Unexplained chronic cough is a persistent cough that persists despite a thorough workup according to clinical guidelines. Refractory chronic cough is defined as a cough that has not resolved despite treatment for a known cause. A review of the literature suggests that up to 60% of adult patients with chronic cough have unexplained or refractory chronic cough. However, according to a rigorous systematic review, this percentage appears to be closer to 10% when patients are thoroughly evaluated and treated for the underlying etiology of their cough.
A review published in the March 27, 2025 issue of the New England Journal of Medicine (NEJM) explores the impact, neuroanatomy and physiology of unexplained or refractory chronic cough in adults, as well as the challenges and misconceptions faced during diagnosis and treatment.
Evidence-based guidelines describe chronic cough treatments that appear to effectively diagnose and treat the multiple underlying causes of chronic cough. However, the detailed and time-consuming protocols outlined in these guidelines challenge the fidelity of effective treatment in many cases. These challenges may contribute to simplified assessment, with some clinicians prematurely diagnosing “unexplained chronic cough” and “refractory chronic cough” in patients who have not yet been fully evaluated but who are thought to have a common clinical condition, namely cough hypersensitivity.
This concept of chronic cough centered on cough hypersensitivity has been very interesting and has driven many studies aimed at finding drugs that target neural signals of cough hypersensitivity. The first and most widely studied drug is the purinergic antagonist gefapixant. however, gefapixant has not been approved by the U.S. Food and Drug Administration (FDA) because it is only marginally more effective than placebo for unexplained or refractory chronic cough. Currently, clinicians have not found the effective medication they were hoping for. Therefore, it may be helpful to review the definition, diagnostic evaluation, and treatment options for chronic cough, especially unexplained or refractory chronic cough.
Effects of coughing
Unexplained or refractory coughs can have multiple important effects.
Vigorous coughing in healthy individuals generates high intrathoracic pressures (up to 300 mm Hg), velocities (up to 28,000 cm per second or >500 miles per hour [>800 km/hour]), and thoracic energies (up to 25 J), and thus coughing is an important defense mechanism that helps to clear excessive secretions and foreign bodies from the airway, and even maintain consciousness in the event of potentially lethal cardiac arrhythmia (i.e., cough CPR). These biophysical properties are also responsible for the spread of infection by cough, for a variety of psychosocial, functional and emotional complications (including fear of personal safety), and for causing extreme physical symptoms in any organ system, all of which may lead to a significant reduction in the patient’s quality of life and, in rare cases, even to death.
As a result of these adverse effects, cough has become a common symptom for which patients seek medical attention and for which they incur significant healthcare costs. In retrospective surveys of the general adult population in the United Kingdom, the prevalence of chronic cough ranged from 2% to 4.9%, and was higher in women than in men (57% vs. 43% in one analysis, and 58.2% vs. 41.8% in another); these results are similar to values reported in outpatient clinics. The impact and cost of cough has been recognized worldwide, and as of 2014, 12 countries have issued guidelines for the clinical management of cough. Although the prevalence of unexplained chronic cough has been widely reported, unexplained or refractory chronic cough accounted for the lowest proportion of patients with chronic cough, at 10.5% (382 of 3636 patients), in a systematic review of only papers with well-defined methodology and presumed adherence to specific clinical guidelines.
Sometimes，why do women seek medical attention for chronic cough more often than men?
There are two possible reasons for this: female chronic cough sufferers are more sensitive to the cough reflex to inhaled capsaicin and citric acid than men; and women’s health-related quality of life is more negatively affected than men’s because women are more prone to cough-induced physical symptoms, such as stress urinary incontinence, which can have psychosocial impacts such as embarrassment. Regardless of gender differences, chronic cough has a profound impact on quality of life that is similar to the impact of shortness of breath due to chronic obstructive pulmonary disease (COPD), which leads to disability.
Research Findings Treatment Considerations found beneficial treatment options in randomized placebo-controlled trials.
