Treatment Of Refractory Chronic Cough Research Articles

The Role of Bilateral Superior Laryngeal Nerve Block in Managing Refractory Chronic Cough.

The aim was to investigate the utilization and efficacy of bilateral superior laryngeal nerve block in patients with refractory chronic cough. A retrospective chart review of 164 patients with refractory chronic cough who underwent bilateral SLN block at a single institution between November 2018 and September 2022 was performed. Demographics, comorbidities, and patient-reported outcomes including pre- and postinjection Leicester Cough Questionnaire (LCQ) scores were collected and analyzed. The cohort underwent an average of 2.97 bilateral injections (range 1-22), containing either corticosteroid and local anesthetic or corticosteroid alone. Notably, 116 of 164 of patients reported an average of 67.3% reduction in their symptoms, with the treatment effect lasting 7.60 weeks on average. The average pre- and postinjection LCQ scores were 9.70 and 13.82, respectively. A lower LCQ score represents a greater impairment of health status due to cough, and the minimum important change is 1.3 points between questionnaires. The average improvement on LCQ following bilateral SLN block was 4.11 points for this cohort. The use of in-office bilateral SLN block is an effective treatment that can be used alone or in conjunction with oral medications for the treatment of refractory chronic cough. 4 Laryngoscope, 134:1773-1777, 2024.

Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

A randomized, double-blinded, placebo-controlled clinical trial of duloxetine hydrochloride enteric-coated tablets in the treatment of refractory chronic cough

IntroductionRefractory cough, a chronic cough with an unclear diagnosis or poor treatment response. The symptoms are often stubborn and persistent, causing serious complications and lowering the patient's quality of life. Cough hypersensitivity syndrome (CHS) is proposed as a potential cause, and reducing sensory nerve hyperresponsiveness is suggested as an effective treatment. However, current drugs have low efficacy and benefit rates and numerous side effects. This trail proposes using duloxetine, a selective 5-HT and norepinephrine reuptake inhibitor, as a potential treatment for refractory cough, which has shown promise in treating pain and depression. Duloxetine may inhibit pain conduction and oxidative stress in peripheral nerves by inhibiting the activity of TRPV1 channels, which play an important role in the peripheral afferent pathway of refractory cough. Meanwhile, the antidepressant effects of duloxetine may also play a role in the treatment of refractory cough.Methods and analysisThis is a single-center, prospective, randomized, double-blind, and controlled trial. A total of 98 individuals will be randomized in a 1:1 ratio to duloxetine group and placebo control group (starting with 20 mg QD, increasing 20 mg daily until 20 mg TID). After a screening period, the second stage runs from baseline to the 42nd (last) day of treatment, with follow-up visits on the 3rd, 7th, 14th, 21st, 28th, 35th, 42nd and 49th days. The main end-stage observation indicators include objective cough frequency, cough visual analog scale (VAS), cough symptom score, Leicester Cough Questionnaire (LCQ), and cough evaluation test (CET); the secondary end-stage observation indicators include capsaicin cough sensitivity, Patient Health Questionnaire-9 (PHQ-9), Major Depression Inventory (MDI), the Generalized Anxiety Disorder-7 scale (GAD-7), Life Events Scale (LES-32), induced sputum supernatant. The safety measures will be AEs/SAEs, vital signs, liver and kidney function, fecal occult blood test.DiscussionThis study is the first randomized, double-blind, and controlled clinical trial investigating the use of duloxetine in the treatment of refractory coughs. The study aims to provide a high-quality basis for evaluating the efficacy and safety of duloxetine for this condition.Trial registrationOur study was registered in the Chinese Clinical Trials Register (www.chictr.org.cn/) (ChiCTR2000037429) in 28/08/2020.

