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Background: Refractory or unexplained chronic cough disrupts quality of life and burdens health care systems around the world. The P2X3 receptor antagonist gefapixant is approved in many countries for its antitussive effects, but taste disturbances are a common adverse effect. Four newer, more selective P2X3 receptor antagonists have been developed to address this problem., Research Question: How does the benefit-risk profile vary across the five available P2X3 receptor antagonists?, Study Design and Methods: A systematic review and network meta-analysis was conducted to evaluate the efficacy of P2X3 receptor antagonists, including gefapixant, sivopixant, eliapixant, camlipixant, and filapixant. Primary outcomes were a reduction rate in 24-hour cough frequency and incidence of taste disturbance. Dose-response curves and median effective dose (ED 50 ) were calculated. Effect size at ED 50 was ranked according to the surface under the cumulative ranking curve. The confidence was evaluated by Confidence In Network Meta-Analysis., Results: Sixteen randomized controlled trials involving 4,904 participants were analyzed. The gefapixant regimen demonstrated an ED 50 of 90.7 mg/d for cough frequency reduction. Gefapixant showed the highest antitussive effectiveness at ED 50 (reduction rate in 24-hour cough frequency: median, 28.1%; 95% credible interval [CrI], 21.0%-35.6%; ranked 1 of 5; moderate certainty) but the highest prevalence of taste disturbance (absolute risk difference per 100 patients: median, 38; 95% CrI, 27-51; ranked 5 of 5; high certainty) and the highest prevalence of discontinuation. Camlipixant had a well-balanced profile (reduction rate in 24-hour cough frequency: median, 14.7%; 95% CrI, 5.4%-26.0%; ranked 3 of 5; low certainty; and taste disturbance; absolute risk difference per 100 patients; median, 2; 95% CrI, 1-6; ranked 2 of 5; low certainty). Placebo had a mean of 33.1% reduction in 24-hour cough frequency., Interpretation: When used at safe doses, gefapixant had a favorable risk-benefit profile compared with the other four agents. Camlipixant showed initial promise, which may be further investigated by phase III trials currently underway., Clinical Trial Registration: University Hospital Medical Information Network Center (UMIN-CTR); No. UMIN000050622; URL: https://center6.umin.ac.jp., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: S. Y. has received overseas scholarships from the Japan Society for Promotion of Science. Y. K., Y. O., T. K., and H. M. received honoraria from Kyorin Pharmaceutical Co Ltd. A. N. received honoraria from Kyorin Pharmaceutical Co Ltd and MSD K.K. None declared (N. H., J. H., M. S., and Y. H.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in an open-label study in CRC patients with chronic refractory cough., Methods: Thirteen patients with daytime cough frequency >3 to <250 coughs/h took orvepitant 30 mg once daily for 4 weeks. Objective cough frequency was measured over 24 h at baseline and weeks 1, 4, and 8. The primary end point was change from Baseline in daytime cough frequency at week 4. Secondary end points included cough severity visual analog scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score., Results: All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 [38%] coughs/h [95% CI, 11.4-42.7; P = .001]) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 [29%] coughs/h [95% CI, 3.2-37.5; P = .020]). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated., Conclusions: Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation., Trial Registry: EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu., (Copyright © 2019. Published by Elsevier Inc.)

