Get expert insights into cough science, monitoring and research
“Inhaled medicines can treat cough-related conditions yet provoke cough themselves. Continuous measurement can help sponsors turn that tension into better product decisions.”
“Inhaled medicines can treat cough-related conditions yet provoke cough themselves. Continuous measurement can help sponsors turn that tension into better product decisions.”
Inhaled medicines can treat cough-related conditions yet provoke cough themselves. Continuous measurement can help sponsors turn that tension into better product decisions.
Inhalation therapy delivers medicine directly to the site of action. For some drugs this gives a quick effect [1,3], a high local concentration, and low systemic exposure when the medicine acts locally [3]. Inhalation can also deliver medicine systemically, as shown by inhaled insulin and other products [3].
Beyond asthma and chronic obstructive pulmonary disease (COPD), inhaled products now include anti-infectives, mucoactive agents, and pulmonary vasodilators. Biologics remain rare, with dornase alfa for cystic fibrosis the main approved example for a respiratory disease [3].
However, this route places a mechanical and chemical load on the airways, which can cause coughing. Airway sensory nerves can respond to particle impact, changes in pH or osmolality, delivered mass, irritant excipients, bronchoconstriction, and sensitivity caused by inflammation [1,2]. Therefore, inhaled medicines may provoke cough during or soon after administration [1,2]. An induced cough may interrupt inhalation, reduce the delivered dose, and contribute to poor adherence[2], especially in certain patient subgroups. Accurate post marketing data about the percentage of patients who discontinue inhaled therapies due to cough are not available nor are reliable information about what measures may mitigate post-inhalational cough.
This situation represents the double edge: while inhaled medicines may help patients with diseases associated with cough, their administration may induce cough. For drug developers, the question goes beyond whether cough occurs after inhalation. What matters is how soon it starts, how often it recurs, how long it lasts, whether it resolves on its own, and how it changes with repeated dosing.
There is no single incidence rate for cough across all inhaled medicines. The risk factors include active substance, nominal dose, formulation, salt form, excipients, aerosol output, aerodynamic particle size, inhaler, inspiratory maneuver, and airway disease [1,2]. In a review of product formulations, the rate of cough was less than 5% for many medicines with nominal doses below 1 mg and increased rapidly as nominal dose approached 100 mg [2]. This dose–incidence pattern is not the whole picture: local chemistry, deposition pattern, and patient susceptibility also matter.
Several studies show that changing the drug–delivery system can substantially alter post-inhalation cough. These studies differ in design and population, so the incidence rates below cannot be compared directly. Together, they suggest that post-inhalation cough is modifiable and can guide drug development.
| Comparison | Population / design | Cough-related finding | Development implication |
|---|---|---|---|
| Nebulized mannitol: 1.2 vs 6.5 micrometre aerosol [4] | Seven participants with idiopathic pulmonary fibrosis; matched target inhaled mass | No participant coughed during inhalation with 1.2 micrometre particles; 6 of 7 coughed with 6.5 micrometre particles | Deposition pattern and particle distribution can materially alter tolerability. This seven-participant result is not a universal particle-size rule. |
| Indacaterol maleate vs acetate [5] | Randomized, double-blind crossover study in 54 adults with asthma | Comparable lung function and systemic exposure; reported coughing was 23.5% with maleate and 0% with acetate | A formulation or salt change can preserve pharmacology while improving cough tolerability. |
These examples also reveal a common limitation: cough is frequently reported as the incidence of adverse events. This metric does not show whether cough occurred after each inhalation or only the first, or whether the patient experienced a single short cough or several consecutive coughing fits. Nor does it show whether cough happened within seconds or hours, or whether the cough burden changed with repeated dosing. These details may be more useful than incidence alone when choosing drug formulations and delivery devices.
Adverse event reporting systems in clinical trials are designed to capture adverse events, their severity, seriousness, relatedness, and outcomes. These measures matter, but a visit-based adverse event report cannot fully describe the cough patterns needed to compare drug candidates. For example, an entry such as “cough: yes” says little about post-inhalation cough.
Spontaneous reporting systems like the FDA Adverse Event Reporting System (FAERS) are designed to detect safety signals, not estimate incidence. They lack a reliable count of exposed patients and are vulnerable to under-reporting, bias, and missing information [9,10]. According to a systematic review, there is a median under-reporting of 94% in spontaneous reporting systems and not just in inhaled drugs or induced cough [9].
In a 2025 analysis of FAERS reports related to three categories of glucose lowering drugs between 2014 and 2023, the dates of events were present in about 50% of FAERS reports examined [11]. This finding does not describe completeness across all FAERS reports. These systems are useful for signal detection but cannot estimate incidence, time from dose to cough, or resolution of post-inhalation cough [9–11].
Patient-reported outcomes remain valuable even when they differ from objective cough counts. Validated scales measure perceived severity, distress, disruption to sleep, and impacts on quality of life, none of which can be deduced from cough counts alone. However, the correlation between objective cough frequency and patient experience was found to be weak to moderate [12–14]. The aim is to combine objective frequency and timing, patient experience, traditional adverse-event assessment, and clinical interpretation.
