Hacking the vagal system to treat chronic cough

For a person with a lingering cough, the local pharmacy would seem to promise relief. There, shelves burgeon with a colourful variety of cough syrups, lozenges, tablets and capsules. Indeed, in the UK, people spend almost £500m annually on over-the-counter (OTC) products for cough and cold relief.

But the variety and expense belies an uncomfortable reality: by and large, these medicines fail to ease a chronic cough.

“These OTC medicines have limited value,” says Anna Murphy, a consultant respiratory pharmacist at the University Hospitals of Leicester NHS Trust.

Chronic cough is usually dry or minimally productive, lasts for at least eight weeks (often much longer) and predominantly affects middle-aged females​[1]​.

Prescription medicines, such as gabapentin and low-dose morphine, can offer relief for some but come with a risk of drowsiness or dizziness.

Yet, chronic cough affects between 5% and 15% of people in the UK, placing a huge burden on the healthcare system, not to mention the exhausted and distressed sufferers​[2,3]​.

“Chronic cough is a very common problem. It is debilitating and profoundly affects quality of life,” says Surinder Birring, a respiratory medicine specialist at King’s College Hospital. “There is a great need to develop drugs that are specifically blocking cough, without the troublesome side effects.”

In the past decade, however, a new view of chronic cough has invigorated clinical trials. This perspective casts the condition as a neural problem, rather than a respiratory one, proposing that chronic cough stems from hypersensitive vagal nerves in the airway, which trigger the cough reflex at the slightest provocation.

New therapeutic approaches to target this hypersensitivity are in the works but, in the meantime, pharmacists have an essential role to play in managing cough for their patients, with recognition of chronic cough as a condition an important first step.

Hacking a cough

Cough serves an important purpose in expelling dust, bacteria and anything else that should not be in the airways. But when cough sticks around for no apparent reason, it can drastically change a person’s life. Some coughing is so intense that it can provoke urinary incontinence, interrupted sleep, retching, blackouts or chest pain, along with the obvious social difficulties that contribute to decreased quality of life​[4]​.

Although COVID-19 has not caused an uptick in chronic cough, the pandemic certainly made life difficult for people with the condition. “They were very embarrassed when others were unkind to them when they coughed in public,” Birring says.

Current cough treatments target a variety of physiological systems: some centre on the respiratory system, with medicines to help expel mucus; antitussives act in the brain to suppress its cough-generating circuitry; bronchodilators open the airways; and proton pump inhibitors act in the stomach to ease cough that results from gastroesophageal reflux disease. A recent clinical statement on chronic cough issued by the British Thoracic Society endorses a systematic approach to chronic cough to find the treatable traits in each patient​[1]​.

The new perspective on chronic cough offers up a different target in the peripheral nervous system — specifically, a hypersensitivity in the vagal sensory neurons innervating the airway epithelium. This accounts for why people with chronic cough report coughing in response to innocuous stimuli, such as the movement of air that comes with talking, or eating spicy food and report sensations in the back of the throat, such as a persistent tickle.

“It doesn’t really matter what the underlying disease is, whether it be asthma, or COPD, or pulmonary fibrosis, or whatever the disease pathology is — at the heart of the problem with cough is that it’s a neural hypersensitivity,” says Stuart Mazzone, a neuroscientist at the University of Melbourne. Mazzone and colleagues study the neural pathways involved in cough.

“In a lot of people, cough is not resolved, even if their disease is well managed. So, cough may well be a parallel problem with its own disease pathology,” Mazzone says.

Within the airway, vagal neurons sense an array of stimuli, such as pressure, cold or chemicals. Normally, if these sensory neurons detect a foreign object or unwanted chemical, such as smoke, in the airway, they send signals to the cough-generating circuitry in the brainstem, which provokes a cough to expel these contaminants (see Figure). Although it is a reflex, coughing is also under some voluntary control, which reflects the input of higher brain regions too.

But with vagal hypersensitivity, something has gone awry — either peripherally, centrally, or both — to put the cough system on a hair trigger. As a result, the vagal sensory neurons become overreactive and voluntary cough suppression is not in working order. Mazzone and colleagues have found that people with chronic cough cannot muster the same brain activation patterns to suppress a cough as people without the condition​[5]​.

Treating the hypersensitivity could simplify chronic cough treatment.

“We are looking for drugs that target the peripheral nerves to modulate that hypersensitivity,” he adds. “If we get it right, then these drugs are going to be useful across a whole range of different conditions.”

Lessons from gefapixant

Aiming to calm vagal nerve hypersensitivity, researchers at Merck Sharp & Dohme have developed gefapixant, which blocks the P2X3 type of purinergic receptors that bind adenosine triphosphate (ATP). ATP is released by airway mucosal cells when they are inflamed or injured; thus, interrupting ATP’s interaction at vagal nerve terminals could quell cough hypersensitivity. Results from two global phase III trials of gefapixant (COUGH-1 and COUGH-2) in 2022 showed a significant reduction of cough frequency in people taking a 45mg tablet twice per day: an 18.5% reduction compared with placebo at 12 weeks in the COUGH-1 study and a 14.6% reduction compared with placebo at 24 weeks in COUGH-2​[6]​.

Although the drug is safe, more than half of participants taking gefapixant experienced taste disturbance side effects. This may be owing to its additional affinity for blocking P2X2 receptors, which are located on taste buds.

Since publication of the trial results, gefapixant has been on a regulatory rollercoaster. In 2023, it received approvals in the EU and the UK, and it is available in Switzerland and Japan. But the drug was rejected — twice — by the US Food and Drug Administration (FDA), even after reanalysis of trial data.

