个治疗 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 环境也做好了迅速实现这种转变的准备。主要结果是综合衡量 疼痛和自我报告功能的临床有意义的变化(联合反应)，50%的比率 与基线相比，4个月后抑郁症状(抑郁反应)有所改善。我们跟踪结果 总共8个月。主要的次要结果是各治疗组药物滥用的比例。 其他次要结果包括睡眠质量、活动水平、焦虑、渴望和阿片类药物的变化。 剂量。我们预期的发现将提供高质量的证据，支持AD+EFAR在 高NA的CLBP患者为高发人群。我们还将确定哪些表型亚群 患者可能只对AD或EFAR有最好的反应。

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.