Efficacy and safety of pharmacotherapy for refractory or unexplained chronic cough: a systematic review and network meta-analysis

Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the optimal treatment for RCC remains controversial. This study aimed to investigate and compare the efficacy and safety of the current pharmacological therapeutic options for RCC. A systematic review was performed by searching PubMed, Web of Science, Embase, and Ovid databases from January 1, 2008 to March 1, 2023. All randomised control trials (RCTs) reporting outcomes of efficacy or/and safety were included in the Bayesian network meta-analysis. Here, we compared the effects on Leicester Cough Questionnaire (LCQ), Visual Analogue Scale (VAS), and objective cough frequency of patients with RCC. Besides, we also compared the incidence of adverse events (AEs) for analysis of safety. PROSPERO registration: CRD42022345940. 19 eligible RCTs included 3326 patients and 7 medication categories: P2X3 antagonist, GABA modulator, Transient Receptor Potential (TRP) modulator, NK-1 agonist, opioid analgesic, macrolide, and sodium cromoglicate. Compared with placebo, mean difference (MD) of LCQ and 24 h cough frequency for P2X3 antagonist relief were 1.637 (95% CI: 0.887-2.387) and-11.042 (P=0.035). Compared with placebo, effect sizes (MD for LCQ and cough severity VAS) for GABA modulator were 1.347 (P=0.003) and-7.843 (P=0.003). In the network meta-analysis, gefapixant is the most effective treatment for patients with RCC (The Surface Under the Cumulative Ranking Curves (SUCRA) is 0.711 in LCQ, 0.983 in 24 h cough frequency, and 0.786 in cough severity VAS). Lesogaberan had better efficacy than placebo (SUCRA: 0.632 vs. 0.472) in 24 h cough frequency. Eliapixant and lesogaberan had better efficacy than placebo in cough severity VAS. However, TRP modulator had worse efficacy than placebo. In the meta-analysis of AEs, the present study found P2X3 antagonist had a significant correlation to AEs (RR: 1.129, 95% CI: 1.012-1.259), especially taste-related AEs (RR: 6.216, P<0.05). In this network meta-analysis, P2X3 antagonist showing advantages in terms of efficacy is currently the most promising medication for treatment of RCC. GABA modulator also showed potential efficacy for RCC but with AEs of the central system. Nevertheless, the role of TRP modulator needed to be revisited. Further research is needed to determine the potential beneficiary population for optimizing the pharmacological management of chronic cough. National Natural Science Foundation of China (81870079), Guangdong Science and Technology Project (2021A050520012), Incubation Program of National Science Foundation for Distinguished Young Scholars (GMU2020-207).

PRIOR SPECIALIST CONSULTATIONS AND TREATMENTS IN A REFRACTORY CHRONIC COUGH POPULATION ENROLLED IN A PHASE 2B STUDY OF THE P2X3 ANTAGONIST BLU-5937

PRIOR SPECIALIST CONSULTATIONS AND TREATMENTS IN A REFRACTORY CHRONIC COUGH POPULATION ENROLLED IN A PHASE 2B STUDY OF THE P2X3 ANTAGONIST BLU-5937

Gefapixant: First Approval.

Gefapixant (Lyfnua®; Merck & Co.) is a first-in-class, non-narcotic, selective P2X3 receptor antagonist being developed for the treatment of refractory chronic cough or unexplained chronic cough. Marketing approval for gefapixant is being sought in the EU and USA, and the drug was recently approved for marketing in Japan as treatment for refractory or unexplained chronic cough. This article summarizes the milestones in the development of gefapixant leading to this first approval.

Chronic cough in China: progress and perspectives

Great progress has been made in regard of mechanism, etiological diagnosis and treatment of chronic cough since the beginning of the 20th century, and Chinese guidelines of diagnosis, management of cough was developed. Moreover, Chinese experts also participated in the formulation of international cough guidelines. Through the promotion of the guidelines, the level of diagnosis and treatment of chronic cough has been significantly improved in China. In the future, we should strengthen the studies on the epidemiology of chronic cough, the central regulation of chronic cough, and the treatment of refractory chronic cough, and promote the cough guidelines in primary community hospitals.