The FDA was not convinced that gefapixant provides patients with a clinically meaningful benefit. Its reanalysis of the trial data found that gefapixant differed from placebo by only one to two coughs per hour​[7]​. This highlights uncertainty in the field about the best cough endpoints in trials, the disconnect between cough frequency and patient-reported outcomes and large placebo responses in trials.

One issue is the day-to-day variability in coughing. The COUGH trials measured cough frequency over a 24-hour period, using a semi-automated cough monitor. Given the episodic nature of cough, this provides only a snapshot of coughing, and would not differentiate an intense coughing bout from mild, interspersed coughs.

“It’s like looking at 24 hours-worth of ECG and then missing the 50 seconds of ventricular fibrillation that killed the patient,” says Alyn Morice, a respiratory medicine specialist at the University of Hull, who was involved in the COUGH trials.

Others note that the slim effect size over placebo in these trials may reflect a heterogeneous patient population; that is, some may have chronic cough stemming from hypersensitivity mechanisms besides overactive P2X3 receptors.

Despite the uncertainty, experts think the gefapixant results are important.

“The bottom line is, despite a large placebo effect, gefapixant was still significantly superior at reducing coughs and improving quality of life,” says Birring, who was also involved in the COUGH trials.

While Merck Sharp & Dohme mulls its options, including whether to try to market gefapixant in the UK, others have taken note of gefapixant’s travails. GSK has its own P2X3 receptor blocker, camlipixant, which is now in phase III clinical trials; these are expected to finish in 2025. GSK is taking care to enrol people with high cough frequencies, with the idea that they may reflect a more homogeneous group.

“We are working to identify the population of patients who would most benefit,” says David Lipson, clinical research head of respiratory diseases at GSK.

Other prospects

Beyond P2X3 receptors, other receptors found on vagal nerve terminals make for promising chronic cough drug targets. Among these are transient receptor potential (TRP) channels. One type, TRPM8 receptors, mediate cold sensations, including those from menthol. AX-8, a TRPM8 agonist, has been developed by pharmaceutical company Axalbion, which reported positive results for chronic cough in a proof-of-concept trial in 2023 and is now in a phase II clinical trial.

Another type of TRP receptor, TRPA1 — also known as the wasabi receptor — senses noxious and mechanical chemical stimuli. Biotech company Genentech has developed a small molecule TRPA1 antagonist called GDC-6599, which is now in a phase IIa study for chronic cough​[8]​.

Beyond these drugs targeting cough hypersensitivity, others are in the works. Extended-release nalbuphine is an opioid similar to other antitussives, but it acts predominantly on the kappa-opioid receptor, with the idea that it can suppress cough without the worrying abuse potential. In a phase II trial, nalbuphine tablets showed a 75% reduction in cough frequency in people with idiopathic pulmonary fibrosis, and a phase II study is underway for chronic cough​[9]​.

Non-pharmacological approaches may also be of help. Speech and language therapy teaches techniques of cough control and has had some success for chronic cough in two clinical studies​[10,11]​.

“[This type of therapy] is really focused on retraining those voluntary suppression networks that don’t seem to be operational in chronic cough,” Mazzone says.

The variety of treatments under study reflects the potentially diverse aetiologies of chronic cough. For example, one person’s chronic cough may rely on P2X3 receptors, whereas another’s may be owing to TRPM8 receptors. To help identify subgroups who may be more responsive to these different therapies, a registry of phenotyped chronic cough patients has been established by the European collaboration NEurOCOUGH​[12]​. The registry, which started in 2018, has enrolled more than 1,000 patients so far.

The consortium also seeks to establish primary chronic cough as a disease entity in and of itself, with an International Classification of Diseases code recognised by the World Health Organization. This would help remedy the research and clinical neglect of chronic cough and convince funding agencies to pay for medicines.

“NEurOCOUGH is also about spreading the word and educating people about chronic cough,” Morice says. “People come with an enormous scepticism about cough being a new disease.”

Frontline pharmacists

In the meantime, pharmacists today can do a lot with current treatments to help people manage their chronic coughs.

Community pharmacists are often the first to hear about a patient’s chronic cough, or to notice that their regular customers are consistently reaching for OTC cough medicine. Importantly, if pharmacists hear about red-flag symptoms, such as coughing blood, weight loss or night sweats, they can urge the person to contact a doctor right away.

“There’s a lot of misunderstanding around managing cough,” says Murphy. “I think, sometimes, we don’t take it seriously enough and are probably not doing a full enough assessment of these patients at the outset.”

Murphy says she follows a mental checklist to systematically evaluate patients who come to her with chronic cough. This includes asking about smoking, as well as any medicines a patient may be taking, such as angiotensin-converting enzyme inhibitors that are known to provoke cough. For situations in which a person is already taking a medicine, such as inhalers for asthma or COPD, Murphy says she would confirm that the patient is taking the medicine consistently, and with optimal inhaler technique. Similarly, for coughs owing to postnasal drip, she would check to be sure the patient is using prescribed nasal sprays correctly.

“A lot can be done by making sure that the treatments we have got are being used effectively,” she says.

Chronic cough can also stem from gastroesophageal reflux, if repeated exposure of the airway to stomach contents irritates the vagal neurons. With rising prevalence of obesity, this may become a common cause of cough hypersensitivity. This possibility also warrants a review of reflux medicines, Murphy says.

“And if patients are still not responding, that’s where you would start to think about antitussives such as morphine or gabapentin, and maybe soon the new treatments that may be coming out, such as gefapixant.”

Acknowledging that chronic cough constitutes a significant medical issue is an important first step.

“Patients with chronic cough often lack recognition by others that they have a real disease,” Birring says. “So, a pharmacist who is uniquely accessible to patients and is a familiar and friendly face can reassure patients that they have a genuine problem and condition.”