Wolfson Palliative Care Research Centre, University of Hull, Hull, HU6 7RX, UK.
York Trials Unit, University of York, York, UK.
ESC Heart Fail. 2019 Dec;6(6):1149-1160. doi: 10.1002/ehf2.12498. Epub 2019 Aug 6.
Morphine is shown to relieve chronic breathlessness in chronic obstructive pulmonary disease. There are no definitive data in people with heart failure. We aimed to determine the effectiveness and cost-effectiveness of 12 weeks morphine therapy for the relief of chronic breathlessness in people with chronic heart failure compared with placebo.
Parallel group, double-blind, randomized, placebo-controlled, phase III trial of 20 mg daily oral modified release morphine was conducted in 13 sites in England and Scotland: hospital/community cardiology or palliative care outpatients. The primary analysis compared between-group numerical rating scale average breathlessness/24 hours at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment-emergent harms (worse or new). The trial closed early due to slow recruitment, randomizing 45 participants [average age 72 (range 39-89) years; 84% men; 98% New York Heart Association class III]. For the primary analysis, the adjusted mean difference was 0.26 (95% confidence interval, -0.86 to 1.37) in favour of placebo. All other breathlessness measures improved in both groups (week 4 change-from-baseline) but by more in those assigned to morphine. Neither group was excessively drowsy at baseline or week 4. There were no between-group differences in quality of life (Kansas) or cognition (Montreal) at any time point. There was no exercise-related desaturation and no change between baseline and week 4 in either group. There was no change in vital signs at week 4. The natriuretic peptide measures fell in both groups but by more in the morphine group [morphine 2169 (1092, 3851) pg/mL vs. placebo 2851 (1694, 5437)] pg/mL. There was no excess serious adverse events in the morphine group. Treatment-emergent harms during the first week were more common in the morphine group; all apart from 1 were ≤ grade 2.
We could not answer our primary objectives due to inadequate power. However, we provide novel placebo-controlled medium-term benefit and safety data useful for clinical practice and future trial design. Morphine should only be prescribed in this population when other measures are unhelpful and with early management of side effects.
吗啡已被证明可缓解慢性阻塞性肺疾病患者的慢性呼吸困难。但在心力衰竭患者中尚无明确数据。我们旨在确定与安慰剂相比，12 周吗啡治疗对慢性心力衰竭患者缓解慢性呼吸困难的有效性和成本效益。
在英格兰和苏格兰的 13 个地点进行了一项平行组、双盲、随机、安慰剂对照、III 期试验，使用每日口服 20 毫克改良释放吗啡：医院/社区心脏病学或姑息治疗门诊。主要分析使用协方差模式线性混合模型比较第 4 周时组间数值评定量表平均呼吸困难/24 小时。次要结局包括治疗后出现的不良反应（恶化或新发）。由于招募缓慢，试验提前结束，共随机分配了 45 名参与者[平均年龄 72（范围 39-89）岁；84%男性；98%纽约心脏协会心功能分级 III]。对于主要分析，调整后的平均差异为 0.26（95%置信区间，-0.86 至 1.37），有利于安慰剂。两组的所有其他呼吸困难指标均有所改善（第 4 周与基线相比的变化），但吗啡组的改善更为明显。两组在基线和第 4 周时均无过度嗜睡。任何时间点两组的生活质量（堪萨斯）或认知（蒙特利尔）均无差异。两组均无与运动相关的低氧血症，且两组在基线和第 4 周之间的生命体征均无变化。第 4 周时，神经肽测量值均下降，但吗啡组下降更为明显[吗啡组 2169（1092，3851）pg/mL 与安慰剂组 2851（1694，5437）pg/mL]。吗啡组无过多严重不良事件。吗啡组在第 1 周时更常见治疗后出现的不良反应，但除 1 例外，其他不良反应均为 2 级及以下。
由于效力不足，我们无法回答主要目标。但是，我们提供了新的安慰剂对照中期获益和安全性数据，这对临床实践和未来试验设计很有用。只有在其他措施无效且早期管理副作用的情况下，才能在该人群中开具吗啡处方。
