Brivaracetam — KV3.1 Modulator

I also think this thread should be moved to the "alternative treatments" forum, unless someone can point me towards peer-reviewed evidence with regard to the efficiency of this drug for tinnitus specifically.

 

I've not read anywhere of Keppra doing anything for tinnitus. Search the internet and there's results of individuals concerned it is causing tinnitus, not improving it.

 

No, it's a "new discovery" made by @Viking 's doctor. I don't think anyone have tried it for T before Viking did. The same with Retigabine. You won't find any anecdotes about that either before Mpt had success with it on this board.

 

@lapidus oh, ok. I would be interested to learn of his experiences. Maybe you can link me to his post.

 

Unfortunately the internet is crammed with clinical trials, ad hoc statements stating this that and the other about drugs, and treatments for tinnitus, some peer-reviewed some not. The conclusion is that there is nothing that works, hence the lengths that sufferers go to in trying to find their own solution.

True, this thread should not be in "Treatments", but then again what should be?

 

I agree with the gist of what you said, but still feel that there is a value in drawing a line between things which at least attempt to be evidence based and are being offered as an insurance-billable medical service, and things which are entirely speculative, experimental, or outright unscientific. So, on the one hand, you have TRT, CBT, neuromonics, actual clinical ACRN... on the other hand you have DIY ACRN, Keppra, and reiki crystals.

 

@linearb
TRT/CBT are helpful to some patients. It's the only treatment offered by the UK health service.
Clinical ACRN/Neuromonics have recently been scientifically re evaluated and major flaws were shown in previous positive findings. There is a thread about it on here.

It's why there is so much interest when serendipity occurs with drugs like retigabine. We all want hard evidence-based and scientific positive findings of something that really works for this condition, but it isn't at that stage yet.

 

This post:
https://www.tinnitustalk.com/thread...um-channel-modulator.7295/page-10#post-109010

 

"Studies conducted by Prof Len Kaczmarek’s group at Yale University suggest that Autifony’s Kv3 modulators may help to restore the timing of firing of neurons in the auditory brainstem important for central auditory processing."

Brivaracetam=KV3.1 modulator=same target as Autifony's new drug. Keppra=KV3.1 modulator Brivaracetam is basically keppra but 10x more potent.

 

Yes, for sure. Animal studies that conclude "may help" are not evidence about what happens in a human. If anything, they are a starting point for human trials, nothing more.

I don't want to be condescending, but this comment makes me think you don't know nearly as much about pharmacology as you think you do. The simple fact that two different molecules act upon the same receptor site is in no way a sign that they're equivalent in action (see: THC vs WIN 55,212-2), and the observation that Keppra is a "KV3.1 modulator" is a vast oversimplication. Do you know what Keppra's mechanism of action is? If you do, then you've got the best minds in the industry beat since the official summary is still 'mechanism of action: unknown'; however, in addition to its potassium activity, it binds to glycoprotein and is also a calcium channel modulator. Does AUT-0063 do either of those things? If not, it's completely unreasonable to suggest that the drugs are anything alike. Benadryl, Prozac and LSD all exert action at 5-HT2 receptors. Are these drugs similar? If you had a runny nose, would you be comfortable taking some LSD to treat it?

 

You're very pessimistic. As you said Keppra has an unknown mechanism which nobody knows how it works, so sorry to tell you, but even the best minds have no clue how keppra works. So if you think I'm oversimplifying things, it's because nobody knows how keppra truly works. Keppra does work on the KV3.1 channels. http://www.ncbi.nlm.nih.gov/pubmed/20065495

Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (KV3.1): contribution to the firing of action potentials.
Huang CW1, Tsai JJ, Huang CC, Wu SN.
Author information

Abstract
Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the K(V)3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K(+) current (I(K(DR))) in a concentration-dependent manner with an IC(50) value of 37 microM. LEV (30 microM) shifted the steady-state activation of I(K(DR)) to a more positive potential by 10 mV, without shifting the steady-state inactivation of I(K(DR)). Neither Na(+), nor erg (ether-a-go-go-related)-mediated K(+) and ATP-sensitive K(+) currents were affected by LEV (100 microM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating I(K(DR)) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating I(K(DR)) (K(V)3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.

