近日，美国特雷维治疗公司James Cassella团队研究了口服纳布啡治疗特发性肺纤维化相关咳嗽的疗效与安全性。2026年1月22日出版的《美国医学会杂志》发表了这项最新研究成果。

对于特发性肺纤维化（IPF）患者，咳嗽会损害生活质量；需要对IPF相关咳嗽进行有效治疗。

为了确定与安慰剂相比，κ阿片受体激动剂和μ阿片受体拮抗剂纳布啡缓释剂（ER）是否能减轻特发性肺纤维化（IPF）相关咳嗽患者的咳嗽症状，研究组进行了一项随机、双盲、安慰剂对照的2b期试验，在10个国家的52个研究机构进行。2024年2月至2025年2月期间，招募患有特发性肺纤维化（IPF）、咳嗽持续至少8周且咳嗽严重程度数值评定量表（0表示无咳嗽；10表示最严重咳嗽）评分≥4的患者，最后一次随访于2025年4月进行。统计分析于2025年5月至8月进行。

将患者按1:1:1:1的比例随机分组，分别接受27 mg、54 mg或108 mg剂量的纳布啡缓释剂或安慰剂，每日2次，持续6周。第6周时，主要结局为纳布啡缓释剂与安慰剂相比，24小时咳嗽频率（咳嗽次数/小时）自基线的相对变化，该变化通过数字咳嗽监测仪进行测量。关键次要结局为第6周时患者报告的咳嗽频率（特发性肺纤维化（IPF）咳嗽症状评估子量表；评分范围为0-4，评分越低表示咳嗽频率越低）自基线的相对变化。

在223例筛查患者中，165例被随机分组（42例、43例、40例和40例分别接受纳布啡缓释剂27 mg、54 mg和108 mg，以及安慰剂），160例被纳入初步分析（中位年龄71岁[范围51~85岁]；女性占28.5%）。基线时咳嗽次数的平均值（标准差）为28.3（27.4）次/小时。与安慰剂组相比，纳布啡缓释剂27 mg、54 mg和108 mg每日两次给药组的咳嗽次数平均相对减少率和每小时咳嗽次数的绝对减少率分别为47.9%（从24.6次减少到11.9次；P=0.008）、53.4%（从28.0次减少到14.9次；P<0.001）和60.2%（从31.5次减少到11.9次；P<0.001）（安慰剂组为16.9%；从29.4次减少到28.1次/小时）。对于第6周患者报告的咳嗽频率这一关键次要结局，与安慰剂组相比，纳布啡缓释剂27 mg、54 mg和108 mg组的相对变化率和绝对变化率分别为-31.4%（从2.3次减少到1.5次；P=0.14）、-40.6%（从2.6次减少到1.4次；P=0.004）和-40.2%（从2.4次减少到1.4次；P<0.005），安慰剂组为-21.9%（从2.6次减少到1.9次）。

研究结果表明，对于特发性肺纤维化（IPF）相关性慢性咳嗽患者，6周时，3种剂量的缓释纳布啡均能减少客观咳嗽频率，且2种较高剂量能改善患者自评的咳嗽频率。

附：英文原文

Title: Oral Nalbuphine in Idiopathic Pulmonary Fibrosis–Associated Cough: The CORAL Randomized Clinical Trial

