Efficacy and Safety of Rapid-Onset Opioids for Exertional Dyspnea in Cancer Patients

项目摘要 呼吸困难是与癌症相关的最常见和最令人痛苦的症状之一，发生率高达70%。 病人。绝大多数呼吸困难患者会频繁发生呼吸困难， 通过日常活动，如散步和洗澡。可以理解的是，劳力性呼吸困难可以显著限制 患者的日常功能，并对他们的生活质量产生负面影响。如果不加控制，这些高度痛苦的呼吸困难 发作可能导致昂贵的急诊室就诊和住院治疗。因为劳力性呼吸困难- 然而，经过研究，几乎没有有效的治疗方案。 我们小组研究的长期目标是开发有效的，以证据为基础的治疗呼吸困难的方法， 癌症患者。呼吸困难是特别难以治疗的，因为它发作快，持续时间短， 和高强度。这就提出了一种可能性，即目前批准用于突破的速效阿片类药物， 癌症疼痛作为预防性治疗可能有效，以减少劳力性呼吸困难并使功能最大化。对 根据我们最近临床试验的初步数据，我们假设芬太尼舌下喷雾剂（FSS） 对缓解劳累性呼吸困难有效。所提出的三臂、双假人、平行- 组随机临床试验是为了比较FSS，硫酸吗啡和安慰剂在劳力性 呼吸困难本研究的主要目的是比较预防性FSS、硫酸吗啡， 和安慰剂对往返步行试验（SWT）结束时劳力性呼吸困难强度的影响。在第二个具体 目的：比较两种方法对SWT距离、平均每日呼吸困难、个体化每日活动、症状 负担和生活质量。第三个目的是探讨它们对神经认知功能，成瘾潜力， 副作用和阿片类药物使用模式。在获得书面知情同意书后，我们将对患者进行监测 在随机分配他们接受FSS、硫酸吗啡或安慰剂之前， 每日一次，持续14天。 拟议的研究是创新的，因为适应症（即，劳力性呼吸困难和预防性 管理）、干预（即，FSS，按比例给药）、患者人群（即，癌症患者）， 患者报告的结局指标（例如，个性化呼吸困难活动，患者报告的结局版本 不良事件通用术语标准工具和药物效应问卷），以及研究 设计（即家庭环境），它将解决是新颖的。拟议研究的预期成果是， 将作为癌症患者劳力性呼吸困难的治疗选择，而丰富的数据集将 提供关于阿片类药物的神经认知作用和成瘾潜力的信息，以告知在此期间安全使用阿片类药物 鸦片危机的时代成功完成这项具有充分把握度的试验将对患者产生积极影响。 通过减轻劳力性呼吸困难的强度，增强患者在日常生活中的功能， 并改善这些高度痛苦的患者的生活质量。

PROJECT SUMMARY Dyspnea is one of the most common and distressing symptoms associated with cancer, occurring in up to 70% of patients. The vast majority of patients with dyspnea experience frequent episodes of breathlessness triggered by daily activities, such as walking and bathing. Understandably, dyspnea with exertion can significantly limit patients' daily function and negatively impact their quality of life. If uncontrolled, these highly distressing dyspnea episodes can result in costly emergency room visits and hospitalizations. Because exertional dyspnea is under- researched, few effective treatment options are available. The long-term goal of our group's research is to develop effective, evidence-based therapies for dyspnea in patients with cancer. Exertional dyspnea is particularly difficult to treat because of its rapid onset, short duration, and high intensity. This raises the possibility that rapid-onset opioids that are currently approved for breakthrough cancer pain may be effective as prophylactic treatment to reduce exertional dyspnea and maximize function. On the basis of our preliminary data from recent clinical trials, we hypothesize that fentanyl sublingual spray (FSS) is effective in relieving exertional dyspnea. The overall objective of the proposed 3-arm, double-dummy, parallel- group randomized clinical trial is to compare the efficacy of FSS, morphine sulfate, and placebo in exertional dyspnea. The primary specific aim of this study is to compare the effect of prophylactic FSS, morphine sulfate, and placebo on the intensity of exertional dyspnea at the end of a shuttle walk test (SWT). In the second specific aim, we will compare their effects on SWT distance, average daily dyspnea, personalized daily activity, symptom burden, and quality of life. The third aim is to explore their effects on neurocognitive function, addictive potential, adverse effects, and pattern of opioid use. After obtaining written informed consent, we will monitor patients closely on usual opioids for 5 days before randomly assigning them to receive FSS, morphine sulfate, or placebo prophylactically once daily for 14 days. The proposed study is innovative in that the indications (i.e., exertional dyspnea and prophylactic management), intervention (i.e. FSS, proportionally dosed), patient population (i.e., patients with cancer), patient-reported outcome measures (e.g. personalized dyspnea activity, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events instrument, and Drug effects Questionnaire), and study design (i.e. home setting) that it will address are novel. The expected outcome of the proposed study is that FSS will be established as a treatment option for exertional dyspnea in patients with cancer while a rich dataset will be provided on the neurocognitive effects and addictive potential of opioids to inform safe opioid use during this era of opioid crisis. Successful completion of this adequately powered trial will have a positive effect on patient care by alleviating the intensity of exertional dyspnea, enhancing patients' ability to function in their daily lives, and improving the quality of life of these highly distressed patients.