Current Management of Chronic Cough and Emerging Therapies

Chronic cough is a problem that can have a major impact on quality of life for patients, but in many cases, no cause can be found, explained Michael S. Blaiss, MD, clinical professor of pediatrics at the Medical College of Georgia at Augusta University, and executive medical director of the American College of Allergy, Asthma, and Immunology (ACAAI).

There are 3 types of cough based on duration:

• Acute cough lasts for a maximum of 3 weeks, and the most common cause is an acute respiratory tract infection.
• Subacute cough lasts for 3 to 8 weeks, and this is most commonly related to a postviral cough, or a cough that continues after a patient loses other symptoms associated with an infection.
• Chronic cough lasts for longer than 8 weeks.

Patients with chronic cough are often frustrated, upset, and frightened, Blaiss said. “Usually the first question I get is, you know, ‘What’s wrong with me? Why can’t someone find out why I’m doing this coughing all the time?’”

Patients with a chronic cough usually try different treatments, including all of the over-the-counter medications, and they have moved onto complimentary or alternative treatments, he explained.

Chronic cough can be so severe that patients may have vomiting or near syncope (the feeling that they may faint); female patients may experience urinary incontinence; and some patients will come in with sore or broken ribs, he noted.

“And one of the big frustrations for these patients is it affects their social life,” Blaiss said. “They can’t go to the theater. They can’t go and do other activities that other people can. And this leads to a great deal of psychological problems seen in this patient.”

In the United States, the prevalence of chronic cough is about 11%, which means it is not an uncommon problem. Research presented in 2019 at the ACAAI meeting estimated the prevalence of self-reported chronic cough and described demographics, health, health care resource utilization, and quality of life for these patients.¹

Respondents with chronic cough had health-related quality of life physical and mental health scores that were 5 to 6 points lower than people without chronic cough, according to the abstract. In addition, based on the responses, 40.15% of patients with chronic cough said they experienced work productivity impairment compared with just 22.45% of respondents without chronic cough. Almost 10% of patients with chronic cough had severe depression compared with 4.1% of respondents without chronic cough; 13.4% of patients with chronic cough had severe anxiety compared with 5.5% of respondents without.

Guidelines from the American College of Chest Physicians on the classification and management of cough highlight that in addition to identifying the duration of cough, providers need to understand any triggers of the cough, such as environmental exposures or occupational exposures. Because patients who have chronic cough may have visited multiple doctors before seeing an expert, they have likely had previous treatments that need to be taken into account. For instance, angiotensin-converting enzyme inhibitors are known to lead to a chronic cough problem, Blaiss said.

Patients for whom clinicians have gone through all possible causes for the cough, including treating for asthma with steroids, would be classified as having a refractory chronic cough or even just an unexplained chronic cough. This tends to happen more commonly in women than men and peaks when patients are in their 50s and 60s.

“We have to go through a very comprehensive evaluation with all of these patients to make sure that we’re not missing anything that may be causing the problem,” Blaiss said. “But unfortunately, I think all of us realize that in many cases, no cause can be found, or the treatment for the underlying cause we’re doing is just not eliminating the patient’s call problem.”

Krishna Sundar, MD, medical director of the Sleep-Wake Center and clinical professor of medicine at the University of Utah, followed with a discussion on current and emerging therapies to treat chronic cough.

Currently, clinicians use different neuromodulatory agents to treat chronic cough, and opiates are the most commonly used agent, because “we know they work very well.” Morphine doses of 5 to 10 mg twice a day (BID) and codeine doses of 60 mg per day have been used in patients in different studies, Sundar explained.

However, one study showed that although morphine significantly improved the cough quality of life score for patients over a period of 28 days compared with placebo, after patients discontinued the opiates, their cough came back.²

“And that’s the finding that we see many a time in our practice, especially in some of the patients that go on codeine cough suppressants: There tends to be a reoccurrence of cough once they’re off these medications,” Sundar said.

Dextromethorphan is another widely available medication and can be found in more than 100 over-the-counter treatments. However, this therapy is typically used for acute and subacute cough, and the results in chronic cough are mixed.

Gabapentin is another neuromodulatory drug that has been shown to improve cough, but similar to opiates, there is a reoccurrence of cough after the therapy is stopped. In addition, there are adverse effects if used at a dose higher than 1800 mg.

The last neuromodulatory drug being used is amitriptyline, which was studied in 10 mg at night. Although a study has shown the drug achieves significant response based on the cough quality of life questionnaire, Sundar said he has not seen that kind of benefit.

Novel compounds being studied are looking to address cough hypersensitivity in chronic cough, and they have a wide range of targets.

Among the purinergic receptor blockers, there are 4 potential therapies being studied

1. Gefapixant is in a phase 3 study for 15 mg BID and 45 mg BID.
2. BLU-5937 is in phase 2 study, and the doses studied are 25 mg to 200 mg BID.
3. BAY 1817080 is in a phase 2 study for doses between 10 mg and 750 mg BID.
4. S-600918 is in a phase 2 study for doses ranging from 50 mg to 300 mg daily.

Among the neurokinin 1 receptor blockers, there have been 2 agents:

1. Serlopitant, which was abandoned after a phase 2 study did not show improvement compared with placebo
2. Orvepitant, which has a proof of concept study that showed 30 mg once a day for 4 weeks reduced coughs by 18.9 coughs per hour

The final group of agents are sodium channel blockers, and currently there is only 1 in development: GSK 2339345. This was given in an inhaled preparation, but unfortunately, it worsened cough counts, but “there is more to come as far as this group of agents go,” said Sundar.

“We are actually at an exciting threshold in terms of the neuropharmacology for the new agents that we are likely to see in the next year or so made available to us for treating our patients,” he concluded.

References

1. Meltzer E, Zeiger R, Schatz M, et al. Chronic cough in America: prevalence and patient characteristics. Presented at: ACAAI Annual Scientific Meeting; November 7-11, 2019. Abstract P351.

2. Morice AH, Menon MS, Mulrennan SA, et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med. 2007;175(4):312-5. doi:10.1164/rccm.200607-892OC