 

I'm optimistic on all these things. I want this stuff to work! But, I don't let my optimism cloud my critical thinking.

At this point you are being very inconsistent in what you're trying to communicate. Look at this:

I did not say "Keppra and by extension brivaracetam are worthless for audiological disorders and not worth pursuing". I don't think that's true at all! All I said was that there's almost no reason to think that Keppra has much in common with AUT-0063, because the simple fact that two drugs exert (some of) their action on the same target doesn't actually tell you much about them.

If I bristle at anything, it's not optimism, or even mindless optimism. The thing that rings my bell is when people make wildly unscientific claims about experimental drugs in an obvious effort to get other people excited to try them. These drugs can clearly be very dangerous. We have two anecdotes from people on this forum that Keppra was in some way helpful for their audiological complaints. Want to hear some other anecdotes about Keppra?

There are many, many more where those came from.

I have no problem with people taking experimental drugs to see what happens, I think that everyone has the right to put whatever they want into their bodies. Encouraging other people to do so is extremely irresponsible. And yes, I am very biased by my own experience, but my experience is that tinnitus is actually a pretty insignificant problem compared to the kind of crazy shit that happens to people when they start gobbling random psych meds.

 

Tinnitus is a insignificant problem? Surely this is a joke? People commit suicide over tinnitus, people would rather die than live with tinnitus. I don't think you personally have really bad tinnitus, as I did...I am sat here, risking my vision with trobalt, just so I can live a few months with peace....I have lived through hyperacsusis, super loud tinnitus and reactive tinnitus. I have to live with this, for the rest my my life, knowing that, if it returns to baseline, I'd have to kill myself, so I won't suffer. That's not insignificant at all.

 

Re-read what I said in context and you will see that I was making a comparison, not speaking in absolutes. Tinnitus is wretched.

I would bet a mint that far, far more people have killed themselves as a result of prescription drug reactions than tinnitus.

You are nitpicking one thing that I said. I was not implying that tinnitus doesn't suck, I was implying that it's far from the worst thing that can happen to a person, and that all of these drugs carry tremendous risks.

You don't know anything about me, you do not know how much I have suffered with tinnitus over the last six years, and you don't know anything about the radical, fundamental changes I've had to make to my life to find a way to be happy in spite of that. I have no idea if my tinnitus is better, worse, louder or softer than yours, and I also don't care because it has no bearing on anything.

 

Listen. You've lasted a far longer time than me. I would've been dead by now, if I didn't try these drugs. If mine goes back to baseline, I promise you I will kill myself and there's nothing that would change my mind. I am not suffering with what I had, it was far too much. Anyway, if you're ok, that's cool, I'm glad for you. I am only trying to find alternatives to the infamous trobalt, as that drug is dangerous. Why don't you comment on the trobalt thread and remind people how dangerous that is, instead of calling in dispute a drug which isn't even out? I like to give people hope, as hope is all that some people have. If you go through my very old messages, you would know that I basically wrote a suicide note on here, that's how bad I was. I lasted 3 months and I went on trobalt, which improved my life and made me want to live again. When my GP told me, this was a few weeks back, that she wouldn't give me trobalt, I cried, I cried because I knew this was the ending for me...I may only have a few months left, as when I run out, if the effect isn't forever, I'll be dead. Might as well, put a gun to my head and just pull the trigger.

 

I think this is completely reasonable. Re-reading my posts here, I think I have made a typical mistake that I make, which is being more concerned with being right than being nice. And that's a fallacy, because there's no such thing as being objectively right.

I had plenty of days early on where I thought I'd kill myself if I had to live with the noise. Where am I know? Well, I sure don't love it. If you asked me, "if you could fix one thing about your body, what would it be?", tinnitus would certainly be in the running there. The thing is, though, the only things that tinnitus really stops me from doing, is going to loud concerts and stuff. I also have some joint problems that keep me from being as active as I'd like to. So, at this point in my life, if I had a magic way to fix one and only one health problem, well, I'd have to think about it very, very carefully.

