Levetiracetam (Keppra) — Another Possible Potassium Channel Modulator?

would keppra work for reactive tinnitus if you have slight hearing loss ie,6htz 30dbs

 

Xexus Danny...you are still saying this???!!! Where did you get this piece of info???

Ref. Keppra and basics, including zero evidence that it works on Kv3 channels see this post in other Keppra thread:
https://www.tinnitustalk.com/thread...d-for-my-hyperacusis.8946/page-23#post-146596
And from that:

Note: For the non 'research oriented' but interested in Keppra, you may want to just skip down to the "key take-aways" in part 2. of this post...as yes, I do tend to drone on. Not changing my 'spots' now, sorry.

@svintegrity ...Ta much for add on info. post as indeed backs up the stuff I seem to be finding as dig deeper. Also much thanks to @111 down under, for two excellent tomes on Keppra (and Brivaracetam) which for the die-hards will get the 'links' below.

1. ~ OK...so for all you could ever want to know about Keppra (& Briv.) here is a link from a more than exhaustive study out of Germany in 2012. And don't get put off by it being in German to start with as the main text is in English. However,do be put off with the fact that it is 170 pages long before the 'references' start!!!

http://hss.ulb.uni-bonn.de/2012/3068/3068.pdf

I did not review it all. No way! However I did skim, and also looked for (search/find) key things of interest to me re. my whole initial approach to taking Keppra...that it was a Kv3.1 drug, like Autifony's famous star - or at least that Keppra had strong elements of Kv3.1 possible modulation.

Short answer...There is absolutely zero back-up or mention of that in this German paper. There is small reference to generalized Potassium channels within epileptic MOA ideas...and yes, in relation to our old comrade in arms (or hell, perhaps to some), Retigabine.

Conclusion on all that, to me OK, is that Keppra is not a Kv drug of any significance.

Thus I am no longer thinking of it in those terms, and no longer acting on it in those terms. Results, are as prior stated...I'm dropping off and not heading for 'break the doors down' dose effective inter-extra cellular neuronal saturation levels. *[And yes, Keppra is considered 'dose linear' but I consider that more relevant for the epilepsy modelnot the 'model' I had in mind. Also the Australian TGA paper next makes me wonder a bit WTF is going on with "dose" anyhow...or my concentration perhaps!].

2. ~ OK...the second paper, c/o the Australian TGA (which does some good work indeed...as per our research efforts on Retigabine, etc., etc.). This one is shorter and more readable, with some easier 'take-aways' that could be of interest to some here considering Keppra, or already taking it. *[And yes, I need to re-read it again (and maybe again!) to see what the hell is going on re the different "studies" quoted. That there is hardly any difference between doses of 1,ooo mg total v. 3,000 mg total, and that maybe Europeans act in a hugely different manner to Americans at even lower dose differentials???!!! Ummmmmmmm...must be me! Though the issue could just be that these 'problems' are all within the "Add-on AED Therapy" department, where more than just one AED...than just Keppra, is involved!. Plus they do not indicate which prior AEDs were actually used...So this could all be a red herring for us anyhow].

http://www.medicines.org.au/files/txplevet.pdf

Key take-aways, summarized in short (thus incomplete) sound bytes:

- Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore, there is no need for plasma level monitoring of levetiracetam.
Translate as: Body weight and size matter! (Also noted c/o @svintegrity).

- Following single dose administration (20 mg/kg) to epileptic children (6 to 12 years of age), the half-life of levetiracetam was 6.0 +/- 1.1 hours. The apparent body clearance was approximately 30% higher than in epileptic adults.
Translate as: Yeah you younger folks with less 'wear and tear' on your body parts are likely to unload Keppra faster and better than us more 'matured' (screwed over by various sundry health insults) folks.

- Monotherapy (i.e. = just Keppra, no other AED add-ons)...The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily very two weeks depending upon the clinical response. The maximum dose is 1,500 mg twice daily.
Translate as: The Aussies seem to believe in classic titration - both in and out of Keppra use. Mmmmmmm...

- Overdosage: The highest known dose of levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse events in the few known cases of overdose in clinical trials.
Translate as: Go wild! Compared to Trobalt, "Twinkies" may be more harmful to your health than this stuff. Well, as usual, not everyone is created equally and treat accordingly.

Ummmm... OK think that's about it for my Keppra 101. Now just observation and reflection...Wunderbar! Or possibly..."Shit, that is a bit of egg in the face!" could be more appropriate, depending on your disposition.

