Tinnitus

Introduction

Tinnitus ‒ also known as ringing in the ears ‒ is a common condition affecting roughly one out of every 10 individuals. The term comes from the Latin word "tinnere" (which means to ring or jingle). Statistics vary but is estimated that more than 100 million people worldwide are afflicted with chronic tinnitus ‒ that is, tinnitus which is always present to some degree. As with other medical symptoms, the severity can range from mild to severe, or even catastrophic. Combined with hearing loss, tinnitus represents the largest disability claim by US veterans and is estimated to cost the US government more than two billion dollars per year. Despite the huge prevalence and cost to society, tinnitus receives very little public or private funding compared with other medical conditions. There is no cure.

New to Tinnitus?

Developing ringing in the ears can definitely be a life-changing event. By far the most common cause of tinnitus is noise exposure (either short or long-term noise exposure). Indeed, tinnitus may develop from a single loud event such as attending a two-hour concert without ear protection. In those instances, the person who develops tinnitus often wonders why only they got it and none of their other concert-going friends did. Other possible causes of tinnitus include (not an exhaustive list): ototoxic medication, ear infections, certain childhood diseases, head trauma, and presbycusis. There is no standardized treatment for tinnitus nor is there a standardized way to diagnose it. And because of that, here is where things start to go wrong when someone suffering from tinnitus goes to see their doctor. When the topic turns to tinnitus, responses from physicians can range from East to West depending on whom you see or even the day of the week. For example, your ENT might tell you that your audiogram shows no hearing loss and as a consequence, it cannot be noise-induced and should therefore likely go away (as opposed to an audiogram that does show some degree of hearing loss).

So... what exactly is inaccurate with that statement coming from your ENT? Well, let's break down the information and perform an analysis on that:

  • An audiogram was not developed to diagnose tinnitus; it was brought into use to diagnose hearing loss ‒ more precisely, to diagnose hearing loss in the speech frequency range (0-8 kHz). It is true that certain traits can be observed via audiograms and be found to correlate with tinnitus (to some degree). But that is only true at the statistical level (i.e. when you have a group of a hundred or a thousand people). Because statistics and associated traits only work at the group level, there is no way any doctor can say with certainty with regards to a specific individual patient: "you have no hearing loss, therefore your tinnitus must be caused by something else (than noise)".
  • It is common practice to only evaluate the speech frequency range (0-8 kHz). However, humans can hear up to about 20 kHz. Any hearing loss in the upper-frequency range above 8 kHz will therefore go undetected in a standard audiometric assessment. Any doctor ‒ no matter how brilliant they are ‒ cannot make a conclusion on something they have not observed. Agree?
  • Regardless of the cause of tinnitus (whether known or not), there is really no way a doctor can make any predictions about the outcome of the patient. So, statements such as "your tinnitus should go away" are flawed. No one can say with certainty what the prognosis will be except, perhaps, in a few limited special cases such as those relating to objective tinnitus.
  • A young person with known noise-induced tinnitus (e.g. acoustic trauma from a firecracker) can absolutely perform as well as any other person undergoing a pure-tone audiometric test. The reason is that the most sensitive part of the cochlea (the synaptic connections) can sustain quite a bit of damage before a decrease in hearing thresholds shows up on an audiogram. More recent research points to the noise-in-speech test as a more reliable objective way to diagnose early-stage hearing loss (and its relationship with tinnitus). Typically young individuals with otherwise good hearing will have no problems passing both a pure-tone audiometric assessment and a speech discrimination test. But when the same test is performed with background noise present (simulating a "cocktail party situation"), those with a history of noise exposure tend to perform less well. This is also known as "hidden hearing loss".

What are some of the other problems that a person diagnosed with tinnitus might face in a consultation setting? Well, like other medical symptoms, ringing in the ears can range from mild to severe ‒ just like pain. For that same reason, the situation and difficulties the patient faces can vary considerably, and yet, by default tinnitus is treated as if "one size fits all". This can leave a patient with a significant amount of frustration and combined with an inclusive diagnosis (e.g. "you have no hearing loss"), can lead the individual on a wild goose chase in order to figure out the cause of his (or her) tinnitus. Because of the inadequate methods of diagnosis within the ENT field, "patient history" becomes an important consideration to include in a consultation. If your general practitioner (or ENT) is not including patient history in the examination, he/she is not asking the right questions.

