Morphine for chronic breathlessness (MABEL) in the UK: a multi-site, parallel-group, dose titration, double-blind, randomised, placebo-controlled trial.

We aimed to assess the effectiveness of oral morphine for breathlessness in long-term conditions.

我们旨在评估口服吗啡在长期疾病中缓解呼吸困难的有效性。

Methods

This phase 3, parallel-group, double-blind, placebo-controlledtrial across 11 centres randomly assigned consenting adults (1:1, stratified by site and causal disease) with a modified Medical Research Council breathlessness score of 3 or more due to cardiorespiratory conditions to receive 5-10 mg twice daily oral long-acting morphine or placebo (as well as a blinded laxative) for 56 days.

这项第三阶段、平行组、双盲、安慰剂对照试验在11个中心进行，随机分配了同意参与的成人患者（1:1，按地点和病因分层），这些患者的改良医学研究委员会呼吸困难评分为3分或以上，由于心脏和呼吸系统疾病，接受每日两次口服5-10毫克的长效吗啡或安慰剂（以及盲法使用的泻药）治疗56天。

The primary outcome was worst breathlessness score in the past 24 h at day 28, measured using a numerical rating scale (NRS; 0=not breathless at all; 10=worst imaginable breathlessness).

主要结果是第28天过去24小时内最严重的呼吸困难评分，使用数字评分量表（NRS；0=一点也不喘；10=最严重的想象中的喘息）进行测量。

Secondary outcomes included physical activity levels, worst cough NRS, quality of life, and morphine-related toxicities.

次要结果包括体力活动水平、最差咳嗽NRS评分、生活质量以及吗啡相关的毒性反应。

Patients who received at least one dose of study drug were eligible for inclusion in efficacy and safety analyses.

接受至少一剂研究药物的患者有资格纳入疗效和安全性分析。

The trial was registered with ISRCTN (ISRCTN87329095) and the EU Clinical Trials Register (EudraCT 2019-002479-33).

该试验已在ISRCTN (ISRCTN87329095)和欧盟临床试验注册处(EudraCT 2019-002479-33)注册登记。

Results

Between March 18, 2021, and Oct 26, 2023, 143 participants were randomly assigned to receive either morphine (73 participants) or placebo (67 participants) and were included in the analyses; three participants did not receive the allocated treatment.

在2021年3月18日至2023年10月26日期间，共有143名参与者被随机分配接受吗啡(73名参与者)或安慰剂(67名参与者)，并被纳入分析；有三名参与者未接受分配的治疗。

Participants had a mean age of 70·5 (SD 9·4) years, were mostly male (93 [66%]), and were mostly White (132 [94%]).

参与者平均年龄为70.5（标准差9.4）岁，大多数为男性（93人，占66%），大多数为白人（132人，占94%）。

By day 28, 64 (88%) participants in the morphine group versus 66 (99%) in the placebo group had 90% adherence or greater.

到第28天，吗啡组中有64名（88%）参与者和安慰剂组中有66名（99%）参与者的依从性达到90%或以上。

We found no evidence of difference in worst breathlessness at day 28 (morphine 6·19 [95% CI 5·57 to 6·81] vs placebo 6·10 [5·44 to 6·76]; adjusted mean difference 0·09 [95% CI -0·57 to 0·75], p=0·78) or any secondary measure, except for improved cough seen at day 56 (adjusted mean difference -1·41 [-2·18 to -0·64]).

我们在第28天没有发现呼吸困难最严重程度的差异（吗啡组为6.19 [95% CI 5.57至6.81]，安慰剂组为6.10 [5.44至6.76]；调整后平均差异为0.09 [95% CI -0.57至0.75]，p=0.78）或任何次要指标，除了在第56天观察到咳嗽有所改善（调整后平均差异为-1.41 [-2.18至-0.64]）。

Increased moderate to vigorous physical activity was seen at day 28 (adjusted mean difference 9·51 min/day [0·54-18·48]) but this was not significant after multiple-measures correction.

在第28天观察到中等到剧烈强度的体力活动增加（调整后平均差异为9.51分钟/天 [0.54-18.48]），但在多重测量校正后，这一结果并不显著。

The morphine group had more adverse events (251 vs 162), serious adverse events (15 vs three, of which three in the morphine group and zero in the placebo group were deemed to be related to the study), and study drug withdrawals (13 vs two).

吗啡组的不良事件（251 vs 162）、严重不良事件（15 vs 3，其中吗啡组有3例，安慰剂组有0例被认为与研究相关）和研究药物撤回（13 vs 2）更多。

There were no treatment-related deaths.

没有治疗相关的死亡事件。

interpretation

We found no evidence that morphine improves worst breathlessness intensity.

我们没有发现吗啡能改善最严重的呼吸困难强度的证据。

Further research is needed to understand whether there is any role for morphine in chronic breathlessness, but our findings do not support its use in this setting.

需要进一步的研究来了解吗啡在慢性呼吸困难中是否有任何作用，但我们的发现并不支持在这一背景下使用吗啡。

funding

NIHR Health Technology Assessment programme (HTA Project 17/34/01).

NIHR 健康技术评估计划（HTA 项目 17/34/01）。