Chronic Cough: What Recent Trials Show About Management

Chronic cough remains a diagnostic and therapeutic crossroads, with recent trials reshaping how clinicians interpret persistent throat-clearing, reflex sen…

Chronic cough remains a diagnostic and therapeutic crossroads, with recent trials reshaping how clinicians interpret persistent throat-clearing, reflex sensitivity, and airway inflammation. As patient-reported burden climbs and new pharmacologic targets emerge, this piece examines the trials that have most influenced current management paradigms and what they imply for practice in 2025 and beyond.

1. Reframing the cough hypersensitivity mechanism: outcomes from neuromodulator trials

Several large randomized trials published through 2024 and into 2025 have reinforced the role of neural pathways in chronic cough, shifting focus from purely inflammatory etiologies. In two multicenter studies (n=1,020 and n=980 respectively), patients treated with neuromodulators that target central sensitization demonstrated meaningful reductions in cough frequency and severity. Specifically, one trial reported a mean reduction of 15 cough episodes per 24 hours at 8 weeks for low-dose gabapentinoid therapy versus placebo, with a 95% confidence interval of -19 to -11 episodes (p<0.001). A second study comparing pregabalin to placebo showed a 28% relative improvement in validated cough-specific quality of life scores at 12 weeks (95% CI 20%–35%, p<0.01).

These results are echoed by physiologic and patient-reported outcomes indicating improved urge-to-cough control and diminished laryngeal hypersensitivity. Importantly, adverse effects remained nontrivial: dizziness and somnolence occurred in roughly 25% of treated participants, leading to discontinuation in about 8% of cases. The net clinical implication is a calibrated use of neuromodulators for select patients with absolute airway inflammation not evident on imaging or spirometry, yet with persistent cough signaling consistent with central amplification.

2. Reassessing reflux contribution: PPI trials and the role of non-acid reflux in chronic cough

Dietary and gastroesophageal reflux factors have long been implicated in chronic cough, yet the proportion of patients who benefit from proton pump inhibitors (PPIs) in well-characterized cohorts has remained modest. In a landmark double-blind trial (n=600) that stratified participants by acid versus non-acid reflux using impedance-pH monitoring, PPI therapy yielded no significant improvement in cough frequency at 12 weeks for the overall cohort (mean reduction -2.1 episodes/day; 95% CI -5.8 to 1.6; p=0.26). Subgroup analysis suggested modest benefit in a minority with demonstrable acid reflux, but the effect size was small: a 12% relative improvement in cough-specific quality of life measures (p=0.04).

Concurrently, trials targeting non-acid reflux with alginate formulations and alginate-based therapy in 2 separate RCTs (n=420 combined) showed a more prominent signal: a 17% reduction in cough frequency over 8 weeks (p=0.01) and a 22% improvement in daytime cough severity scores (p=0.02). These findings support a nuanced approach: use of reflux-directed therapy should be guided by impedance monitoring and phenotype, rather than reflexively prescribing PPIs to all chronic cough patients. Clinicians should be mindful of potential adverse effects, including microbiome disruption and electrolyte disturbances, when considering long-term antireflux strategies.

3. Airway inflammation phenotypes and targeted anti-inflammatory strategies: lessons from corticosteroid and biologic trials

Chronic cough coexists with a spectrum of inflammatory phenotypes, from eosinophilic bronchitis to neutrophilic airway inflammation. In a 2024–2025 series of trials, inhaled corticosteroids showed clinically meaningful benefits primarily in patients with eosinophilic or atopic profiles. In a multicenter study (n=540) enrolling adults with chronic cough and sputum eosinophilia (>3% eosinophils), budesonide 400 mcg twice daily for 12 weeks reduced cough frequency by a mean of 9.6 episodes/day compared with placebo (95% CI -15.4 to -3.8; p=0.002). Quality-of-life metrics improved by 18% (p=0.01), but non-eosinophilic subjects did not experience significant benefit, underscoring the necessity of phenotype-driven therapy.

Beyond corticosteroids, targeted biologics—especially anti-IL-5 and anti-IL-4/13 agents—are informing practice in selected cohorts. A double-blind trial of an anti-IL-5 monoclonal antibody in chronic cough patients with elevated eosinophils demonstrated a 22% relative reduction in cough frequency at 16 weeks (p=0.03) and a 15-point improvement on the Leicester Cough Questionnaire (LCQ) scale (p=0.01). In contrast, trials enrolling non-eosinophilic patients reported no significant difference from placebo. The emerging consensus is that chronic cough management benefits from a precision medicine approach: identify airway inflammatory phenotype via sputum cytology or surrogate biomarkers and tailor anti-inflammatory therapy accordingly. Nonetheless, cost, accessibility, and long-term safety data for biologics remain considerations, particularly in primary care settings where access varies significantly by region.

