Rethinking chronic cough: is the brain to blame?

Here’s the latest research from the Respiratory Sensory Neuroscience group on the brain’s role in chronic cough – and learn how you can get involved in the lab’s latest clinical studies.

Explore the Mazzone Lab Clinical Studies here

Chronic cough affects up to 10% of the global population. And it may be caused by the brain wrongly magnifying nerve signals about irritation in the airways, according to new research from the Respiratory Sensory Neuroscience Research Group led by Professor Stuart Mazzone in the Department of Anatomy & Physiology.

So what is ‘chronic cough’? It’s a cough that lasts longer than 8 weeks. Chronic cough is more common in smokers, those with a history of smoking, women and people aged over 65 – but it may also be a sign of an underlying medical condition. Chronic cough that lasts more than 8 weeks should be seen to by a doctor.

People who have chronic cough typically have cough hypersensitivity - a condition in which less irritation in the airways is required to trigger coughing. The cause of this hypersensitivity is unknown.

The findings of Mazzone lab’s latest research, published in eBioMedicine (part of The Lancet), have challenged the belief that hypersensitive cough reflex is caused by overly sensitive airway nerves. Instead, their research found that the brain may act as an amplifier of the irritant signals in the airway.

Participants with chronic cough involved in the study were exposed to chemicals that triggered coughing while having their brain activity monitored using functional magnetic resonance imaging. Here the researchers saw that there was less activation in the part of the lower brain – the part that first processes information about airway irritation – and an increase in activity in the part of the midbrain that filters incoming airway sensory information and engages networks that suppress cough.

Image: Prof Stuart Mazzone demonstrating how cough brain circuits are studied using magnetic resonance imaging

We concluded that the midbrain may act as an amplifier of airway sensory signals in chronic coughers, leading to their hypersensitivity to usually harmless levels of airway irritants.

Prof Stuart Mazzone

This research may reshape future therapeutic approaches to manage chronic cough and has highlighted the importance of participants and volunteers for human cough studies.

“Cough research in animal models can only tell us so much, since a huge component to cough and its regulation involves the ‘urge-to-cough’ that animals cannot describe. This makes it especially challenging to study the neural networks in higher brain centres involved in perceiving an 'urge-to-cough' and cough suppression,” Stuart said.

The Mazzone Lab currently is currently recruiting for two clinical studies. Here’s what you need to know.

Participants now wanted for cough clinical studies

Gefapixant and brain activity in chronic cough

The Mazzone Lab is looking for participants who suffer from a refractory or unexplained chronic cough to conduct a clinical trial to study the effect that a new investigational medicine for chronic cough, named Gefapixant, has on the nervous system processes that regulate coughing.

This study is in collaboration with Merck Sharp and Dohme, Royal Melbourne Hospital and Monash Biomedical Imaging.

What’s the study about?

The purpose of this study is to investigate the effect that a new investigational medicine for chronic cough, named Gefapixant, has on the nervous system processes that regulate coughing. Gefapixant is being developed by the pharmaceutical company Merck for chronic cough that is unresponsive to other common medications used to treat conditions that give rise to cough. This type of cough is called ‘refractory’ or ‘unexplained’ chronic cough and proves to be very difficult to control.

Merck have completed phase III clinical studies and found Gefapixant to be safe and effective for people with refractory or unexplained chronic cough. Gefapixant is gaining approval for market release but remains an investigational drug in Australia at this stage. This is partly because how Gefapixant works is not fully known.  The purpose of our study is to investigate this mechanism in more detail.

Why is this study important?

Chronic cough continues to be one of the most difficult to treat conditions and affects many millions of people around the world. There have been no approved therapies in over 50 years. The information obtained from this study about brain circuits involved in chronic cough and the effect of Gefapixant will help towards developing more approved therapies for chronic cough patients.

Who can take part?

18–65-year-old people of all genders who suffer from a refractory or unexplained chronic cough.

How long will the trial last?

Participants must be willing to commit to a 13-week study period, including 12 weeks of taking Gefapixant twice daily. They will be required to undergo cough assessments and have several brain imaging scans (MRI) while inhaling reagents that tickle the throat to trigger coughing. Continued participation in the study by taking Gefapixant for up to 12 months is optional.

Will participants be compensated?

Participants will be compensated for their time.

How do I get involved?

Contact Principal Investigator Prof Stuart Mazzone
Email: stuart.mazzone@unimelb.edu.au
Phone: +61 3 8344 6457

Flurbiprofen and the role of inflammation in acute cough

The Mazzone Lab are looking for participants conducting a clinical study on the effect of over-the-counter non-steroidal anti-inflammatory treatments on cough reflex sensitivity in subjects with upper respiratory tract infection.

This study is in collaboration with Reckitt Benckiser.

What’s the study about?

The aim of this study is to investigate the inflammation in the nose and throat of people with a viral upper respiratory tract infection, also known as the common cold. We believe this inflammation is the reason people with upper respiratory tract infections often have an increased sensitivity to things that make them cough. The relationship between throat and nose inflammation and cough sensitivity during upper respiratory tract infection will be determined by testing cough sensitivity before and after reducing inflammation using an anti-inflammatory drug. The drug we will use is flurbiprofen, which is a non-steroidal anti-inflammatory drug (NSAID), like ibuprofen.

Why is it important?

Why our normal cough reflex becomes overly sensitive during a common cold or flu is unknown. We hope to confirm the role of nose and throat inflammation in producing this increase in sensitivity. Understanding the mechanism underlying the increase in sensitivity will help us develop more effective therapies to treat acute cough.

Who can take part?

You must be aged 18-70 and who are suffering from a cough associated with a current infection with the common cold or flu. Cough must be acute and not be ongoing, i.e. duration must be less than 8 weeks.

How long will the trial last?

Participants must be willing to commit to a visit to our laboratory for approximately 4-5 hours. During the visit, we will test the participant’s cough sensitivity, take fluid samples from their nose and mouth, and ask questions about their experience with their cough before and after they take a medication containing flurbiprofen or a placebo.

Will participants be compensated?

Participants will be reimbursed for their time.

How do I get involved?

Contact Clinical Research Coordinator Dr Tara Bautista
Email: tara.bautista@unimelb.edu.au
Phone: +61 3 8344 8900

About Prof Stuart Mazzone

The Respiratory Sensory Neuroscience Research Group

Using their expertise in studying cough in humans, the Respiratory Sensory Neuroscience Research Group builds on clues revealed by animal studies to develop a deeper understanding of the nerve processes and brain networks involved in cough and how their activity may be altered in people suffering from acute (short-term) and chronic (long-term) cough.

Read about the Mazzone Lab

Eavesdrop on Experts

Prof Stuart Mazzone featured on Episode 93 to discuss the science of coughing.

Listen to the podcast

In the Lab

Prof Stuart Mazzone featured on in our micro-documentary series, In the Lab. Find out what he had to say about the research higher degree experience in the Department of Anatomy & Physiology.

Watch In the Lab here