Because of the inadequate (and at times even incorrect) information that permeates the medical field in relation to the topic of tinnitus, it is worth taking note of the excellent clinical guidelines provided by the Tinnitus Research Initiative (TRI).

Where are we in Terms of Finding a Cure?

This is a subject quite often discussed on online tinnitus forums. The short answer is that a single standardized effective treatment i.e. one that works for all tinnitus patients – and which in all cases abolishes tinnitus completely – is many years away. However, the past decade has seen quite a surge in the amount of research being undertaken in relation to inner ear disorders. Some of that research has led to the first wave of clinical trials sponsored by various pharma companies. For tinnitus, a differentiation between the acute and the chronic stage should be made and kept in mind. The is reason is that the chronic stage of tinnitus is believed to be a more complex pathology than while the condition is still acute. For the same reason, the clinical trials that have so far advanced the furthest are investigating drugs for patient profiles with acute-stage tinnitus. Probably the most well-known clinical trial at this point is that of AM-101 which was sponsored by Auris Medical AG. AM-101 is a gel-based intratympanic treatment containing the active component, esketamine (an NMDA-receptor antagonist). In a "classic" case of acoustic trauma, excess release of glutamate takes place inside the cochlea. This, in turn, leads to cell toxicity, inflammation, and nerve fibre loss. Through an intratympanic injection with AM-101, the proposed theory is that the drug diffuses across the round window membrane and blocks the NMDA-receptors and hence provides an inhibitory effect to the action of glutamate. Results of the trial indicate that the proposed mechanism of action is only effective during the acute stage of tinnitus (i.e. within the first three months, or less). Final results from the 2nd of two phase-III trials is expected in early 2018. Other potential avenues being explored for treating tinnitus include drugs that activate the so-called Kv7-channels. Two newer versions of Trobalt/Potiga have been designed and may progress to clinical trials at some point. The first drug is named SF0034; the second is called RL-81. SF0034 is owned by the Pittsburgh pharma company, SciFluor Life Sciences. RL-81 ‒ which is actually a series of compounds ‒ was developed by researchers at Pittsburgh University and has yet to find ownership with a pharma company. In another development, back in 2015 while the AM-101 phase-III trial was ongoing, a UK-based pharma entity initiated a phase-II study based on a novel drug targeting the Kv3-channels. The clinical trial, called QUIET-1, was sponsored by Autifony Therapeutics and the research behind the new drug looked promising. However, already during an interim assessment of the phase-II data from the trial was it found that no efficacy could be demonstrated versus the placebo arm of the investigation. Auris Medical does have a 2nd generation tinnitus drug called AM-102. Development has been underway for about a decade with few details emerging on the drug's mechanism-of-action or the patient profile (i.e. acute- vs. chronic-stage tinnitus). However, in a conference call hosted by Auris Medical in March 2017, it was stated that the ongoing collaboration with King's College London (in relation to AM-102) will continue with the aim to "identify and characterize our lead compound with high potential to treat acute tinnitus". And so also AM-102 – despite being a 2nd generation development – would appear not to target chronic tinnitus (which is by far the largest segment of the overall patient population). And finally, in a separate development, research from the University of Michigan has yielded promising results. The research made the headlines in 2018 when both results of preclinical work, as well as a small-scale human study, were released in a publication. A larger investigation using the same study's bimodal stimulation treatment is planned.

With the above information, it is evident that effective treatments aimed at chronic tinnitus are not likely to emerge in the immediate future. However, besides the topic of devising effective drugs and medical interventions, there is also the aspect of diagnostics. At the molecular level, what exactly defines a tinnitus patient compared with those who do not have the condition? And within the patient population itself, how can tinnitus sufferers be categorized in a scientifically meaningful way? In order to address some of these questions and pave the way for better future treatments, several long-term projects are underway such as TINNET and ESIT.