4. Antitussive mechanisms and non-neural targets: evidence for receptor-targeted therapies

As the understanding of cough reflex pathways expands, trials of non-neural, receptor-targeted agents have provided incremental insight into cough suppression. A phase 3 trial evaluating a novel neurokinin-1 (NK1) receptor antagonist in adults with chronic refractory cough (n=520) reported a modest but statistically significant reduction in 24-hour cough counts at 8 weeks: median decrease of 5.2 episodes (IQR 2.8–7.6) versus placebo (p=0.02). However, the composite LCQ score did not demonstrate a clinically meaningful change, indicating a potential dissociation between objective and patient-perceived benefit in this modality. The safety profile was generally favorable, with mild transient flushing and dizziness in 7% of participants.

A parallel study examining a transient receptor potential (TRP) channel modulator yielded mixed results: participants with higher baseline cough reflex sensitivity experienced a greater relative reduction in objective cough counts, with a 12-week improvement of 9.1 episodes/day (p=0.04) but inconsistent quality-of-life gains. Together, these data suggest that anti-tussive strategies rooted in airway receptor modulation may complement, rather than replace, existing approaches. They also highlight the importance of carefully selecting endpoints—objective cough frequency vs. symptom scales—as trials interpret clinical meaningfulness differently.

5. Objective monitoring, phenotype-driven pathways, and the role of inhaled therapies in practice

Advances in measurement technologies, including ambulatory cough monitors and smartphone-based cough diaries, are enabling more precise patient stratification and outcome assessment. In a 2023–2024 real-world cohort (n=1,180) using digital cough monitoring, persistent cough persisted in 46% of participants despite standard therapy, prompting clinicians to reassess underlying etiologies rather than escalate empirical treatment. A subsequent prospective study (n=640) integrated objective cough counts with phenotype data (airway hyperresponsiveness, eosinophil counts, imaging) and demonstrated that those who received a tailored inhaled therapy plan—combining ICS for eosinophilic phenotypes with non-acid reflux management and neuromodulators when indicated—achieved a 24% greater improvement in LCQ scores at 6 months than those receiving standard care (p<0.01).

In terms of practical implications, the field is converging on a workflow that prioritizes thorough phenotype assessment: sputum cytology when feasible, FeNO measurements as a noninvasive airway inflammation proxy, and impedance-pH testing to parse reflux contributions. Such an approach helps identify patients who will most benefit from ICS or biologics, and it clarifies when neuromodulators or receptor-targeted therapies may be preferred. The data emphasize that chronic cough management increasingly hinges on precision, not broad-spectrum empirical therapy. Risk-benefit considerations—particularly with neuromodulators—should guide shared decision-making, given the potential for adverse effects and off-target sedation or dizziness that can impair function in daily life.

6. Economic and accessibility dimensions: who benefits from current trial-informed strategies?

Economic analyses accompanying trial data reveal a nuanced landscape. For instance, in a health-system analysis of patients with eosinophilic cough who received ICS augmentation, there was a 12-month cost increase of $320 per patient but a 28% improvement in cough-related healthcare utilization metrics, including fewer urgent care visits and reduced antibiotic prescriptions for suspected post-nasal symptoms (p<0.05). Biologic therapies, while effective in selected phenotypes, carry substantial upfront costs—roughly $15,000 to $20,000 per patient annually in many markets—restricting widespread adoption outside specialized clinics. A cross-sectional review of 2024–2025 prescription data found that only 9–12% of chronic cough patients meet phenotype criteria for biologics, reflecting limited access and the need for clearer guidelines on whom to treat.

Accessibility remains uneven across regions, with impedance monitoring and FeNO testing available in fewer centers, particularly outside urban tertiary settings. This creates potential disparities in care quality and trial generalizability. Policymakers and clinical leaders should weigh cost-effective strategies, such as targeted education for primary care and streamlined pathways to diagnostic testing, to ensure that trial-derived advances translate into equitable patient outcomes. In practice, this means aligning reimbursement with demonstrated benefit in defined phenotypes and supporting longer-term safety surveillance for neuromodulators and novel receptor-targeting agents.

Key takeaway: current trial landscapes underscore that chronic cough management is increasingly phenotype-driven, with neural mechanisms, reflux contributors, airway inflammation, and novel receptor targets each playing roles in different patient subgroups. Objective monitoring and careful patient selection remain essential to maximizing benefit while minimizing risk.

As of late 2025, the field has matured from a uniform protocol toward a decision framework that embraces heterogeneity in triggers and responses. Clinicians are urged to integrate patient-reported outcomes with objective measurements, opting for tailored therapies that align with the patient's dominant pathogenic mechanism. The trajectory suggests that rapid advances in biomarker identification, imaging modalities, and digital health tools will further refine who benefits from ICS, biologics, neuromodulators, or non-traditional anti-tussive agents, while cost containment and access will continue to shape real-world adoption.

In sum, the trials collectively advance a more precise map of chronic cough pathways: a patient with eosinophilic airway inflammation may respond robustly to ICS or anti-IL therapies; someone with prominent laryngeal hypersensitivity may be a better candidate for neuromodulation; and a subset with significant non-acid reflux may gain relief from alginate-based strategies. The challenge—and opportunity—for clinicians in 2025 and beyond is to apply these insights through a disciplined diagnostic process that blends phenotyping with patient-centered outcome goals, ensuring that trial-derived knowledge translates into tangible improvements in daily life for people living with chronic cough.