Explain the Mechanisms of Action of Therapeutic Agents in the Treatment of Cough

In the third of three podcasts focusing on Cough, host Dr. Purvi Parikh joins with Dr. Kevin Murphy and Dr. Mandel Sher to look at the what does and doesn’t work in treating cough. They review the current therapies and what new therapies options are coming in the future.
Explain the Mechanisms of Action of Therapeutic Agents in the Treatment of Cough
Mandel Sher, MD, FACAAI | Kevin Murphy, MD, FACAAI
Mandel Sher, MD is a Clinical Professor Allergy & Immunology, University of Southern Florida Morsani College of Medicine and  Specialist Johns Hopkins All Children Hospital. 

Kevin Murphy, MD is an Allergy and Immunology Specialist and Pulmonologist, Boys Town National Research Hospital, Boys Town Nebraska.

Dr. Purvi Parikh: Welcome to this special edition of allergy talk from the American college of allergy, asthma and immunology. I am Dr. Purvi Parikh and this is the third episode in a three part series on cough. Treatment Options in Cough. Joining me are Dr. Kevin Murphy, the Director of Clinical Research at Boys Town National Research Hospital in Omaha, Nebraska. He completed a fellowship in Allergy, Asthma, Immunology and Pediatric Pulmonary at National Jewish Hospital. He is a spokesperson for the American College of Allergy, Asthma, and Immunology. And Dr. Mandel Sher, Clinical Professor of Medicine and Pediatrics at Morsani College of Medicine at University of Southern Florida in the division of Allergy and Immunology. Dr. Sher is Head of the Center for Cough in Largo, Florida, with the large chronic cough population and is engaged in clinical investigation and promising and novel cough suppressants and controllers. He is a speaker on the local, regional, and national level on diagnosis and treatment of chronic cough and is also a spokesperson for the American College of Allergy, Asthma, and Immunology. Thanks for joining us again, Doctors. So on the topic of treatment, Kevin, to get started, maybe it would be helpful to talk about what approaches are not acceptable in cough treatments.

Dr. Murphy: Purvi, I think that's an important question and the answer to that comes from an excellent expert round table meeting that occurred in April of 2017 convened by the FDA. Dr. Sher was part of that that round table. And there was a great deal of discussion particularly in the pediatric population about treatments that were not acceptable and the participants recommended that the use of cough suppressants really depend upon the clinical situation. That cough, however, should not be suppressed unless the cough is causing significant clinical consequences. And they gave some examples, cough that leads to consecutive nights of poor sleep or vomiting, cough that's so severe that it leads to rib fractures, and of course cough that is severe enough to lead to, to apnea or hypoxemia. It was clear that overall the participants agreed that the treatment of cough in children with opioid containing products was not appropriate, and that alternative treatments for cough would really differ depending on the age of the child. One of the conclusions, and I think is important is that the participants did agree that the availability of non-opioid cough controlling products approved for children particularly as we look to the future would be of great benefit.

Host: It's very interesting. So then what does work, what current therapies are appropriate for treating cough?

Dr. Sher: Sure. Thank you. So how do we treat cough? Your grandmother was right, honey works. It's interesting. There's actually a evidence base data that sweetness and swallowing actually reduce that tickle in the back of your throat. So the concept of sucking on honey in your tea actually is very useful. We use menthol cough drops, which are a local anesthetic for the back of the throat for acute cough again, that may help with that tickle. Actually, we find that in the chronic coughers it's counterproductive because menthol can be very dry. And the problem with our chronic coughers is that they have laryngeal irritation. Think of it as the analogy to our neurodermatitis, who have very dry, itchy skin. What do we do? We lubricate it so that we do that same with our larynxes in our chronic cough patients. We have them sip on water, not gulping, and we have them, instead of using drying menthol cough drops, we use lubricating cough drops, which contains pectin. And there's several commercial brands out there of pectin cough drops, which can be very helpful in this lifestyle approach to our patients with chronic cough.

I've mentioned before that the last time the FDA approved a medication for cough was in 1958, was Benzonatate and dextromethorphan. So Benzonatate has been out there since then and has some modest impact as a local receptor antagonist. Dextromethorphan works centrally and it's an over counter preparation. However, for really a highly effective dose of dextromethorphan would have to be at a level that would be prescriptive and have significant side effects. So those are two drugs that are available, but only have modest impact. The first generational anti-histamines have some data supporting the use of antitussive Benadryl actually or diphenhydramine I should say, has some data supporting it as an antitussive and using it at night, which will help with sedation. And some of us have been using slow release chlorpheniramine as an antitussive. Finally, there are the opiates, but as Kevin mentioned relatively contra-indicated in children and adults in light of our opiate epidemic in this country. We really try not to use the opiates, but they are kind of left as a last resort for therapy for those who have significant dysfunction or disability from their cough.

Dr. Murphy: Mandel, I would like to ask your thoughts in regard to the over the counter cough medications. Do you find in your practice any clinical benefit besides the placebo effect for symptom relief?

Dr. Sher: Well, Kevin the placebo effect is there and actually seeing it in the new novel cough drugs in development up to almost a 40% placebo effect in patients with chronic cough in these drugs that are being used. So there may be that otherwise, again, what's out there is really dextromethorphan the DMs. You know, there is the guiafenesin or the mucolytics, but again, for chronic acute cough that may be helpful if they're actually having mucus production from a viral type of infection or chronic bronchitic. But in the chronic cough world where there is not much mucus production the guaifenesin really doesn't have much role. And again, the dextromethorphan does have its clinical efficacy is somewhat limited.