Obviously this issue still distresses me more than I'd like; when I let it bother me, then I do contemplate Trobalt (got a script at one point, never filled it), Fasoracetam (bought several samples of it, never consumed any), going back on benzos (fat chance! That crap was actually worse for my quality of life than the ringing).

When this was a new problem for me, I let it bother me all the time, and had literally no idea that I had any say in the matter at all. These days, any time I find myself really distressed about my T, I can generally look at my lifestyle over the weeks/months prior and identify a couple obvious things I've done "wrong". Maybe I'm too stressed, I haven't been sleeping well enough, I've been drinking too much, etc, etc. So, that's a drag, because it does impose some constraints on my life that people without this problem do not have to accept. But, I've also spent some amount of time around people with chronic illnesses which are much more physically disabling, and so I understand that the constraints that tinnitus poses on my life are not that bad compared to a lot of the things that other people live with. That wouldn't make me feel better on the face of it, but I've known a good number of people with problems that make me think "I would kill myself if I had to live like that", and the thing is not that they merely survive, it's that they describe big chunks of their lives in glowing terms, and talk about how happy they are.

I really hope that this doesn't turn into a chronic problem for you, and that you're able to recover and hopefully just take it as a brush with chronic illness, think "thank God that's over", and move on with your life. But I am also saying, if that does not happen and this is a chronic problem, your relationship with it will change over time.

When I was 14 I contemplated suicide because some kids were mean to me at school. So, the simple fact that someone contemplates suicide over something, doesn't mean that it's actually a horrible, unfixable problem: it often means that they are caught up in the situation and letting their anxiety cloud and color everything.

I absolutely, 100% agree with you that finding a way to hold on to hope and have faith that things can and will get better in time, is an absolute requirement for weathering tinnitus or any other chronic disease with a smile on your face. But, I don't think people need to necessarily look to artificial molecules to find that.

I apologize for derailing this thread a little bit with a bunch of boring 900 word posts. For the record, I do think the calcium-channel racetam drugs are an interesting potential avenue of exploration for hearing disorders.

 

Listen, I honestly don't believe for one second your tinnitus is that bad. I have it in both ears, I had hyperacusis and reactive tinnitus and there was no masking. I had amplification to noises where I couldn't go out and all the noises hurt...I just caved in and trobalt was my last resort. To me, I would rather have aids, have cancer or die than have lived with what I had. My tinnitus is low, but the risk? My vision, I could go blind. And I'm scared. You have no idea what am I am going through....I could lose my vision and if I stop I'd have to kill myself. I can't handle all these choices. I hope you or nobody has to go through what I had to go through. I wish euthanasia was legal over here, so I could just apply and have it over and done with...But I can't...So I have two choices, take trobalt so I have low tinnitus and trust me, trobalt is costing me 500 dollars a month to buy...So I am desperate...So I'm waiting for this, to go blind, run out and hope it's caused a permanent change or just kill myself if it hasn't.

 

I have experienced all these things. More frequently than I would like to!

It's pretty irritating for you to tell me that you do not believe me about my own personal experience, but it's also a bit telling. You are stuck in a place where you literally don't believe that anyone could experience sounds like you are, and react to them differently. I don't know what my tinnitus sounds like compared to yours, but I too definitely had a period where I did not believe it was possible to react to my own ringing with anything other than aversion, horror and desperation.

This is a an example of a very classic cognitive distortion, specifically polarized thinking. That is, it is not the case that if you stopped taking Trobalt you'd have to kill yourself. I know that you very much believe that, but that doesn't make it true.

I have watched someone I love die of cancer. I had no idea what that meant until I saw it for myself, and I don't believe you do, either. So, I'm fairly convinced that you would be quite happy to trade tinnitus for cancer until you felt it ripping through your body, at which point you would no doubt be horrified at the tradeoff you'd made.

Think about it this way. Based purely on the available longitudinal data, tinnitus is a disease that nearly everyone who is stuck with it, learns to live with to some extent, and almost everyone who truly has it long term gets to a point where they at least say that it is not as distressing as it was during the first months/years, even if it continues to be a significant bother. Cancer is a very serious disease that ravages the body, is often fatal or worse, and the treatments for which can themselves cause terrible suffering (including horrendous tinnitus and deafness in many cases.)