P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough

Gefapixant/AF-219, a selective inhibitor of the P2X3 receptor, is the first new drug other than dextromethorphan to be approved for the treatment of refractory chronic cough (RCC) in nearly 60 years. To date, seven P2X subtypes (P2X1-7) activated by extracellular ATP have been cloned, and subtype selectivity of P2X inhibitors is a prerequisite for reducing side effects. We previously identified the site and mechanism of action of Gefapixant/AF-219 on the P2X3 receptor, which occupies a pocket consisting of the left flipper (LF) and lower body (LB) domains. However, the mechanism by which AF-219 selectively acts on the P2X3 receptor is unknown. Here, we combined mutagenesis, chimera construction, molecular simulations, covalent occupation and chemical synthesis, and find that the negative allosteric site of AF-219 at P2X3 is also present in other P2X subtypes, at least for P2X1, P2X2 and P2X4. By constructing each chimera of AF-219 sensitive P2X3 and insensitive P2X2 subtypes, the insensitive P2X2 subtype was made to acquire the inhibitory properties of AF-219 and AF-353, an analog of AF-219 with higher affinity. Our results suggest that the selectivity of AF-219/AF-353 for P2X3 over the other P2X subtypes is determined by a combination of the accessibility of P2X3 binding site and the internal shape of this pocket, a finding that could provide new perspectives for drug design against P2X3-mediated diseases such as RCC, idiopathicpulmonaryfibrosis, hypertension and overactive bladder disorder.

The discovery and development of gefapixant.

Gefapixant is the approved generic name for a compound also known as MK-7264, and prior to that AF-219 and RO-4926219. It is the first-in-class clinically developed antagonist for the P2X3 subtype of trimeric ionotropic purinergic receptors, a family of ATP-gated excitatory ion channels, showing nanomolar potency for the human P2X3 homotrimeric channel and essentially no activity at related channels devoid of P2X3 subunits. As the first P2X3 antagonist to have progressed into clinical studies it has now progressed to the point of successful completion of Phase 3 investigations for the treatment of cough, and the NDA application is under review with US FDA for treatment of refractory chronic cough or unexplained chronic cough. The molecule was discovered in the laboratories of Roche Pharmaceuticals in Palo Alto, California, but clinical development then continued with the formation of Afferent Pharmaceuticals for the purpose of identifying the optimal therapeutic indication for this novel mechanism and establishing a clinical plan for development in the optimal patient populations selected. Geoff Burnstock was a close collaborator and advisor to the P2X3 program for close to two decades of discovery and development. Progression of gefapixant through later stage clinical studies has been conducted by the research laboratories of Merck & Co., Inc., Kenilworth, NJ, USA (MRL; following acquisition of Afferent in 2016), who may commercialize the product once authorization has been granted by regulatory authorities.

Presentation of the Therapy Program for Management of Chronic Cough.

To present a proposal for speech-language pathology rehabilitation called the Therapy Program for Management of Chronic Cough (TMCC) for the treatment of refractory chronic cough. TMCC was developed based on two stages: literature and clinical analysis. The literature analysis stage was carried out through the following procedures: electronic and manual search for articles and books published until June 2019 that included adult participants with chronic cough and intervention with speech-language pathology therapy; selection of sources; analysis of articles and books included; and, preparation of the initial version of the therapy program. The initial version of the therapy program resulting from literature analysis stage was submitted to clinical analysis stage through the following procedures: analysis by three judges; revision of the proposal by the authors; judges' re-analysis; elaboration of the final version called the Therapy Program for Management of Chronic Cough (TMCC). TMCC synthesizes scientific knowledge and current clinical experience on the behavioral management of refractory chronic cough into a program with three main components, each one with specific objectives and strategies. TMCC consists of four sessions, with weekly frequency and duration between 30-45 minutes per session, executed in hierarchical phases, with specific objectives and strategies per session. TMCC is a program structured to offer global cough rehabilitation. To obtain scientific evidence about its effectiveness is necessary, so that it can be used in clinical practice.

Advances in the treatment of refractory chronic cough with specific neuromodulators

本文综述特异性神经调节剂（加巴喷丁、普瑞巴林、阿米替林、巴氯芬）用于难治性慢性咳嗽的研究进展，为临床合理使用此类药物提供循证依据。基于目前的研究结果表明，特异性神经调节剂可改善难治性慢性咳嗽患者的咳嗽症状，不良反应为头晕、疲劳、头痛等，多可耐受，但未来还需高质量的研究进一步探索其最佳剂量、疗程及长期的治疗效果和安全性。.

The role of ATP in cough hypersensitivity syndrome: new targets for treatment.