Background: Cough is common in patients with lung cancer, and current antitussive treatments are suboptimal. There are little published data describing cough in patients with lung cancer or work assessing clinical associations. The aim of this study is to fill that gap., Methods: This was a longitudinal prospective observational single-cohort study over 60 days. Patients were assessed through self-reported validated scales and, in a subsample, ambulatory cough monitoring at study entry (day 0), day 30, and day 60., Results: At study entry, 177 patients were included and 153 provided data at day 60. The median duration of cough was 52 weeks (interquartile range, 8.5-260). Cough was described as severe enough to warrant treatment in 62% of the patients. Depending on the scale used, performance status was associated with both cough severity and cough impact (P < .001) at study entry, whereas higher cough severity at study entry was associated with female sex (P = .02), asthma (P = .035), and reflux disease (P < .001). Cough impact at study entry was additionally associated with experiencing nausea (P = .018). Cancer characteristics (ie, cancer stage, histology) were not associated with cough severity nor cough impact; neither was smoking or COPD., Conclusions: This is the first study to describe characteristics of cough in patients with lung cancer and to identify clinical associations that may be relevant for its treatment. Our data suggest that cough is a frequent and distressing symptom and an unmet clinical need. Its association with gastrointestinal symptoms in this study may improve our understanding of pathophysiology and therapeutic options for cough occurring in patients with lung cancer., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Chronic cough is a significant problem, and in many patients cough remains refractive to both disease-specific therapies and current cough-suppressing medicines, creating a need for improved antitussive therapies. Most patients with chronic cough also display heightened sensitivity so that they experience a persistent sense of the need to cough, and often innocuous stimuli can trigger their coughing. This hypersensitivity underpins the newly described concept of cough hypersensitivity syndrome (CHS), a term that encapsulates the notion of common underlying mechanisms producing neuronal activation, sensitization and/or dysfunction, which are at the core of excessive coughing. Understanding these mechanisms has been a focus of recent research efforts in the field in the hope that new therapies can be developed to selectively target sensitized unproductive cough while maintaining the reflexive cough essential for airway protection. However, efforts to achieve this have been slower than expected, in part because of some significant challenges and limitations translating current cough models. In this review, we summarize recent advances in our understanding of the sensory circuits innervating the respiratory system that are important for cough, how cough sensory pathways become hypersensitive, and some of the recently described neural targets under development for treating chronic cough. We present the case that better use of current cough models or the development of new models, or both, is ultimately needed to advance our efforts to translate the discovery of basic cough mechanisms into effective medicines for treating patients with chronic cough., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Cough is produced by the same neuronal pool implicated in respiratory rhythm generation, and antitussive drugs acting at the central level, such as opioids, may depress ventilation. Levodropropizine is classified as a nonopioid peripherally acting antitussive drug that acts at the level of airway sensory nerves. However, the lack of a central action by levodropropizine remains to be fully established. We set out to compare the effects of levodropropizine and the opioid antitussive agent dihydrocodeine on the respiratory responses to a conventional CO 2 rebreathing test in patients with chronic cough of any origin., Methods: Twenty-four outpatients (aged 39-70 years) with chronic cough were studied. On separate runs, each patient was randomly administered 60 mg levodropropizine, 15 mg dihydrocodeine, or a matching placebo. Subsequently, patients breathed a mixture of 93% oxygen and 7% CO 2 for 5 min. Fractional end-tidal CO 2 (Fetco 2 ) and inspiratory minute ventilation (V˙i) were continuously monitored. Changes in breathing pattern variables were also assessed., Results: At variance with dihydrocodeine, levodropropizine and placebo did not affect respiratory responses to hypercapnia (P < .01). The ventilatory increases by hypercapnia were mainly accounted for by a rise in the volume components of the breathing pattern., Conclusions: The results are consistent with a peripheral action by levodropropizine; the assessment of ventilatory responses to CO 2 may represent a useful tool to investigate the central respiratory effects of antitussive agents., Trial Registry: European Union Clinical Trials Register (EudraCT No.: 2013-004735-68); URL: https://www.clinicaltrialsregister.eu/., (Copyright © 2017. Published by Elsevier Inc.)

Background: Since the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings., Methods: By following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel., Results: We recommend for adults, adolescents (≥ 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality-of-Life Questionnaire in adult and adolescent patients and the Parent Cough-Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges., Conclusions: Validated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough.