Multimodal Speech Therapy：
Two randomized controlled trials comparing multimodal speech therapy with healthy lifestyle recommendations in patients with uncontrolled or refractory chronic cough showed that multimodal speech therapy reduced cough-related symptoms more substantially and improved quality of life. According to the original results reported by Vertigan et al. in 2006, the therapy included instruction, cough suppressant techniques, and breathing exercises. The activation of the cerebral cortex, which is responsible for regulating subcortical and brainstem activity, after being stimulated by coughing may account for the success of this intervention, but the mechanism is unclear.
Drug Neuromodulation：
In randomized controlled trials, centrally acting neuromodulators (e.g., amitriptyline, gabapentin, morphine, baclofen, and nalbuphine) alone positively affected cough-related outcomes. In addition, a randomized placebo-controlled trial showed that when multimodal speech therapy was combined with the neuromodulator pregabalin, patients had favorable cough-related outcomes. These combinations may be considered if speech therapy alone is not effective. All neuromodulators acting centrally that are promising for trial have potential adverse effects. Therefore, the risks and benefits of medications should be discussed with the patient before treatment is initiated and reassessed and discussed again at regular intervals (e.g., monthly) before continuing treatment. In a recent population-based cohort study that included patients with COPD, the risk of severe exacerbation was 39% higher in patients treated with the gabapentin analogs gabapentin and pregabalin than in a matched group of patients who were not treated with these agents. Therefore, caution should be exercised when considering the use of these therapies in patients with COPD.
The evidence for the use of supraglottic nerve block therapy for the treatment of unexplained or refractory cough is very limited. Only one randomized trial suggested that 10 of 17 patients who received two nerve blocker injections had a significant improvement in cough-related quality of life after 27 days, compared with only 1 of 10 patients in the placebo group. Although no adverse events were reported during or after the trial, it was small, short-lived, and none of the patients completed multimodal cough-relieving speech therapy before or during the trial.
Coping with Reactive Anxiety and Depression：
Reactive anxiety, depression, or both can be a complication of unresolved chronic cough, and efforts should be made to cope with the condition if it exists. These cough-related complications will lessen as the cough improves.
antagonist：
For patients with truly unexplained or refractory chronic cough, effective antagonists of vagal signaling would be a good choice in the absence of serious adverse effects. Because unexplained or refractory cough may be caused by different mechanisms, multiple types of antagonists may be needed to effectively treat different subgroups of patients. Although antagonists of transient receptor potential cation channels (TRPV1 and TRPA1) on vagal C fibers have shown initial promise in animal models, such antagonists have not significantly reduced cough in clinical trials.
More recently, purinergic receptor (e.g., P2X3 and P2X2/3) antagonists (especially gefapixant) have offered promise. However, gefapixant causes severe taste disturbances, which may be related to P2X2/3 antagonism, and it is not approved by the FDA for the treatment of chronic cough because, at least in the study population, gefapixant had little effect compared with placebo. Other purinergic antagonists with varying selectivity for P2X3 and P2X2/3 receptors have also been studied or are under investigation, but none have yet been approved for clinical use. Safe and effective pharmacologic therapies remain an unmet need for patients with cough hypersensitivity, and the development of pharmacologic therapies would help to address the difficult clinical problems associated with unexplained or refractory chronic cough.
Chronic cough is an important clinical challenge worldwide. Although some literature reviews claim that up to 60% of adult patients with chronic cough suffer from unexplained or refractory cough, according to a rigorous systematic review, this percentage appears to be closer to 10% when patients are thoroughly evaluated and the underlying cause of the cough is treated.
In a minority of such patients, the unexplained or refractory cough may be due to an underlying psychological or psychiatric condition. For the remaining patients, i.e., those with truly unexplained or refractory cough due to prolonged cough hypersensitivity, treatment options are limited and include speech therapy, neuromodulatory medications, or both, as well as anxiety or depression treatment.
We hope that further research on purinergic antagonists or other inhibitors of neural signaling acting peripherally or centrally (e.g., sodium channel blockers, transient receptor potential cation channel subtype M8 agonists, opioids, neurokinin 1 antagonists, and γ-aminobutyric acid B agonists) will yield promising results, and that these medications will help us to deal with the clinical challenges posed by unexplained or refractory cough.