Tinnitus Boards: A Review

Online tinnitus forums tend to form their own little cosmos ‒ each with certain specific characteristics depending on which one you visit. However, regardless of which board you land on, there are at least certain traits that all tinnitus forums tend to have in common. For one, almost every online tinnitus community will have a certain depressive state that permeates more or less the entire site. And depending on the level of moderation by the admins, toxic members may be allowed to flourish and spread vitriol in every possible direction. As a 2nd observation, it is usually always the case that the population of a tinnitus board can be split into roughly four distinct member types (with some overlap possible):

  • The newbies. These are the folks who are new to tinnitus and (usually) totally overwhelmed by the condition. This may be because they have severe ringing in the ears and/or because they never knew the condition existed beforehand. Because this group of people are totally new, they make easy prey for the "practitioners of self-deceit" and the "wannabe experts".
  • The chronics. Despite the fact that habituation is often preached as a certainty that will occur eventually, it is not uncommon for people who have had the condition for a number of years to sign up with a tinnitus forum. So is habituation a certainty, then? Don't count on it. Quite often this population subgroup will be upfront about their difficulties and clash ‒ in particular ‒ with the "practitioners of self-deceit".
  • The practitioners of self-deceit. Almost all boards will invariably have a small minority of members who aggressively will defend the position that they did not sign up because they are suffering from tinnitus but because they want to help others. For some "strange" reason, these same members tend to be pro-habituation (as opposed to pro-treatment) ‒ usually through the employment of TRT or CBT treatment protocols. However, despite their claims to the contrary, it is quite easy to spot that these very same members are in the same boat as everyone else. How to spot that? Well, of all the world's online forums, tinnitus communities are probably some of the least interesting places to "hang out" and so, if a person really had successfully recovered, you can be fairly certain they would not be spending half their lives contributing to the trivial daily routine that makes up a tinnitus message board. More specific signs that a person has not recovered can be ascertained via the time stamps of the posts he or she writes: if a member is posting late into the night or during the early morning hours, well, again, you can be pretty sure that their so-called recovery is nothing but a concocted fantasy inside their own heads. So why do these "practitioners of self-deceit" exist? Well, I don't know the answer to that exactly, but my feeling is that it has to do with basic psychology relating to self-identity: a person who has lost everything (family, job, money, house, etc.) ends up seeking "status" via the only place they can now achieve that: a tinnitus forum! Call it a way to collect "social capital". Oddly enough such people think that they can successfully conceal their real reasons for being online 24/7. It's a bit like reading a chapter from "The Emperor's New Clothes" really. The "practitioners of self-deceit" are adept at preying on the "newbies" but often find themselves in hot water when they encounter the more veteran members who easily see straight through their futile behaviour and sometimes expose it (just like I have now).
  • The wannabe experts, keyboard warriors, and armchair critics! Along the same lines as the "practitioners of self-deceit", there tends to be a number of "wannabe experts" who populate the various tinnitus boards. Such members can be easily recognized as they dish out advice and knowledge on the cochlea like they have a ph.d in inner ear biology. Again, I perceive it as a way for them to collect social capital and status. Why does this type of behaviour manifest itself this way? Well, a person who has a chronic and disabling condition (possibly for life), will have nowhere else to go, and in a sense, their world shrinks leaving them with nothing to attend to but to focus on the condition itself. In the severe cases, tinnitus can be an all-consuming condition ‒ something I have definitely experienced myself (before I managed to recover). That is ‒ in my opinion ‒ why certain personality traits can be observed on tinnitus boards, specifically.
Making The Headlines

Research into inner ear therapies has exploded over the past decades. There are at least +10 pharma companies pursuing developments that may lead to cochlear therapies in the future. But there have also been setbacks: a much anticipated clinical trial (QUIET-1) for the treatment of chronic tinnitus was discontinued in 2016. And other pharmaceuticals have seen their share price decline sharply as a result of clinical trial delays or failures. All of which highlights the need for further research. Below, a look at some of the stories that made the headlines for one reason or another...

