Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis. The PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40–90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at , , and has been completed. Between Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82% (17·3), and mean predicted diffusion capacity of carbon monoxide was 48% (10·9). Of the 44 patients who were randomised, 43 completed morphine treatment and 41 completed placebo treatment. In the intention-to-treat analysis, morphine reduced objective awake cough frequency by 39·4% (95% CI –54·4 to –19·4; p=0·0005) compared with placebo. Mean daytime cough frequency reduced from 21·6 (SE 1·2) coughs per h at baseline to 12·8 (1·2) coughs per h with morphine, whereas cough rates did not change with placebo (21·5 [SE 1·2] coughs per h to 20·6 [1·2] coughs per h). Overall treatment adherence was 98% in the morphine group and 98% in the placebo group. Adverse events were observed in 17 (40%) of 43 participants in the morphine group and six (14%) of 42 patients in the placebo group. The main side-effects of morphine were nausea (six [14%] of 43 participants) and constipation (nine [21%] of 43). One serious adverse event (death) occurred in the placebo group. In patients with cough related to idiopathic pulmonary fibrosis, low dose controlled-release morphine significantly reduced objective cough counts over 14 days compared with placebo. Morphine shows promise as an effective treatment to palliate cough in patients with idiopathic pulmonary fibrosis, and longer term studies should be the focus of future research. The Jon Moulton Charity Trust.

中文翻译：

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吗啡治疗特发性肺纤维化咳嗽（PACIFY COUGH）：一项前瞻性、多中心、随机、双盲、安慰剂对照、双向交叉试验

特发性肺纤维化是一种进行性纤维化肺部疾病，大多数患者报告有咳嗽。目前，还没有经过验证的治疗方法。我们研究了使用低剂量控释吗啡与安慰剂作为特发性肺纤维化个体的镇咳治疗的比较。 PACIFY COUGH 研究是一项 2 期、多中心、随机、双盲、安慰剂对照、双向交叉试验，在英国三个专科中心进行。符合条件的患者年龄在40-90岁，5年内诊断为特发性肺纤维化，自我报告咳嗽（持续>8周），并且咳嗽视觉模拟评分（VAS）评分为30毫米或更高。患者被随机分配 (1:1) 服用安慰剂，每日两次，或控释吗啡 5 mg，口服，每日两次，持续 14 天，然后在 7 天的清除期后进行交叉。根据计算机生成的时间表，患者被依次随机分配到一个序列组，该序列组定义了吗啡和安慰剂的给药顺序。患者、研究人员、研究护士和药房人员对治疗分配情况不知情。主要终点是意向治疗人群（包括所有随机参与者）在治疗第 14 天通过客观数字咳嗽监测评估客观清醒咳嗽频率（每小时咳嗽）相对于基线的百分比变化。总结了所有服用至少一种研究药物且未撤回同意的患者的安全性数据。这项研究已在 、 、 注册，并已完成。 2020年12月17日至2023年3月21日期间，对47名参与者进行了资格评估，其中44名参与者入组并随机分配接受治疗。平均年龄为 71 (SD 7·4) 岁，44 名参与者中有 31 名 (70%) 为男性，13 名 (30%) 为女性。肺功能中度受损；平均用力肺活量（FVC）为2·7 L（SD 0·76），平均预测FVC为82%（17·3），平均预测一氧化碳扩散能力为48%（10·9）。在 44 名随机分组的患者中，43 名完成了吗啡治疗，41 名完成了安慰剂治疗。在意向治疗分析中，与安慰剂相比，吗啡使客观清醒咳嗽频率降低了 39·4%（95% CI –54·4 至 –19·4；p=0·0005）。使用吗啡时，平均日间咳嗽频率从基线时的每小时 21·6 (SE 1·2) 次咳嗽减少至每小时 12·8 (1·2) 次咳嗽，而安慰剂组的咳嗽率没有变化 (21·5 [SE 1] ·2] 次咳嗽/小时至 20·6 [1·2] 次咳嗽/小时）。吗啡组的总体治疗依从性为 98%，安慰剂组为 98%。吗啡组 43 名患者中有 17 名（40%）观察到不良事件，安慰剂组 42 名患者中有 6 名（14%）观察到不良事件。吗啡的主要副作用是恶心（43 名参与者中有 6 名 [14%]）和便秘（43 名参与者中有 9 名 [21%]）。安慰剂组发生了一项严重不良事件（死亡）。对于与特发性肺纤维化相关的咳嗽患者，与安慰剂相比，低剂量控释吗啡在 14 天内显着减少了客观咳嗽次数。吗啡有望成为缓解特发性肺纤维化患者咳嗽的有效方法，长期研究应该是未来研究的重点。乔恩·莫尔顿慈善信托基金。