Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial.

BACKGROUND: 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. METHODS: 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 ClinicalTrials.gov, NCT04429516, and has been completed. FINDINGS: 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. INTERPRETATION: 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. FUNDING: The Jon Moulton Charity Trust.

A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough.

Objective: Baclofen is a centrally acting γ-aminobutyric acid type B (GABAB) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABAB agonist, but its effects on refractory chronic cough are unknown. Design: We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions. Patients were randomised to treatment with lesogaberan 120 mg modified release twice daily or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary end-point was 24-h cough frequency measured with an acoustic monitoring system. In addition, cough responses to capsaicin were measured, and gastro-oesophageal reflux assessed by 24-h pH/impedance at screening. Results: 22 patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan (female (73%); mean±sd age 63.7±7.2 years; median (interquartile range) cough duration 10.5 (5.8-17.0) years; mean (95% CI) 45 (29-67) reflux events in 24 h; two patients had abnormal oesophageal acid exposure times). Although lesogaberan reduced cough counts by 26% over placebo, this did not reach statistical significance (p=0.12). However, lesogaberan did significantly improve cough responses to capsaicin (p=0.04) and the number of cough bouts (p=0.04) compared with placebo. Lesogaberan was well tolerated in this study. Conclusions: Lesogaberan improved cough hypersensitivity and the number of bouts of coughing, but not coughs per hour. This implies a possible role for peripheral GABAB receptors in refractory chronic cough.

Effect of centrally and peripherally acting GABAB agonism on the healthy human cough reflex.

BACKGROUND: Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABAB receptors in both the peripheral and central nervous systems inhibit cough. OBJECTIVE: To compare the effect of central and peripherally acting GABAB agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers. METHODS: We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120 mg MR), with baclofen (40 mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50). RESULTS: Fifteen participants enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p = 0.04], but had no effect on ED50 [geometric mean 47.4 µM (95%CI 24.4-91.7) vs 37.6 µM (95%CI 19.2-73.5), p = 0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p = 0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2 µM (95%CI 37.2-151.8), p = 0.002). CONCLUSION: This data suggests the anti-tussive actions of GABAB agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.

17q12-21 variants are associated with asthma and interact with active smoking in an adult population from the United Kingdom.

BACKGROUND: Although an association between 17q12-21 and asthma has been replicated across different populations, some inconsistencies have been found between different studies. OBJECTIVE: We investigated the association between genetic variation in this region with asthma, lung function, airway inflammation, hyperresponsiveness (AHR), and atopy in a case-control study of United Kingdom adults. The interaction between genotype and smoking was also evaluated. METHODS: Study subjects (n = 983) were carefully phenotyped using questionnaires, measurement of lung function, AHR (methacholine challenge), exhaled nitric oxide (eNO), and assessment of atopic status. Blood/saliva/buccal swabs were collected, and 47 single nucleotide polymorphisms (SNPs) in 17q12-21 were genotyped using MALDI-TOF (Matrix-assisted LASER desorption/ionisation-time of flight) mass spectrometry. We conducted a comprehensive investigation of 28 common SNPs within 6 genes of interest (IKZF3, ZPBP2, ORMDL3, GSDMA, GSDMB, TOP2A). RESULTS: Sixteen SNPs were significantly associated with asthma after multiple testing correction (P ≤ .01), of which 5 (rs2290400, rs8079416, rs3894194, rs7212938, and rs3859192) were strongly associated (FDR P ≤ .0002), and one was novel (IKZF3-rs1453559). For 3 of these SNPs, we found significant interaction with smoking and asthma (rs12936231, rs2290400, and rs8079416). Smoking modified the associations between 8 SNPs and lung function (rs9911688, rs9900538, rs1054609, rs8076131, rs3902025, rs3859192, rs11540720, and rs11650680). We observed significant interaction between 5 SNPs and smoking on AHR, and 3 interacted with smoking in relation to asthma with AHR (rs4795404, rs4795408, rs3859192). CONCLUSION: We found 1 novel association and replicated several previously reported associations between 17q12-21 polymorphisms and asthma. We demonstrated significant interactions between active smoking and polymorphisms in 17q12-21 with asthma, lung function, and AHR in adults. Our data confirm that 17q12-21 is an important asthma susceptibility locus.

Understanding cough and its management in lung cancer.

PURPOSE OF REVIEW: This article summarizes the current understanding of cough in lung cancer, strategies for its management and highlights areas where further research is warranted.Cough is common, severe and distressing for many lung cancer patients. Currently few effective cough interventions exist for lung cancer patients. This review proposes some of the mechanisms that may underlie cough in lung cancer and presents the existing data on antitussive therapy in cancer patients. A greater focus on the cough mechanisms may enable effective antitussives to be developed in the future for lung cancer patients. A brief overview of the validated cough assessment tools is provided. The use of such tools will enable robust clinical endpoints to be determined for future cough intervention studies. A 'cough treatment pyramid' is presented to provide a pragmatic approach to the management of cough in lung cancer patients. RECENT FINDINGS: Despite the small number of publications on cough in lung cancer, some recent research has characterized cough for the first time in lung cancer patients. Its impact on quality of life domains such as psychological, social and physical is significant. The lung cancer symptom cluster of cough, breathlessness and fatigue has also been described. A recently developed cough severity assessment tool has provided researchers with a short well validated seven-item questionnaire to determine this important cough characteristic. In addition, a Cochrane Database Systematic Review on Interventions for Cough in Cancer has also been published. These studies are all described in the present review. Understanding the impact of a symptom such as cough, the assessment of cough and its potential underlying mechanisms is crucial if we are to manage this symptom effectively. SUMMARY: Current cough management in lung cancer patients is lagging behind the management of other cancer symptoms. There is now an increasing need to diagnose and treat cough more effectively, as lung cancer patients are living longer with chronic symptoms such as cough.

Quantification of atopy, lung function and airway hypersensitivity in adults.

BACKGROUND: Studies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR). OBJECTIVE: To determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK. METHODS: FEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5-breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population-based birth cohort enriched with 183 patients with physician-diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes. RESULTS: Spirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose-response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10-8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10-8, cat p = 3.93 × 10-10, dog p = 3.03 × 10-15, grass p = 2.95 × 10-9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT-3 mm>negative control). CONCLUSIONS: In the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR.

New insights in cough.

Chronic cough is common, blights patients' lives and is hard to treat. Chronic cough patients demonstrate high objective cough rates and as a group have increased cough reflex sensitivity. However, conventional cough challenge techniques show substantial overlap with normal subjects. This suggests that other important mechanisms have yet to be determined. For the last two decades, chronic cough has been considered to be caused by gastro-oesophageal reflux, post-nasal drip or asthma. However, many patients with these conditions do not have cough, and in those with cough, the response to specific treatments is unpredictable at best. In addition, many chronic cough patients do not have an identifiable cause. This raises questions about the concept of a triad of treatable causes for chronic cough. Our current understanding of the neurophysiology of the cough reflex is largely derived from animal work with limited data in humans. By analogy with chronic pain syndromes, both peripheral and central sensitization may be important mechanisms in chronic cough, and are under active investigation. We need to understand the mechanisms underlying sensitization, how they interact with cough triggers and their relationship with the sensations that drive the urge to cough, and the subsequent motor cough response in chronic cough. Only then will we develop effective interventions.