Interview with Richard Kopke, M.D., F.A.C.S., Chief Executive Officer, The Hough Ear Institute, and Medical Director, INTEGRIS Cochlear Implant Clinic at HEI

Topic: Pharmacological Prevention of Noise-Induced Hearing Loss - New Research Findings

CAROLYN SMAKA: This is Carolyn Smaka and I'm speaking today with Dr. Richard Kopke from The Hough Ear Institute.

Dr. Kopke, welcome to AudiologyOnline and thanks for taking the time to speak with us today.

DR. RICHARD KOPKE: Well thanks for your interest Carolyn. It's a pleasure to be able to speak with you today.

SMAKA: Can you tell us about your background before we get started on the interview?

KOPKE: Sure, I'd be happy to. I was formerly in the U.S. Army as an otolaryngologist and later developed an interest in otology. I was in the Army for 22 years and had a wonderful opportunity to begin doing some research on prevention and treatment of noise induced hearing loss through pharmacological means. As you know, that's a big problem in the military now, noise-induced hearing loss from roadside bombs and weapons firing. About three or four years ago, I retired from the Army and began working at Hough Ear Institute and we've been privileged to be able to continue and extend that research here at Hough Ear Institute with the support of the Office of Naval Research, Integris Health System, our institute and Oklahoma Medical Research Foundation.

SMAKA: Can you give us an overview of the current research projects underway at Hough Ear Institute?

KOPKE: Yes, and I might give a little bit more of a global rundown on some of the research that's being currently done in the Navy as yet as well, if that would be all right.

SMAKA: That would be great.

KOPKE: Overall, we have three primary research focuses at this time at Hough Ear Institute. One is the research already mentioned to prevent and treat acute acoustic trauma noise-induced hearing loss. Another area involves auditory and vestibular hair cell regeneration and that approach involves the use of nanotechnology for targeted delivery of therapeutics to the inner ear. The third area, which I'm not as involved in, but is ongoing in our institute, is the middle ear mechanics research and trying to develop a totally implantable hearing aid. So those are the three things we're currently working on.

The Office of Naval Research, the Navy, and the Naval Medical Center in San Diego, where I previously worked when I was in the Army, are continuing on some clinical research that was initiated prior to my retirement, looking at a pharmacological prevention and treatment of noise induced hearing loss in the military.

SMAKA: That just sounds fascinating. You had mentioned that acute acoustic trauma or noise-induced hearing loss from acute acoustic trauma is on the rise in the military and so the military is looking for creative solutions. What are some of the latest research findings in that area?

KOPKE: Noise-induced hearing loss in the military right now is at epidemic proportions. With the current conflicts we're in, noise injury is very common, partly because of the roadside bombs, unfortunately. Noise-induced hearing loss and tinnitus are two of the most common reasons for disability in the military and affect tens of thousands of soldiers, sailors, marines and airmen. They create huge expenditures for the military having to replace these trained folks and cause a lot of expense in the VA system, having to provide hearing aids and disability benefits. Hearing loss costs the U.S. Department of Defense about one billion dollars a year, and having a noise-induced hearing loss affects people's ability to be employed and to be promoted. It greatly affects their quality of life, in terms of leading to difficulties with communication and social isolation. If we can prevent it or treat it, I think we can really enhance our population's quality of life.

The Navy is trying to develop better hearing protection devices, such as more sophisticated ear plugs and sound cancelling headsets, that sort of thing. They're also very interested in pharmacologic approaches to either preventing or treating noise induced hearing loss, acutely with oral medications or nutritional supplements.

SMAKA: And this has been one of your research areas.

KOPKE: Yes. One of the compounds that we've been working with over the past number of years is N-acetylcysteine, or NAC, which is both an FDA approved drug for the treatment of Tylenol overdosage and a nutritional supplement. There's a lot of scientific data in animal models, with several different species with steady-state noise, impulse noise and kurtotic noise that that approach is very effective in reducing permanent hearing loss. Not too long ago, a 600 or so subject placebo control, double-blind study of NAC plus earplugs vs. earplugs plus the placebo was conducted. The subjects who had taken NAC orally during weapons training time showed approximately a 25% lower incidence of permanent hearing loss. That was a very significant breakthrough and was a sort of pilot study. Now the Navy has launched a larger study with different dosing at several different sites, and that study is currently underway.