Clinically, chronic cough can be effectively controlled in most patients by etiological treatment; however, there remain a small number of patients whose cough has unidentifiable etiology or where treatment efficacy is poor following etiology identification, whose condition is described as unexplained chronic cough or refractory chronic cough. Patients with refractory chronic or unexplained chronic cough commonly have increased cough reflex sensitivity, which has been described as cough hypersensitivity syndrome. The adenosine triphosphate (ATP)-gated P2X3 receptor may be a key link in the activation of sensory neurons that regulate cough reflexes and has recently draw attention as a potential target for the treatment of refractory chronic cough, with a number of clinical studies validating the therapeutic effects of P2X3 receptor antagonists in patients with this condition. As the energy source for various cells in vivo, ATP localizes within cells under normal physiological conditions, and has physiological functions, including in metabolism; however, under some pathological circumstances, ATP can act as a neuromodulator and is released into the extracellular space in large quantities as a signal transduction molecule. In addition, ATP is involved in regulation of airway inflammation and the cough reflex. Here, we review the generation, release, and regulation of ATP during airway inflammation and its role in the etiology of cough hypersensitivity syndrome, including the potential underlying mechanism.

Gefapixant in two randomised dose-escalation studies in chronic cough.

Gefapixant has previously demonstrated efficacy in the treatment of refractory chronic cough at a high daily dose. The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose-escalation approach. Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50-200 mg, study 2: 7.5-50 mg) or placebo for 16 days, then crossed-over after washout. The primary end-point was awake cough frequency assessed using a 24-h ambulatory cough monitor at baseline and on day 4 of each dose. Patient-reported outcomes included a cough severity visual analogue scale and the cough severity diary. In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg. P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Studies of longer duration are warranted.

Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough .

Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4hours apart during three study periods. Patients were monitored for cough for 8hours post-first dose using the VitaloJAK, ambulatory cough monitor. In parts B and C, patients underwent full dose-response cough challenges with capsaicin and citric acid respectively following single doses of randomly assigned GSK2339345 or placebo (4 study days). Part A was analyzed using a mixed effects model and parts B and C using population non-linear mixed effects models. Of 16 enrolled patients, 11 completed the study. 8-hour cough counts increased following GSK2339345 treatment compared with placebo (GSK2339345/placebo ratio of adjusted geometric means: 1.26 (90% credible interval 1.10, 1.44), associated with GSK2339345-evoked coughing, recorded during the 2 minutes post-dose. This was not observed with placebo. The effect of GSK2339345 on cough responses during cough challenges was inconclusive. GSK2339345 was well tolerated. While these data could not determine if GSK2339345 reached the target VGSC, they strongly suggest that GSK2339345 has no anti-tussive effect despite reaching airway sensory nerves as evidenced by the evoked transient cough. .

Bilateral Thyroarytenoid Botulinum Toxin Type A Injection for the Treatment of Refractory Chronic Cough.

Refractory chronic cough is a debilitating condition with limited therapeutic options. Laryngeal botulinum toxin type A (BtxA) has been anecdotally reported to benefit patients with chronic cough. We report on our experience with the use of BtxA for the treatment of patients with refractory chronic cough. To describe the effects of electromyography (EMG)-guided thyroarytenoid (TA) BtxA injection for the treatment of refractory chronic cough. For this single tertiary referral center retrospective case series, we included all patients with refractory chronic cough who received bilateral EMG-guided TA BtxA injections (n = 22) between July 1, 2013, and July 31, 2014, at the Mayo Clinic in Rochester, Minnesota. Bilateral TA BtxA injection. The primary outcome is a self-reported improvement of 50% or more in cough severity and/or symptoms by a 2-month follow-up telephone call. Adverse events and patient-reported quality measures were also assessed. A total of 22 patients (median [interquartile range] age 61 [57.5-85] years; 19 of 22 women) underwent 31 distinct laryngeal BtxA treatment sessions. The primary outcome of self-reported improvement of 50% or more of cough severity and/or symptoms was achieved in 16 of 31 (52%) treatment sessions. Eleven patients (50%) reported greater than 50% improvement after the first BtxA injection. No major complications occurred. Postprocedural liquid dysphagia had a positive predictive value of 84% and negative predictive value of 100% for response to therapy. In this case series, laryngeal BtxA injection was well tolerated in patients with refractory chronic cough with half of participants experiencing at least short-term improvement in their cough. The occurrence of liquid dysphagia after a BtxA injection appeared to be predictive of a beneficial response. The durability of response, patient selection criteria, and optimal BtxA dosage remains to be determined.

Recent additions in the treatment of cough.