Host: Wow. I still can't get over, you know, that nothing has been approved since 1958. That's quite staggering, especially given how common of a chief complaint chronic cough is. Mandel what about other approaches such as behavioral therapy or other off label uses that you haven't mentioned yet?

Well, Purvi, this is what we're really using to treat our patients with chronic cough, with the lack of having a real good pharmacologic safe cough modulator suppressant or antitussive. There is emerging evidence of behavioral or speech therapy in the treatment of particularly chronic cough. As we've talked about in these discussions. The increase urge to cough, that tickle cough has higher cortical involvement. We know that cough is voluntary, cough is voluntary, so we know that there can be a behavioral component involved. And there's been the development of speech therapy, particularly emphasizing laryngeal relaxation techniques which I personally use in my patients. And the evidence supports that it really reduces the urge and actually data shows reducing objective cough counts. So I find that extremely, extremely useful. Now the issue is, so we use off label drugs that are approved for other reasons. And most of them what I call are brain meds, we're dealing with obviously a central nervous system issue. And there is data in the literature supporting objectively some of these medications. The most common one I use is Gabapentin.

I generally will start at a hundred to 300 milligrams at night and then titrate up or down depending on clinical efficacy and side effects. Gabapentin can have a plethora of side effects from memory loss, sedation dysphoria, edema, tremors. So we have to look for all of that and I will gradually increase every five to seven to 10 days, eventually at night getting real high. The literature will go up to 1800 milligrams. I generally don't get that high. And there you can have some clinical efficacy. The other drug I will use it and is out there as amitriptyline. Again used as our theme of itch and pain used commonly in chronic pain and headache starting at 10 milligrams and usually not going higher than 20 or 30 milligrams. But again, that should be titrated individually. And finally, there's some data, particularly in the pain literature to use cab penton and amitriptyline synergistically. So lower doses together may have a synergistic type of effect. Other medications that are used by clinicians include fregablin, Tramadol as an opiate derivative, other tryciclics and Baclofen have all had literature and clinical usage and last one is duloxetine as used by some clinicians as an SSRI, in an attempt to be a cough suppressant.

Host: Great. That's very, very interesting. Do you have any thoughts, Kevin, on the same topic regarding any other off label or behavioral uses? I know specifically, with the habit cough behavior is a big component.

Dr. Murphy: Yes, I would say that when we think habit cough, if you will, I think for many of us that the treatment of habit cough can be quite a challenge. I would say that over the years I've found that there are now some new thoughts and approaches that can be very effective in the treatment of, of habit cough in children. One of those is working with the family to have them think about the chronic cough as muscle memory or habit and that this memory or habit can be changed. This approach has been outlined in the past by a number of individuals and most recently Myles Weinberger has reported in the angles of allergy, an approach, if you will, to helping families and clinicians with this suggestive therapy. In fact, there's an excellent website, www.habitcough.com, that's again www.habitcough.com that I would suggest that all clinicians who are caring for children with have a cough, a review and also pass on to their patients because there's very important approaches and suggestions that, that I have found to be very effective in helping children who present with habit cough.

Host: Right. No, I know it can be very challenging even with my own personal experience. Mandel, I know you had earlier mentioned about novel therapies being on the horizon. What can we expect? What's coming in the future of cough treatment?

Dr. Sher: Well, yeah, I think this discussion gets to kind of cap off the trio of podcasts that we're doing on particularly chronic cough because I think this is what is exciting and there are some really good candidate therapies for chronic cough. What help open the world of clinical investigation for chronic cough was actually the development of the cough monitor. So well, studies again, like we talk about pain in nature are primarily subjective and so have cough. We now have an objective monitor the number of coughs that are occurring. And that's really opened up over the last decade along with the development of these medications to be able to properly assess the efficacies of these medications. And the most promising drug is called gefapixant. It is a P2X3 receptor antagonist which is a receptor on the notes. He has septic type C receptors, one of the group of multiple receptor pathways. And gefapixant attaches to P2X3. ATP is the ligand. So ATP which is involved with inflammation and neuronal injury, injury which will then activate the P2X3 which is involved in cough. gefapixant also will attach to P2X2 which is involved with taste, and the results of a phase 2B studies show that at 50 milligrams twice a day had a significant improvement in cough based on the cough monitoring plus a lot of lifestyle measurements.

And the side effect, major side effects that of taste alteration which is reversible. But other than that, there was no significant side effects, particularly that of a sedation or upper brain type function. gefapixant is now close to finishing a two arm phase three year long study looking at efficacy over three and six months with safety data over 12 months dosing at 15 and 45 milligrams twice a day. And top line data that just came out recently showed that the 45 milligrams in their top line announcement did have a clinical efficacy. So there is a drug that may be approaching the finish line, which will again be the first drug approved since 1958 for the treatment of cough. In this case, the indication will be refractory or unexplained chronic cough. There are three other P2X3 selective molecules that are now all in phase 2A or 2B development. And the other drug that is in the pipeline in phase two studies is a neurokinin one antagonists. There are other candidates in various phase one, phase two studies. So again, I think over the next couple of years we will be able to have a greatly needed antitussive available to us.

Host: Well, that's great news because I know as clinicians that can be extremely frustrating when we have such limited treatment options. So you know, I look forward to all of these novel therapies coming out. Well, that's all the time that we have. Thank you to our guests and to the listeners. That concludes our three part series on cough from the American College of Allergy, Asthma, and Immunology. For other interesting episodes from Allergy Talk, please visit college.acaai.org/allergytalk. And to receive CME credit for this or other eligible Allergy Talk podcasts, visit education.acaai.org/allergytalk. I am Purvi Parikh for the American College of Allergy, Asthma, and Immunology.