So, what you are saying here is, "I would rather have a disease that stands a good chance of ravaging my entire body and killing me very painfully, than a disease which almost everyone eventually comes to terms with". That's just not a reasonable thing to say, it can't be defended logically, and it implies that the person saying it is not thinking clearly.

So, which of these two things do you not believe?
1) do you not believe that cancer/AIDS stand a good chance of ravaging your entire body and killing you painfully?
2) do you not believe that almost everyone eventually comes to terms with tinnitus?

If you disbelieve either of these things, what is your basis for disbelieving them? There is a large amount of peer-reviewed data on both subjects, and no data I am aware of to contradict either.

So then, I believe what you are really saying, is "I don't believe that I am capable of coming to terms with this problem, I am too scared and stuck in my head with my suffering to believe that's possible." And to that, I say, "AMEN, BROTHER! I have been there! It is the worst feeling in the world!" But, it truly does get better with time. So, if you want to hold on to hope and have faith, then have faith that you are not alone, that other people have walked this path, and that there is a way forward that will leave your sanity intact and your life much as it was before any of this nonsense came in to the picture.

As long as you only give yourself two options, then you only have two options. Once you start giving yourself more options, then you will have more options. If you are truly saddled with this issue long term, then the odds are overwhelmingly good that you will find more options, because the number of people who commit suicide over tinnitus is staggeringly small compared to the number of people who have it (and I am only counting the serious cases, who end up in ERs and worse).

 

Listen mate. I was trying to hang myself every single day last year, asking everyone to kill me and to let me die...I wanted to kill myself in every imaginable way possible. I don't think you've ever had reactive tinnitus or hyperacusis have you? Because if you did, you'd understand. I have saw what cancer can do, it leads to death. Tinnitus not so, with tinnitus you either try to live with it or you give up and try and find a horrible way to kill yourself. And everyone in your family will hate you for that. Nobody blames the person with cancer for having cancer, even if it was through smoking or other things. But with tinnitus, I had no choice, I got an ear infection and bang tinnitus and that was not preventable as I always suffered with ear infections and there was not much I could do. And now, I feel that if this keppra, campral and trobalt combo doesn't work, I will have to kill myself. That's just how I feel, if you can't understand that some people have tinnitus so bad that they have to kill themselves then I am not going to convince you. With cancer, there's treatments which may help...With aids there's treatments which can ensure you live longer, with tinnitus there are no official treatments.

 

You weren't very good at it, then. Bodies are fragile and not that hard to disable in a permanent way.

I just said that I had in my last post.

More black and white distorted thinking; many people do not try to live with it, they only try to do so until they learn how, and then it becomes automatic like breathing.

This definitely is not true, https://www.google.com/search?q=my family blames me for having cancer&rct=j

Yup, it sucks! I was hit by a truck on my bicycle a few years ago and my knee has never been the same since. It's a real bummer that bodies can't repair a lot of the damage they are subjected to over time, and coming to grips with that in some way is a fundamental part of human experience.

Oh, I believe you! I believe that you feel that you have to kill yourself. But, that doesn't make it true, it's just a feeling. When you are in a state of severe, protracted, unpleasant anxiety you should not believe many of the thoughts you think, because feelings and thoughts change over time.

Okay, so from this is it fair to assume that even though you believe you'd rather have cancer or AIDs than tinnitus, you would not rather have ALS or parkinson's than tinnitus, since neither of those diseases have solutions or cures either, and they are more physically disabling?

 

You're right. So you're never gonna try keppra even though you can help yourself? Anyway, look. All the information is out there now, so honestly I don't care. I can't be fussed with any of this.

 

Hang in there, man. It will get better. I promise. I wish I could say it'll get better tomorrow, or a week from thursday, but unfortunately I have no way of knowing, and for me it took a lot longer. And, to be clear, I still have days where I obsess with the noise and think about it a lot and get sad/distressed. But, there are less and less days like that in my life, and more and more days where I think about it very little.

