The Association for Research in Otolaryngology (ARO) 2023 MidWinter Conference

Our next update is coming up now, and it's about Sound Pharmaceuticals! As per the request of @InNeedOfHelp (and no doubt many others) I caught up with Jonathan Kil, who was more than happy to present some of their latest tinnitus results and plans to us. I think it will answer some of your questions, in as much detail at least as Sound Pharmaceuticals is willing and able to give at this time.

Watch our video to see Jonathan Kil, CEO of Sound Pharmaceuticals, talk about Ebselen. This drug is currently undergoing a Phase 3 trial for the reduction of acute noise-induced hearing loss, following a seemingly succesful Phase 2 trial, the results of which were published in The Lancet.

In the meantime, they have been looking at using the drug for tinnitus as well, and in this video Jonathan Kil presents promising findings from an animal study, that seem to show signficant reduction/suppression of tinnitus in noise-exposed mice. This study used the same 4-day treatment protocol as in the Phase 2 human study. But the thinking is that a longer treatment period would be better, so they are seeking to repeat the animal study with a 4-week treatment period.

The good news is that, based on the success in animal studies, and assuming positive outcomes from the Phase 3 human trial (coming out at the end of this year), Sound Pharmaceuticals does plan to go after tinnitus as a chief complaint. This would require an additional, and differently designed, human trial.

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Tinnitus Disorder Strikes Back!

I reported previously, in this blog post, about the term “tinnitus disorder”. A group of researchers has been promoting this concept as a supposed cornerstone of tinnitus research. The paper that coined the term was co-authored by over 50 tinnitus researchers, with Dr. Dirk de Ridder as its main author.

In my blog post I talked about my struggle to understand the usefulness of this concept. Proponents of Tinnitus Disorder talk about its usefulness in a clinical setting regarding getting help and benefits for people who are suffering severely. That makes sense. But in a research setting, how does recognizing Tinnitus Disorder get us closer to a cure?

At ARO, I again came across Tinnitus Disorder here and there – for instance in Christopher Cederroth’s presentation about the genetics of tinnitus, which I did not mind too much, because it could be worth investigating whether severe sufferers have different genes than mild sufferers; and in fact, his research did seem to point in that direction. Also, he makes a very good point – see this episode of the Tinnitus Talk Podcast – when he states that the group of chronic, severe sufferers needs to be prioritised in any research efforts. For instance, when recruiting for a clinical trial, it makes no sense to include mild and severe, and acute and chronic, all in one.

But... there is still something not sitting right with me. Obviously, the term “disorder” is somewhat stigmatising and pathologizes what is, in my view, a normal human reaction. According to the aforementioned paper, Tinnitus Disorder should be incorporated in the American Psychiatric Association's DSM-V. That makes no sense to me because tinnitus distress is not a psychiatric disorder. My suspicion, which might seem very cynical, is that some researchers find Tinnitus Disorder a convenient concept, because it allows to shift the goalpost from solving tinnitus to solving the distress. And distress, whatever the cause, can of course be treated much more easily than a complex neurophysiological phenomenon like tinnitus.



Was I being too cynical? I decided to ask around a bit. I was doing some recordings with Will Sedley, Elouise Koops, and Joel Berger (the results of which we will publish here shortly) and afterwards expressed my concerns to them. To my positive surprise, they wholeheartedly agreed with me. They told me that although 50 researchers co-authored the paper, there were probably at least as many that were approached but declined to take part. The concept itself just didn’t make sense to them. I believe it was Will Sedley who said: “We don’t talk about pain versus pain disorder either, do we?”. Indeed, we don’t. Perhaps there is hope yet

 

It's good to see some debate and hear different viewpoints, since I am myself not 100% sure how I feel about the issue, as is hopefully clear from my original post. A few additional points from my side:

1. When it comes to the intentions of the paper's authors, these are unclear to me, and in fact they probably diverge a lot, since there are 50+ of them. The reasoning that came forward most clearly from the TRI conference that I attended last year was that in order to get tinnitus patients access to healthcare and get their costs covered by insurance plans, we need to classify it as a disorder. That's a pragmatic argument related to access to care, which I am in fact very sensitive to.
2. I am also sensitive to the argument that we should not lump all forms of tinnitus together during clinical research (as all too often happens today). It makes a lot of sense to focus clinical trials only on chronic, severe sufferers as the target population for any treatment or intervention. Christopher Cederroth argued this quite convincingly during the Tinnitus Talk Podcast episode I mentioned. But, this argument is in fact NOT made explicitly in the paper, so I'm not sure to what extent this is even part of TRI's research agenda. Furthermore, we don't need the term Tinnitus Disorder to achieve this aim; we could simply talk about 'severe, chronic tinnitus'.
   
3. Re-reading the paper, it does not state very clearly, in my opinion, what the purpose or end goal is of redefining tinnitus in this manner. They talk a lot about the need for clear definitions, and then come up with the proposal of Tinnitus Disorder, meaning tinnitus + associated suffering. The closest they come to defining a goal is: "If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right." This comes back to the pragmatic (and I believe valid) argument I outlined in point 1 above, i.e. getting sufferers access to care. But no other goal is defined, specifically in relation to research.
   
4. In fact, the paper does not mention the word "cure" or even "treatment." So I have a hard time believing that curing tinnitus could be part of the authors' objectives. Certainly, it couldn't be their primary objective or they would have said so. At the TRI conference, when I asked the question (this was during a Q&A session after Dirk de Ridder's presentation): "How does the concept of Tinnitus Disorder get us closer to a cure?" I did not get an answer — not even an attempt at an answer in fact.
5. As I mentioned in my original post, the undertone I am getting from the paper and the TRI meeting is that Tinnitus Disorder is a way of shifting the goal posts for research from "let's solve tinnitus" to "let's solve tinnitus-related suffering." It's not made explicit, but clearly implied when you read the following paragraph (I removed references for readability): "For the purpose of clinical research, the degree of suffering is most relevant, but there are no commonly accepted clinical diagnostic criteria for quantifying tinnitus-related suffering and the functional disability associated with that suffering. In chronic pain, which is commonly considered the somatosensory analogue of chronic tinnitus, it has been shown that the perceived disability of the pain is only weakly correlated with pain intensity, but strongly with catastrophic misinterpretations of pain. In the tinnitus field, it has also been shown that the quality of life is predicted by tinnitus catastrophizing and tinnitus-related fear, rather than the psychophysical measures of tinnitus." Following this argument to its logical conclusion (although again, it's not stated explicitly) this would mean that treatments should focus on resolving the distress, not the tinnitus itself.
   
6. Another issue I have with the paper — and this is a bit of a tangent, but it shows the paper is internally inconsistent — is that, for all their talk about the need for clear definitions, they are actually using confusing terminology when they say (in the abstract): "In other words “Tinnitus” describes the auditory or sensory component, whereas “Tinnitus Disorder” reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right." Here, they seem to equate, or at least conflate, the concepts of chronic tinnitus and tinnitus disorder, which does not make sense because it's perfectly possible to have chronic tinnitus without suffering.
7. Finally, and sorry to keep coming back to this, but the reference to the DSM (in the first paragraph of the abstract) does not sit well with me. It does imply strongly that tinnitus related suffering is somehow a psychiatric defect, rather than a normal human response to an unpleasant stimulus.

Again, to be clear, I am not convinced that the intent is bad per se, nor that this will necessarily lead to bad outcomes for us. Let's just say I have a healthy scepticism. I'm definitely open to being persuaded otherwise. Simply getting a clear answer from the TRI or any of the researchers involved in this initiative about how this concept will get us closer to a cure would go a long way to removing my scepticism.