SMAKA: You mentioned that the military is looking at newer and better hearing protection devices as well. How does that play into the pharmacological treatment for acute acoustic trauma?

KOPKE: That's a great question. We envision pharmacological treatment and hearing protection devices as working together, hand in hand. Especially in the military, you can't always wear your hearing protection devices and you don't always know when you're going to be exposed to loud noise. There are also some civilian jobs where you can't always wear hearing protection devices because of the need for communication. In addition to that, in the military and certain other industries in the United States, like mining and oil and natural gas, as well as in some manufacturing settings, noise levels are very high and hearing protection is limited due to constraints in the devices so that you never get as much protection as you need, except at times when the noise levels are fairly low.

The other important point is that the skull, as you all know, is a very good transmitter of acoustic signal, acoustic energy. So you can have loud noises going right through the skull to the inner ear and bypassing the hearing protection device. That's a very hard problem to mitigate against.

SMAKA: Bone conduction transmission, exactly.

KOPKE: So the pharmacological approach just supplements the hearing protection device, trying to get around some of those limitations.

SMAKA: It sounds like it adds another layer of protection for people.

KOPKE: I like that you mention another "layer of protection." I would say that's a nice picture, multiple layers of protection.

SMAKA: I'm trying to understand what NAC actually does in the inner ear to help prevent the noise induced hearing loss. How does it actually work?

KOPKE: We're still learning answers on that through more basic science research. Basically, high level noise induces oxidative stress in the cochlea. Essentially through causing decreased blood flow, release of excessive amounts of glutamate, and stressing the mitochondria, free radicals are generated in the cochlea. These free radicals are toxic to the tissues;they damage and destroy hair cells and neurons and other tissues in the cochlea. So NAC can be used by the body to make more of one of the body's own antioxidant defenses, which is something called glutathione. So when loud noise occurs, glutathione levels drop because glutathione is trying to counteract these toxic free radicals, but after awhile, the source of the glutathione is depleted. So NAC can be taken into the body and used to re-synthesize more glutathione, which is then available to act as the natural antioxidant to reduce that stress and get rid of those toxins. Does that make sense?

SMAKA: Yes, thank you, you certainly made it very clear and concise and I can't even imagine how complex it is. Dr. Kopke, you mentioned that there are several different injury mechanisms.

KOPKE: Right. Well, in biology in general, nothing is ever as simple as you'd like it to be, unfortunately. When the ear sustains a noise injury or a noise stress, there are a variety of free radicals that are generated: reactive oxygen species (these are oxygen free radicals), nitrogen free radicals, and free radicals that come from lipids in the cell membrane and other places. In addition to that, there is the increase in activity of something called inducible nitric oxide synthase or iNOS, which leads to an inflammatory response, among other things, which is also damaging. So, in addition to that, the cell membrane is damaged, the mitochondria are damaged, and glutathione levels are depleted. All of these things and more are occurring and need to be addressed. You have to address the different types of free radicals, you have to address the cell membrane, the mitochondria, and you have to address things like inducible nitric oxide synthase.

So, even though NAC works very well by itself, we've taken an approach recently to determine if we could improve on that by combining one or more medications or compounds into the treatment, and that's been the subject of some of our latest research. We've combined NAC with a nitrone, a different type of medical compound, and the two compounds together seem to address more of the mechanisms of injury than one compound by itself. Just to give you an example, in our animal models for acute acoustic trauma, if you give NAC four hours after noise injury, you reduce the permanent hearing loss by about 50%. But if you give NAC and the nitrone four hours after the noise injury, you reduce the permanent hearing loss by about 90%. If given 24 hours after the acute injury, NAC by itself reduces the permanent hearing loss maybe only 10 or 15%, but with NAC plus the nitrone, you get about a 50% reduction in permanent hearing loss, even 24 hours later.

SMAKA: From a practical standpoint, especially in the military where you may have some logistical limitations to administering something immediately following acoustic trauma, that combination would make the application much more useful in the field.