Auris Medical Completes Phase-III Enrollment For AM-101 (TACTT3)

AM-101 has the potential to become the first-ever drug specifically approved for the treatment of acute cochlear tinnitus. Having learnt from the patient profiles in the phase-II trial, the first of the two phase-III trials (TACTT2) was expected to demonstrate a statistically significant result. However, when the findings of the North American TACTT2 investigation were released in mid-2016, only certain subgroups in the study population demonstrated a clinically meaningful result. To compensate for the overall lack-of-efficacy, the 2nd of the phase-III trials (TACTT3) was extended to recruit an additional 120 candidates while also making adjustments to the evaluation of primary endpoints that determine efficacy. In September 2017, Auris Medical AG announced that the TACTT3 trial taking place in Europe had completed enrollment. Topline results are expected in the first quarter of 2018. AM-101 is an intratympanic delivered drug. [Media Link]

Towards An Understanding Of Tinnitus Heterogeneity

Frontiers Media has a so-called "Spotlight Award" which allows researchers to win a sponsored conference worth $100,000. In 2016, a group of tinnitus researchers decided to enter the competition and launched their chosen research topic on tinnitus. Through a lot of dedicated work via the social media channels, the topic marked a significant milestone earlier in 2017 as it reached one million views. Later on, it took the leading spot out of more than 4000 other research topics and is currently ranked number one. The research topic is therefore a strong contender for the 2018 award. I have personally contributed some 100 hours of my time towards making the research topic successful. More information on the one-million-views milestone can be seen here. [Media Link]

Otonomy Phase-III Trial For Ménière's Disease Recovers After Missing Primary Endpoint in AVERTS-1 Trial

The OTO-104 trial for Ménière's disease (AVERTS-1) unexpectedly did not meet its primary and secondary endpoints (for the treatment of vertigo). The announcement came at the end of August 2017. Having spent years to progress all the way to the end of the first of two phase-III studies meant that millions of dollars were potentially wasted in the process. The effect on the share price was palpable: the OTIC-stock lost roughly 80% of its value instantly. As a consequence of the trial failure, Otonomy Inc decided to suspend all current trial-related activities (including a separate study on chemotherapy-induced hearing loss). An internal reorganization of staff followed – along with a decision to prioritize OTIPRIO over pipelines that were still in clinical trials (such as OTO-311 (now-OTO-313) for tinnitus). The scenario was almost a repeat of what transpired at the same time a year earlier when Auris Medical saw its share value decline substantially after the inability to demonstrate efficacy in the TACTT2 trial for acute tinnitus. However, a subsequent data readout from the 2nd of the two similar AVERTS studies did meet its primary endpoint and Otonomy therefore shifted strategy once again with plans to bring OTIVIDEX to market – a move that may require an additional clinical trial. A bumpy ride is not uncommon for pharma entities that specialize in inner ear disorders. [Media Link]

RL-81 (Potassium Channel Activator)

In 2016, it was announced that Pittsburgh University had designed a new type of Kv-channel activator with improved specs compared to SF0034 and Retigabine. Trobalt (Retigabine) was originally marketed as an anti-epileptic, but with preclinical studies suggesting that it may also be useful for treating symptoms of tinnitus. Both SF0034 (developed by SciFluor Lifesciences) and RL-81 are more potent and selective versions of Trobalt. As a consequence, they may have the potential to treat tinnitus with fewer side-effects. Because of my involvement with Team Trobalt and contacts we had established, I was personally aware of the RL-81 development a whole year before it was announced in the media. [Media Link]

Mechanisms Behind Chronic Tinnitus

In October 2016, Pittsburgh University announced a partnership with the global pharmaceutical, Allergan. The aim of the partnership is to unravel the mechanisms that lead to sustained tinnitus (as opposed to what is responsible for triggering tinnitus in the first place). It is believed that acute- and chronic-tinnitus are two different pathologies and that each will require a different intervention to treat. When exactly tinnitus becomes chronic is not known, but Autifony Therapeutics was originally slated to be one of the first pharma companies to attempt to treat the condition (but the phase-II trial, QUIET-1, was halted towards the end of 2015). [Media Link]

European School For Interdisciplinary Tinnitus Research (ESIT)

2017 saw the birth of a new and large-scale tinnitus initiative that will stretch over a four-year period. The project which is EU-funded recognizes tinnitus as interdisciplinary study and aims to provide future students with academic rigour beyond what a single university can offer. The homepage of ESIT can be found via this link. I recall discussing ESIT with TRI as far back as the Summer of 2015, but it wasn't until 2017 that the project went live – a reminder of the timelines often involved in academic matters as well as clinical trials subject to rules and regulations. [Media Link]