Background: Understanding the comparative effectiveness of treatments for patients with unexplained or refractory cough is important to increase awareness of proven therapies and their potential adverse effects in this unique population., Methods: We performed a literature search for English-language studies published up to June 2012 that compared symptomatic therapies for chronic cough. Two investigators screened each abstract and full-text article for inclusion, abstracted data, and rated quality. Meta-analysis with random-effects models was used to summarize effects of treatments., Results: We identified 49 studies (3,067 patients) comprising 68 therapeutic comparisons. Of the studied agents, opioid and certain nonopioid and nonanesthetic antitussives had demonstrated efficacy for chronic cough in adults. Compared with placebo, effect sizes (standardized mean differences for cough severity and rate ratios for cough frequency) for opioids were 0.55 (95% CI, 0.38-0.72; P &lt; .0001) and 0.57 (95% CI, 0.36-0.91; P = .0260), respectively. For dextromethorphan, effect sizes were 0.37 (95% CI, 0.19-0.56; P = .0008) and 0.40 (95% CI, 0.18-0.85; P = .0248), respectively. The overall strength of evidence was limited by inconsistency and imprecision of results and by small numbers of direct comparisons. Nonpharmacologic therapies and the management of cough in children were infrequently studied., Conclusions: Although evidence is limited, opioid and certain nonopioid and nonanesthetic antitussives demonstrated efficacy for treating chronic cough in adults. There is a need for further studies in patients with unexplained or refractory cough as well as for more systematic study designs, assessment of patient-centered outcomes, and reporting.

The US Food and Drug Administration (FDA) drug approval and over-the-counter drug monograph processes play an essential role in ensuring that all drugs are both safe and effective for their intended uses. Manufacturers of drugs that lack required approval have not provided the FDA with evidence demonstrating that their products are safe and effective. Some of these prescription drugs have been marketed for many years and have remained on the market despite changes to the Federal Food, Drug, and Cosmetic Act, which requires approval for safety and efficacy purposes. Many health-care providers may be unaware that unapproved drugs exist because the product labels of these drugs do not disclose that they lack FDA approval. The FDA recently took action against unapproved prescription oral cough, cold, and allergy drug products because of concerns about the potential risks of these products, particularly some extended-release formulations that have not been reviewed for quality. There is a potential for medication errors because product names and labeling have not been reviewed for potential confusion, with some products inappropriately labeled for use in children aged ≤ 2 years. FDA-approved prescription drugs or drugs appropriately marketed as over the counter remain available for treatment of cough, cold, and allergy symptoms. Such products are of known efficacy, safety, identity, quality, and purity. Removing unapproved drugs from the marketplace and encouraging manufacturers of unapproved products to seek FDA review and approval is a top priority for the FDA. Since the initiation of the Unapproved Drugs Initiative in 2006, the FDA has removed ~1,500 unapproved products from the market and has worked with firms to bring other unapproved drugs into the approval process. The FDA remains committed to its mission of ensuring that safe and effective drugs are available to American consumers.

The best available data support the hypothesis that there are at least two types of vagal nerves responsible for initiating coughing reflexes. One type of nerve conducts action potentials in the A-range and is characterized by rapidly adapting responses to mechanical probing or acidification of the large airway epithelium. Stimulation of these nerves can evoke cough in unconscious experimental animals and humans. These nerves are important in immediate cough evoked by aspiration and as such perform a critical role in airway defense. The other type of primary afferent nerve involved in cough is the vagal C-fiber. Inhalation of selective C-fiber stimulants leads to cough only in conscious animals. In clinical studies, inhalation of a low concentration of a C-fiber stimulant causes an irritating, itchy urge-to-cough sensation that mimics the urge-to-cough sensations associated with respiratory tract infection, post-infection, gastroesophageal reflux disorders, and inflammatory airway diseases. Here we discuss the recent advances in sensory neurobiology that allow for the targeting of vagal C-fibers for novel antitussive therapy. No attempts are made to be all-inclusive with respect to the numerous possible molecular targets being considered to accomplish this goal. Rather, two general strategies are discussed: decreasing generator potential amplitude and decreasing the efficiency by which a generator potential evokes action-potential discharge. For the first category we focus on two targets, transient receptor potential vanilloid 1 and transient receptor potential A1. For the latter category we focus on recent advances in voltage-gated sodium (Na(V)) channel biology.