Worldwide, cough is regarded as a challenging clinical problem due to its frequency and often limited therapeutic options. Chronic cough that remains refractory to usual medical treatment causes significant quality of life impairment in people with this problem. We have examined current evidence on recent additions in the treatment of cough, specifically treatment of refractory chronic cough with speech pathology and gabapentin. Relevant randomised control trials, reviews and case reports were identified through a PubMed and SCOPUS search of English-language literature referring to these concepts over the last eight years. Of the one hundred and two articles comprising this review the majority investigated the role of the transient receptor potential (TRP) receptors TRP Vanilloid 1 (TRPV1) and TRPA1 in cough and the potential of TRP antagonists as effective anti-tussives. However, these have only been tested in the laboratory and therefore their clinical effectiveness is unknown. Behavioural treatments such as speech pathology have gained momentum and this was evident in the increasing number of articles investigating its positive effect on cough. Investigation on the effectiveness of neuromodulating medications in the treatment of cough have been supported primarily through case series reports and prospective reviews however; their use (particularly gabapentin) has been significantly advanced through recently conducted randomised controlled trials. Recent additions in the treatment of chronic cough have been significant as they consider cough to have a unifying diagnosis of cough hypersensitivity with or without the presence of a neuropathic basis. Primarily, effective treatments for chronic cough target these areas and include behavioural treatment such as speech pathology and pharmaceutical treatment with neuromodulating medications such as gabapentin.

Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial

Refractory chronic cough causes substantial symptoms and quality-of-life impairment. Similarities between central reflex sensitisation in refractory chronic cough and neuropathic pain suggest that neuromodulators such as gabapentin might be effective for refractory chronic cough. We established the efficacy of gabapentin in patients with refractory chronic cough. This randomised, double-blind, placebo-controlled trial was undertaken at an outpatient clinic in Australia. Adults with refractory chronic cough (>8 weeks' duration) without active respiratory disease or infection were randomly assigned to receive gabapentin (maximum tolerable daily dose of 1800 mg) or matching placebo for 10 weeks. Block randomisation was done with randomisation generator software, stratified by sex. Patients and investigators were masked to assigned treatment. The primary endpoint was change in cough-specific quality of life (Leicester cough questionnaire [LCQ] score) from baseline to 8 weeks of treatment, analysed by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000248369. 62 patients were randomly assigned to gabepentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in LCQ score during treatment period 1·80, 95% CI 0·56-3·04; p=0·004; number needed to treat of 3·58). Side-effects occurred in ten patients (31%) given gabapentin (the most common being nausea and fatigue) and three (10%) given placebo. The treatment of refractory chronic cough with gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough. National Health and Medical Research Council of Australia and Hunter Medical Research Institute, Newcastle, Australia.

Gabapentin: a suppressant for refractory chronic cough

In The Lancet, Nicole Ryan and colleagues 1 Ryan NM Birring SS Gibson PG Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012; (published online Aug 28.)http://dx.doi.org/10.1016/S0140-6736(12)60776-4 Google Scholar report on a placebo-controlled, double-blind trial of the effects of gabapentin—a drug used for epilepsy and neuropathic pain—on quality of life, cough frequency, and cough severity in people with chronic cough. This report does more than address the effectiveness of this cough suppressant—it emphasises that refractory chronic cough is an increasing clinical problem that is difficult to control even with the best available management. 2 Chung KF Pavord ID Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008; 371: 1364-1374 Summary Full Text Full Text PDF PubMed Scopus (450) Google Scholar This study is also one of the few that have used newly validated measures of cough, including cough-specific quality-of-life measures, cough severity, and cough counts to assess treatment effects. The findings provide hope for patients with chronic cough, a disorder that, although non-life-threatening, can be both psychologically and physically disabling, and is not helped by the ineffectiveness of available antitussives. 3 Pavord ID Chung KF Management of chronic cough. Lancet. 2008; 371: 1375-1384 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar The results also suggest that central sensitisation is the potential mechanism underlying cough persistence, which adds to growing support for a new classification termed chronic cough hypersensitivity syndrome. 4 Chung KF Chronic “cough hypersensitivity syndrome”: a more precise label for chronic cough. Pulm Pharmacol Ther. 2011; 24: 267-271 Crossref PubMed Scopus (122) Google Scholar Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trialThe treatment of refractory chronic cough with gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough. Full-Text PDF