Continuous cough monitoring can serve as a valuable tool for two pharmaceutical use cases across the lifecycle of aerosolized or inhaled products.
At the stage of formulation and delivery device development, sponsors can compare dry powder, nebulized, metered-dose, or soft-mist delivery; particle-size distributions; salts; excipients; pH and tonicity; inspiratory flow instructions; dose levels; titration schedules; and pretreatment strategies. Once validated for the intended use, continuous monitoring can compare cough in individuals with similar pharmacokinetics or treatment effects. It can measure how often cough occurs, how soon it starts, how long it lasts, and how it changes with repeated dosing.
In phase 1 and early phase 2, this allows a clearer assessment of benefit and tolerability. Rather than use the vague term “mild, transient cough,” sponsors should measure cough frequency, duration, the incidence of episodes of severe coughing (bouts) and the proportion affected, alongside patient self-reports and clinical evaluations of severity and distress. This information can help sponsors choose an appropriate formulation before costs and complexity increase in late-stage development.
For an approved or late-stage drug, the focus switches from comparing candidates to epidemiology and mitigation. Continuous cough monitoring can characterize the real-world frequency of cough after use and whether the burden is concentrated at the start of treatment. It can also examine associations with technique, device handling, and persistent symptoms, and whether cough predicts missed doses, dissatisfaction, and discontinuation. Such evidence can help to develop patient education, inhaler training, titration strategy, labeling discussion, post-approval studies, and targeted support for vulnerable subgroups.
The predefined resolution analysis can measure how long participants take to return to their baseline cough range, and what percentage of episodes resolves without intervention after the dose. This requires linking cough times with dose times, observation periods, rescue medication use, and other interventions.
While a single 24-hour recording can be valuable, cough has day-to-day variability. In addition, recent evidence suggests that people cough differently on days in which obtrusive cough monitors are used[18]. Known as the “Hawthorne Effect”, this phenomena calls into question results obtained with such monitors. In a real-world smartphone study, 43 of 65 recruited participants completed monitoring. The study found that the median monitoring period was 13.9 days and the median adherence was 91% with high daily variability in cough [15]. In a 30-day study, there was also pronounced within-person variability; a single day might not predict long-term cough burden [16].
These studies involved persistent or chronic cough populations and were not designed to study inhalation-induced cough. They support monitoring over time rather than relying on isolated measurements.
A 2025 multicenter validation of the Hyfe CoughMonitor demonstrated good agreement between device-generated events and trained human annotations over 546 hours and 4,454 cough seconds from 23 analyzed participants (seconds containing at least one cough, not individual cough sounds). The system had overall sensitivity of 90.4%, 1.03 false positives per hour, and hourly cough rate correlation of 0.99 [17].
The direct evidence base for inhaled drug development is somewhat limited: only a few studies have used multiday continuous monitoring to characterize the cough caused by an inhaled drug after each dose. This distinction is important. Continuous cough monitoring has a methodological rationale and validation evidence, but this does not prove that it will reduce cough throughout the pharmaceutical lifecycle. Its immediate value is making the problem measurable enough to test, compare, and mitigate.
Pharmaceutical programs interested in continuous cough monitoring should define the measurement strategy before enrolling the first participant:
- Define the context of use: formulation screening, safety characterization, endpoint support, real-world evidence, or post-market mitigation.
- Define the cough measure in advance: for example, cough seconds, individual coughs, bouts, or hourly rate, and specify how clustered events are handled.
- Anchor analyses to verified dose times and prespecify post-dose windows, baseline periods, missing-data rules, intervention-free resolution criteria, and clinically relevant contrasts; link rescue medication and intervention records.
- Validate the system in the target population and use environment, including device placement, background sound, comorbidity, disease severity, and expected cough rate.
- Use objective measures with adverse-event assessment and validated patient-reported outcomes; cough frequency does not replace patient experience.
- Report both benefit and burden: wear time, adherence, false positives, missing data, participant acceptability, and any association between cough and treatment discontinuation.
Inhalation therapy will keep expanding because it delivers medicines efficiently to the lungs and, in certain cases, to the systemic circulation. Post-inhalation cough will be relevant across various drug classes. If measured and mitigated it is likely to be transient and manageablen but can interfere with administration, complicate the patient experience, and lead to discontinuation. Importantly for sponsors, cough burden can be modified by changing product characteristics.
The aim is not to replace the patient’s voice, safety signals, or clinical judgment, but to add a clearer picture of cough over time. By observing therapy over repeated doses, continuous cough monitoring can help sponsors distinguish an isolated side effect from an ongoing tolerability problem, compare candidates sooner, understand adaptation, and target support more effectively after approval.
The future of inhaled products is not automatically cough-free. When both the therapeutic effect and cough burden are measured carefully, the double-edged sword becomes a development problem that sponsors can study and address.
References
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18. Frankel M, Brew J, Ellis J, Shaw J, Small P, Batycky R. The Hawthorne effect of conspicuous short-term cough monitoring. Abstract submitted to the American Thoracic Society International Conference 2027.