Background: When the etiology of a patient's chronic cough is established, specific antitussive therapy that is aimed at a particular cause of cough is highly effective. Nevertheless, in certain situations, therapy with cough suppressants, which previously were classified as nonspecific antitussive therapy, and which aim at suppressing the cough reflex regardless of the cause of cough, will be necessary., Methodology: The data for this review were obtained with the aid of a National Library of Medicine (PubMed) search, which was performed in June 2004, of literature published in the English language from 1966 to 2004, using the search terms "cough," "antitussive," "pharmacotherapy," "future therapies, " and "potential therapies.", Results/conclusions: Currently available cough-suppressant therapy is severely limited by a dearth of effective agents and/or their unacceptable side effects. Several classes of pharmacologic agents are currently under investigation in an attempt to develop clinically useful cough suppressants.

Background: Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis., Methods: Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms "cough," "double-blind placebo-controlled," "antitussive," "mucolytic," "cough clearance," "common cold," "protussive," "guaifenesin," "glycerol," and "zinc.", Results: Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further., Conclusions: These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants.

Background: gamma-Aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in peripheral tissues, including the lung. The GABA-agonist baclofen has been shown, in animal studies, to inhibit cough via a central mechanism, but has not been investigated in humans (to our knowledge)., Study Objective: To evaluate the antitussive effect of baclofen in normal human subjects., Design: Randomized, double-blind, placebo-controlled study., Setting: Academic medical center., Participants: Twenty healthy, adult volunteers., Interventions: Subjects underwent cough challenge with inhaled capsaicin before and after a 14-day course of baclofen, 10 mg three times daily, or placebo. Capsaicin cough threshold (C5) was defined as the concentration of inhaled capsaicin inducing five or more coughs., Results: Subjects receiving baclofen (n=10) demonstrated a significant elevation of capsaicin cough threshold compared with placebo subjects (n=10). Mean delta log C5 after treatment was 0.48+/-0.19 (SEM) for the baclofen group, and -0.06+/-0.12 for the placebo group (p=0.024). Six of 10 subjects receiving baclofen, but none of the 10 subjects receiving placebo, demonstrated a fourfold or greater increase in capsaicin cough threshold (p=0.0054)., Conclusion: The antitussive activity of low-dose, oral baclofen demonstrated in this study supports further investigation of this drug, or other GABA-agonists, for a potential therapeutic role in the treatment of pathologic cough.

The efficacy of guaifenesin in reducing cough frequency in young adults with acute respiratory disease was evaluated by both an objective cough counting system and a questionnaire. A guaifenesin cough preparation and the syrup vehicle were administered in a double-blind manner. Coughs were recorded on tape over a 24-hour baseline evaluation period and a 36-hour treatment period for 42 patients. A pronounced diurnal variation in cough frequency was observed. The evaluation of efficacy was based upon comparisons between equivalent six-hour time periods of successive days. No antitussive effect of guaifenesin was demonstrated. The questionnaire was administered to 65 patients, including the 42 whose coughs were recorded. Of 26 patients with productive cough receiving guaifenesin, 25 (96 percent) reported a decrease in sputum thickness compared to 13 (54 percent) of 24 patients receiving the vehicle (p = 0.01, Fisher exact test). Twenty-three of 26 (88 percent) patients receiving guaifenesin also reported reduction in sputum quantity compared to 15 of 24 (62.5 percent) receiving the vehicle (p = 0.07, Fisher exact test). The diurnal variation in cough frequency measured by the tape recording was not apparent from the subjective cough frequency estimates obtained by the questionnaire.