Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Home Postal Code AA11, PO Box 30001, 9700 RB, Groningen, The Netherlands.
Groningen Research Institute of Asthma and COPD (GRIAC), University of Groningen, Hanzeplein 1, 9713 RB, Groningen, The Netherlands.
BMC Pulm Med. 2021 Sep 10;21(1):289. doi: 10.1186/s12890-021-01647-8.
Refractory dyspnea or breathlessness is a common symptom in patients with advanced chronic obstructive pulmonary disease (COPD), with a high negative impact on quality of life (QoL). Low dosed opioids have been investigated for refractory dyspnea in COPD and other life-limiting conditions, and some positive effects were demonstrated. However, upon first assessment of the literature, the quality of evidence in COPD seemed low or inconclusive, and focused mainly on morphine which may have more side effects than other opioids such as fentanyl. For the current publication we performed a systematic literature search. We searched for placebo-controlled randomized clinical trials investigating opioids for refractory dyspnea caused by COPD. We included trials reporting on dyspnea, health status and/or QoL. Three of fifteen trials demonstrated a significant positive effect of opioids on dyspnea. Only one of four trials reporting on QoL or health status, demonstrated a significant positive effect. Two-thirds of included trials investigated morphine. We found no placebo-controlled RCT on transdermal fentanyl. Subsequently, we hypothesized that both fentanyl and morphine provide a greater reduction of dyspnea than placebo, and that fentanyl has less side effects than morphine.
We describe the design of a robust, multi-center, double blind, double-dummy, cross-over, randomized, placebo-controlled clinical trial with three study arms investigating transdermal fentanyl 12 mcg/h and morphine sustained-release 10 mg b.i.d. The primary endpoint is change in daily mean dyspnea sensation measured on a numeric rating scale. Secondary endpoints are change in daily worst dyspnea, QoL, anxiety, sleep quality, hypercapnia, side effects, patient preference, and continued opioid use. Sixty patients with severe stable COPD and refractory dyspnea (FEV < 50%, mMRC ≥ 3, on optimal standard therapy) will be included.
Evidence for opioids for refractory dyspnea in COPD is not as robust as usually appreciated. We designed a study comparing both the more commonly used opioid morphine, and transdermal fentanyl to placebo. The cross-over design will help to get a better impression of patient preferences. We believe our study design to investigate both sustained-release morphine and transdermal fentanyl for refractory dyspnea will provide valuable information for better treatment of refractory dyspnea in COPD. Trial registration NCT03834363 (ClinicalTrials.gov), registred at 7 Feb 2019, https://clinicaltrials.gov/ct2/show/NCT03834363 .
难治性呼吸困难或呼吸急促是晚期慢性阻塞性肺疾病（COPD）患者的常见症状，对生活质量（QoL）有很大的负面影响。低剂量阿片类药物已被用于治疗 COPD 和其他生命受限疾病的难治性呼吸困难，并且已经证明了一些积极的效果。然而，在首次评估文献时，COPD 中的证据质量似乎较低或不确定，并且主要集中在吗啡上，而吗啡的副作用可能比芬太尼等其他阿片类药物更多。对于本次发表的研究，我们进行了系统的文献检索。我们搜索了安慰剂对照随机临床试验，以评估阿片类药物治疗 COPD 引起的难治性呼吸困难。我们纳入了报告呼吸困难、健康状况和/或生活质量的试验。在十五项试验中，有三项显示阿片类药物对呼吸困难有显著的积极影响。在报告生活质量或健康状况的四项试验中，只有一项显示有显著的积极影响。三分之二的纳入试验研究了吗啡。我们没有发现关于透皮芬太尼的安慰剂对照 RCT。随后，我们假设芬太尼和吗啡都能比安慰剂更有效地减轻呼吸困难，而且芬太尼的副作用比吗啡少。
我们描述了一项设计严谨、多中心、双盲、双模拟、交叉、随机、安慰剂对照的临床试验的设计，该试验有三个研究臂，分别研究透皮芬太尼 12 mcg/h 和吗啡持续释放 10 mg bid。主要终点是使用数字评分量表测量的每日平均呼吸困难感觉的变化。次要终点是每日最严重的呼吸困难、生活质量、焦虑、睡眠质量、高碳酸血症、副作用、患者偏好和持续使用阿片类药物的变化。60 名患有严重稳定型 COPD 和难治性呼吸困难（FEV < 50%，mMRC ≥ 3，在最佳标准治疗下）的患者将被纳入研究。
阿片类药物治疗 COPD 难治性呼吸困难的证据并不像通常认为的那样可靠。我们设计了一项研究，比较了更常用的阿片类药物吗啡和透皮芬太尼与安慰剂。交叉设计将有助于更好地了解患者的偏好。我们相信，我们的研究设计比较了持续释放的吗啡和透皮芬太尼在难治性呼吸困难中的应用，将为更好地治疗 COPD 难治性呼吸困难提供有价值的信息。
NCT03834363（ClinicalTrials.gov），于 2019 年 2 月 7 日注册，https://clinicaltrials.gov/ct2/show/NCT03834363。
