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

项目总结 呼吸困难是与癌症有关的最常见和最令人痛苦的症状之一，高达70%的人会出现呼吸困难 病人的数量。绝大多数呼吸困难的患者经常经历由呼吸困难引发的呼吸困难。 通过日常活动，如散步和洗澡。可以理解的是，疲劳性呼吸困难可以显著限制 影响患者日常生活功能，对患者生活质量产生负面影响。如果不加以控制，这些令人痛苦的呼吸困难 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在- 经过研究，几乎没有有效的治疗方法可用。 我们小组研究的长期目标是开发有效的、循证的治疗呼吸困难的方法 癌症患者。劳力性呼吸困难尤其难以治疗，因为它起病快，持续时间短， 和高强度。这增加了目前被批准突破的快速起效阿片类药物 癌性疼痛可能是一种有效的预防性治疗，可以减少劳力性呼吸困难，最大限度地发挥功能。在……上面 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) 能有效缓解劳力性呼吸困难。拟议的三臂、双假人、平行的总体目标- 分组随机临床试验是比较FSS、硫酸吗啡和安慰剂在劳累中的疗效 呼吸困难。本研究的主要具体目的是比较预防性使用FSS、硫酸吗啡、 并在穿梭行走试验(SWT)结束时对劳力性呼吸困难的强度进行安慰剂治疗。在第二个具体例子中 目的比较两种方法对SWT距离、日均呼吸困难、个性化日常活动、症状的影响 负担和生活质量。第三个目标是探索它们对神经认知功能、成瘾潜力的影响， 不良反应和阿片类药物的使用模式。在获得书面知情同意后，我们将对患者进行监测 在随机分配接受FSS、硫酸吗啡或安慰剂之前，密切服用普通阿片类药物5天 预防性服用，每日一次，连续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呼吸困难) 管理)、干预(即按比例剂量的FSS)、患者群体(即癌症患者)、 患者报告的结果衡量标准(例如，个性化呼吸困难活动、患者报告的结果版本 不良事件量表和药物影响问卷的通用术语标准)和研究 它将解决的设计(即家居环境)是新颖的。拟议研究的预期结果是FSS 将被确定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 提供阿片类药物的神经认知效应和成瘾潜力，以便在此期间安全使用阿片类药物 阿片类药物危机的时代。这项动力充足的试验的成功完成将对患者产生积极的影响 通过缓解劳力性呼吸困难的强度，提高患者的日常生活能力来进行护理， 并改善这些高度痛苦患者的生活质量。

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.