Author: Philip L. Molyneaux, Nesrin Mogulkoc, Hakan Gunen, Anna Doboszyńska, Michael Kreuter, Blue Neustifter, Vandana Mathur, James Cassella, CORAL Study Group, Peter Bremner, Mon M Chia, Nicole Goh, Francis Thien, Elizabeth Veitch, John Wheatley, Nasreen Khalil, Emilie Millaire, George Philteos, Christopher Ryerson, Claudia M Cartagena Salinas, Matias R Florenzano Valdes, Roxana I de L Maturana Rozas, Juana R Pavie Gallegos, Felipe Saavedra Gonzalez, Absalon R Silva Orellana, Francesco T Bonella, Lars Hagmeyer, Stephanie Korn, Marc O Kornmann, Michael Kreuter, Benjamin Seeliger, Hubert Wirtz, Donato Lacedonia, Fabrizio Luppi, Paolo Spagnolo, Luca Richeldi, Carlo Vancheri, Henk Kramer, Marieke Overbeek, Rein Van Rijswijk, Marlies Wijsenbeek-Lourens, Iwona Damps-Konstanska, Anna Doboszyńska, Miroslaw Necki, Malgorzata Nocen-Piskorowska, Wojciech Piotrowski, Jose M Cifrian Martinez, Walther I Giron Matute, Maria Molina-Molina, Juan Roldan Sanchez, Aykut Cilli, Hakan Günen, Nesrin Mogulkoc Bishop, Nihal A Mirici, Nesrin Ocal, Baykal Tulek, Cristina Avram, Nazia Chaudhuri, Rory Convery, Anjali Crawshaw, Christine Fiddler, Sophie Fletcher, Simon Hart, Nikhil Hirani, Philip Molyneaux, Joanna Porter, Gauri Saini, Peter Saunders, Andrew Wilson

Issue&Volume: 2026-01-22

Abstract:

Importance  For patients with idiopathic pulmonary fibrosis (IPF), cough impairs quality of life; effective treatments for IPF-associated cough are needed.

Objective  To determine if nalbuphine extended release (ER), a κ opioid receptor agonist and μ-opioid receptor antagonist, decreases cough compared with placebo in patients with IPF-associated cough.

Design, Setting, and Participants  In this randomized, double-blind, placebo-controlled phase 2b trial conducted at 52 sites in 10 countries, patients with IPF, chronic cough for at least 8 weeks, and a Cough Severity Numerical Rating Scale (0, no cough; 10, worst possible cough) score of 4 or higher were enrolled from February 2024 to February 2025, with last follow-up in April 2025. Statistical analyses were conducted from May to August 2025.

Intervention  Patients were randomized 1:1:1:1 to receive nalbuphine ER at doses of 27 mg, 54 mg, or 108 mg or placebo twice daily for 6 weeks.

Main Outcomes and Measures  The primary outcome was the relative change from baseline in 24-hour cough frequency (coughs/h), measured with a digital cough monitor, for nalbuphine ER compared with placebo at week 6. The key secondary outcome was the relative change from baseline in the patient-reported cough frequency (Evaluating Respiratory Symptoms in IPF cough subscale; scores range from 0-4, lower scores indicate lesser cough frequency) at week 6.

Results  Of the 223 patients screened, 165 were randomized (42, 43, 40, and 40 to receive nalbuphine ER 27 mg, 54 mg, and 108 mg, and placebo, respectively) and 160 were included in the primary analysis (median age, 71 [range, 51-85] years; 28.5% female). The baseline mean (SD) cough count was 28.3 (27.4) coughs/h. In the nalbuphine ER 27 mg, 54 mg, and 108 mg twice-daily groups, the mean relative decrease in the cough count and the absolute decrease in coughs/h were 47.9% (from 24.6 to 11.9; P=.008), 53.4% (from 28.0 to 14.9; P<.001), and 60.2% (from 31.5 to 11.9; P<.001), respectively, compared with placebo (16.9%; from 29.4 to 28.1 coughs/h). For the key secondary outcome of patient-reported cough frequency at week 6, the relative and absolute changes were 31.4% (from 2.3 to 1.5; P=.14), 40.6% (from 2.6 to 1.4; P=.004), and 40.2% (from 2.4 to 1.4; P<.005) in the 27-mg, 54-mg, and 108-mg groups, respectively, compared with –21.9% (from 2.6 to 1.9) with placebo.

Conclusions and Relevance  For patients with IPF-associated chronic cough, all 3 doses of nalbuphine ER reduced objective cough frequency and the 2 higher doses improved patient-reported cough frequency at 6 weeks.

DOI: 10.1001/jama.2025.26179

Source: https://jamanetwork.com/journals/jama/fullarticle/2844186