I had a fantastic night out with my wife last night. We went to a nice restaraunt. I will admit that when we first walked in, I did check the volume level of the music, to make sure I'd be comfortable hanging out there for a couple hours (72db, yay for places that don't feel the need to crank it up to 11). I'm pretty sure that was the last time I thought about my ears during that dinner until I put my earplugs in to get on my motorcycle on the way home. I'm also confident that if you end up dealing with this for as long as I have, you will also eventually find that you have more and more happy days thrown in where you just don't think about your T very much.

 

I honestly wish I could.

 

@linearb just because you have mild t doesnt mean tinnitus isnt insignificant to other things.. I have very very very bad T.. I have 5 different tones in my head which are very horrid.. 90% of t sufferes will never get severe t. So consider ur self lucky. If u had my symptoms u will be running towards the nearest bridge to jump off of. I am still here luckily hoping for a miracle.Dont u think people that are going out of there way experimenting maybe have nothing to loose as they are on the verge of suicide.. I had mild t for my first 1 1/2 years..with permanent spikes even then , i shouldved known that wasnt normal as i know now.. Ive contracted H twice the first time it was mild and didint affect my T .. Now this time around it came with a vengeance since december my T has worsened so much and still is. My H is so bad when ever i hear anything remotely loud that my ears percieve as loud it triggers something in my head and my T spikes bad and my tones change in sounds it is very terrifiying. I would give anything if i can have regular mild t again that is pancake compared to this.. Idk why my t and h react the way they do.. I really cant find anyone like me.. Mostly everyone on here has mild t and cant relate. I dont even feel safe at my house.. I hear lawnmoreres, loud cars with bumping stereos i hear everything and my t reacts to it.. And before u say its anxiety it isnt. I dont sufferer much from it as when this happens i just sit down and take it all in and wait for the madness to begin. Dont generalise ur situation with everybody . Dont say tinnitus is not that bad, say your t isnt that bad. I get really offended when i hear people saying t isnt bad becuase there are real sufferers out there and everyday its a challenge and mix that with H and you have a disaster waiting to happen.. And the reason why real bad sufferes get looked down is because certain ppl think we are exaggerating how bad it is because everyone seems to the same.

 

You're spot on there mate!

 

Just so tired of people that try to generalize everyone.. Or saying it isnt that bad.. If we had the same t then im pretty there will be no need for this site..

 

I agree with you Geo..100%. The lack of understanding between tinnitus sufferers seems to be dividing...No wonder why a normal person looks at tinnitus and finds to to be nothing if people with so called tinnitus call it insignificant.

 

Yes it is.. Its like we should be seperated into two groups severe/ mild seems like mild sufferers cant stand to bare when a severe one speaks on his..when i had mild t suicide never crossed my mind once, i lived my life i still worked outside with loud noise , hanged with friends, exercised.. And i would say it was a bit over mild as i can hear ot easily but not severely. I cant even function right this noise drains my whole body and brain as soon as i wake up, it seems in waiting til i cant tolerate it anymore its very gruesome.

 

You know both sides of the story, so I know for sure you know what it's like. I'm just hoping to god people like us can find some permanent relief.

 

For the fiftieth time, don't pretend to tell me what my tinnitus is or isn't, you have no idea and your condescension will earn you no smiles. I don't know how my tinnitus compares to yours, or care, but I have spent years of my life and thousands of dollars exploring and trying to make peace with this issue, and it has driven me to the absolute brink of desperation, despair and even into fully delusional thinking that I'd say borders on actual insanity. I don't pretend to have the worst tinnitus in the world, I don't know what that even means or what it's like, but I can tell you about nights spent awake figuring out how to kill myself painlessly, I can tell you about periods of time where I had to leave my home and family and go spend time in quiet, calm, peaceful environments by myself, I can tell you about laying under the shower smacking myself in the face over and over, and my wife can tell you about time she had to spend watching her adult husband sobbing on the floor, swearing that he wants to die and leave her alone forever because he can't come to terms with the sounds in his head.

So, is my tinnitus worse than yours? I have no idea and neither do you, but that has literally zero to do with anything I've said here. Get back to me when you've been dealing with this for as long as I have, and let me know what you think then.