@Mentos, I'd be very curious to hear your thoughts on my points above . I hope that you're right and I'm somehow misinterpreting the authors' intentions.

 

I'm leaning towards that device being in the "never happening" category, whatever it might have been. The way how the document lacks any basic information whatsoever raises some immediate red flags. Frankly, makes me think it's everything but innovative. What's the basic science/hypothesis behind this? Who did the research, what studies were carried out?

The document mentions patent application filed in the UK in 2010, but I did an extensive search just now and couldn't find anything remotely matching (tinnitus, device, treatment, etc.). I doubt the patent was ever granted.

Also, in the PDF it says to contact Sandy Reid for more information, but it appears she left University of Leicester in 2017. The PDF is very outdated.

But, I sent some inquiries to the University regardless. I will let you know if I learn of anything new about this.

 

Yes! Definitely. I just need to find time, that's my biggest challenge right now. I started a new role (in my day job) a few weeks ago and it has been extremely challening. I've been working 60h weeks and at the end of my workday I just drop into bed and sleep. I really want to provide more updates; I have tons of notes to work through and we still have a bunch of videos to edit. But time is my enemy

I did have a very good interview with Rauschecker at Georgetown University! Looking forward to publishing that

 

Thanks for the offer, Philip! We’ll contact you for the details.

 

This year, there were approximately 1700 people registered for the Association for Research in Otolaryngology (ARO) midwinter meeting held February 11- 15 in Orlando, Florida. Tinnitus research was presented in three of the sessions, which by itself seemed a good sign for a condition that generally does not receive much attention. The three sessions were:

Podium #2 – Tinnitus Experiments and Model
Symposium #18 – Putting Tinnitus Theories to the Test
Symposium #15 – Multiomics Approaches to Further the Understanding of Hearing Loss and Tinnitus.

Let us share our general impressions of the conference, or what Linda and I found to be of most interest. We will follow up with more detailed reporting later!

Quality of presentations:

• Compared to other hearing/tinnitus research conferences, we found the presentations to be of generally higher quality. While there were still a handful of underwhelming studies, mostly related to ‘innovative’ measures for measuring tinnitus distress, there were some genuinely new insights presented on the biomedical front.
  
• We also observed a bit more cohesion and less fragmentation than in the past. Researchers seemed to be more aware of each other’s work, and attempts were made to compare different studies to consolidate new insights.

Imaging studies:

• When compared to hearing and age matched controls, people with tinnitus have better preserved gray matter than people who only have hearing loss.
  
• New meta-analyses show that it is important not only to control for hearing loss (as we have known for some time) but also for hyperacusis. Otherwise, we cannot know whether the differences seen between tinnitus versus non-tinnitus groups are in fact due to tinnitus itself or hyperacusis.

Genetics and metabolomics:

• Genetic and metabolomics (study of metabolites) are ongoing and promising for identifying those at risk for developing tinnitus as well as areas to target for treatment.
  
• There is a need for large-scale data collection to support these efforts.

Tinnitus and hyperacusis models:

• Emerging consensus points at the importance of both bottom-up and top-down mechanisms for the development of tinnitus. [Bottom-up refers to the signals sent from the ear and lower brain up through the auditory pathway, while top-down refers to how our higher brain functions analyze and interpret the bottom-up signal.]
  
• Tinnitus can be summarized as ‘central noise’ while hyperacusis can be summarized as ‘central gain’. [This somewhat upends the older central gain theories of tinnitus.] The two mechanisms can mutually reinforce each other.

Networking:

• Contact between the NIDCD – the institute within the National Institute of Health that is responsible for conducting and funding tinnitus research – and Tinnitus Hub has been established. We now have a better idea of what potential channels for funding of tinnitus research are available.
  
• Three board members of Hyperacusis Research were present at the conference. They organized a symposium on hyperacusis. Tinnitus Hub and Hyperacusis Research agreed to collaborate on future projects together, regarding awareness raising and stimulating research.