KOPKE: Exactly. One of the approaches that we've been thinking about is the medics who are with the soldiers or marines in the field. They would be able to carry this treatment in their medical gear. When someone is exposed to loud noise, either through an explosion or in a period of combat, and has the symptoms of injury from noise, i.e., a persistent ringing in the ears lasting for more than 15 minutes, or a subjective sense that his or her hearing is muffled, etc. - the medic could treat that person in the field. In that scenario, you could certainly treat most people within four hours, 12 hours, and for sure within 24 hours.

SMAKA: In addition to application in the military, you also touched on application for some occupational noise exposure. What about people with long standing hearing loss or presbycusis - do you foresee that any of this research may be applicable to other types of hearing loss?

KOPKE: That's a very insightful question. Two major causes of sensorineural hearing loss in the U.S., as you know, are noise and presbycusis. People are just starting to explore presbycusis, and it turns out that there is some evidence that oxidative stress and the generation of free radicals play an important role in causing presbycusis. We're beginning to research this area as well. The thought is if you start having some detectable decline in your hearing as you age, perhaps we could give people something in the way of a nutritional supplement or a vitamin or a very safe and not too expensive pharmacologic agent that they could take once a day or once a week, for example, to prevent further progression of the presbycusis.

SMAKA: Excellent. It sounds as if the research is in the very early stages and there's nothing currently on the market approved for that type of use.

KOPKE: Correct. There's nothing FDA-approved at this time either for the treatment of acute acoustic trauma or presbycusis that I'm aware of, although new things are always coming up.

SMAKA: How long do these things take to come to fruition and when would you foresee something would be available?

KOPKE: With NAC, especially if these new clinical trials prove positive, we could see something in that area in the next several years. However, it's hard to predict, it's kind of a look at the crystal ball. It depends on the results at each stage of the research and having positive results so you can move to the next stage. The FDA process is thorough, which is good, but it also takes a lot of time. Hopefully, within the next several years, there could be something on the market that has good safety and also good efficacy demonstrated in well-run clinical trials. Both compounds that are being studied, by the way, are very safe, so that's very positive.

SMAKA: What is scary is that we're hearing so much about noise-induced hearing loss being on the rise with children. Maybe this research will yield new solutions for noise-induced hearing loss that will be available for these children when they're a little older.

KOPKE: Yes, that is disturbing. You wonder if kids would really be willing to take a pill to reduce their hearing loss. It's kind of like the teenage mindset is well, you know, "we're invincible".

Something we're going to be exploring in the near future, I hope, relates to this issue. Previously, researchers had thought that once the noise exposure is over, then the hearing stabilizes and that's the end of the story. At Harvard at the Massachusetts Eye and Ear Infirmary, Sharon Kujawa and Charles Liberman have some intriguing data that show that the noise-injured ear ages differently than an ear that has not been injured by noise. So that chain of reactions is set in place that causes that ear to, if you will, age a lot faster than an ear that hasn't been injured by noise.

SMAKA: Interesting.

KOPKE: When I was in the military, I would often see patients with sensorineural hearing loss on their exit physical. I saw a large number of patients in their mid to late 30's or early 40's who had noise exposure for the first three years of their military career and then they had a desk job the rest of the time. As I looked at their audiograms, their hearing continued to deteriorate, even though they weren't around noise anymore, and they were too young, I think, to really have what we could classically term as presbycusis.

SMAKA: If people were interested in reading more about the fascinating research we've discussed today or wanted more information, where generally is it published?

KOPKE: Most of it is published in peer-reviewed literature. Some of the data that I have talked about is not yet published;it's still in peer review.

SMAKA: Thank you so much again, Dr. Kopke, for taking the time to share this information with AudiologyOnline. We sincerely appreciate it and best of luck with your research.

KOPKE: Thank you again for your interest, Carolyn. It's been a pleasure.



About The Hough Ear Institute

The Hough Ear Institute (HEI) is a non-profit research, educational and humanitarian service institute. As a Center of Excellence of INTEGRIS Baptist Medical Center (IBMC), the IBMC Cochlear Implant Clinic and Hearing Enrichment Language Program are an integral part of the institute. HEI also interacts with Otologic Medical Clinic Inc. and Audio Recovery Inc.. All of these entities are located within the Hough Ear Institute campus. In addition, research collaborations exist between the University of Oklahoma, Oklahoma Medical Research Foundation and Oklahoma State University.

Hough Ear Institute personnel conduct research, provide education and serve humanitarian needs relating to hearing and balance improvement or restoration.