Best, Zimichael

 

"The SV2A, a presynaptic vesicle protein, was thought to be
involved in synaptic vesicle exocytosis and neurotransmitter
release (45). Several studies have demonstrated that the synaptic
vesicle protein 2A
(SV2A), a presynaptic vesicle protein, is the
binding site of LEV
in the brain, with which this drug can interact
to modulate the function of SV2A
(1, 6, 46, 47).
W
ith the aid of
the LAIGN program, we further evaluated the similarity of amino-
acid sequence between the SV2A
protein and the
α
-subunit of
K
v
3.1. Notably
, the portion in K
V
3.1
α
-subunit (human:
NP_001
106212), to which the sequence of SV2A
(human:
AAH00776) shares the similarity (36.2% identity), was found to
be located extracellularly at 385-431.
This region was located in
the S6 segment of the K
V
3.1 channel.
This comparison leads us to
speculate that the LEV
molecule binds to similar docking
region(s) to block
I
K(DR)
as well as to interact with SV2A
protein.
In fact, cortical neurons
in vivo
are subject to varying overall
levels of stochastic synaptic background activity
, which is
particularly intense during active states of the brain (48).
The noise itself is shown to generate an effective potential function
for the dynamics that is asymmetric and bistable. In our
simulations, LEV-induced changes in membrane potential tend
to be responsive to extraneous factors that control the resting
potential, such as synaptic input or neuromodulation.
Furthermore, based on our simulation results, the adding effect
of inhibition of
I
K(DR)
under the condition in which inhibition of
I
Na
occurs, causes the termination of AP firing, reflecting the
practical add-on role of LEV in Na
+
channel blocking therapy,
such as phenytoin or carbamazepine (49).
Voltage-gated potassium channels have become potentially
important molecular targets in modifying action potentials in
various disorders including neuropsychiatry disorders,
cardiology and oncology (50, 51). In addition to Kv3.1, there are
still several components contributing to
I
K(DR)
, including Kv 1
and 2 subunits. Although ubiquitous, in different tissues, the
components of the potassium channels and their physiological
function vary (52). Adequate modulation of these potassium
channels including
I
K(DR)
and
I
K(erg)
would potentially be useful in
clinical treatment (50, 53).
Taken together, from our study, the effect of LEV on
I
K(DR)
(Kv3.1), could provide a therapeutic potential in treating
epilepsy"


https://www.researchgate.net/public...ntribution_to_the_firing_of_action_potentials

 

@Danny Boy ... This study you reference is that "Huang study" again, which if I recall, we have been over before. I am not going to wade through it all again. But my memory serves, it was the only one with speculative reference to KV3.1 influence as part of a huge laundry list of neurotransmitters/synaptic trigger bio-chemicals/channel modulators and so forth, that had possible potential neurological implications for the MOA of Levetiracetam. There were just too many darn things that LEV triggered to say anything for sure!!! And the more recent studies post 2009 seemed to refute any reference to Kv3.1, etc., etc.
Yes it may have Kv3.1 action...but so do probably three dozen other AED's (anti-epileptic drugs) out there that have the classic "Mechanism of Action not understood" as their by-line!

Thus the words "may be" are more suitable than "is" or "does"...in my layman's scientific, but very thoroughly covered research on Keppra, and talking to some Kv researchers about it's MOA.

Zimichael

 

@Zimichael : my line of thinking is that if you swallow the various pills out there which may have impact on the various Kv-channels - all at once (and just once) - then I am pretty sure the person's tinnitus would go away...

 

@attheedgeofscience ...and if you don't want to try your novel approach there are always "the darts"!
Pin up names of all the common AED's out there (let alone the 'speculative ones')...or print this handy list below (which leaves out a lot of others I have run into, for some reason). Stick it on a wall, then just throw a dart and see which name it hits. Try it, and it may darn well affect your H, and/or your T!!!

NOTE: The observant will note that the list below does not even include the most common group of AED's that indeed a lot of us use! Our well tried and true (yet addictive) Benzodiazepines!!! That bunch could add another half dozen to the list below. *[Thus you could print out this list that does include them as major line, common AED's] ... http://www.healthline.com/health/epilepsy/medications-list#Broad-SpectrumAEDs3

• Carbogen modified release
• Convulex
• Desitrend
• Diacomit
• Diamox SR
• Emeside
• Epanutin
• Epilim
• Epilim Chrono
• Epilim Chronosphere
• Episenta (prolonged release)
• Epival
• Frisium
• Fycompa
• Gabitril
• Inovelon
• Keppra
• Lamictal
• Lyrica
• Neurontin
• Nootropil
• Phenytoin Sodium Flynn
• Rivotril
• Sabril
• Tapclob
• Tegretol
• Tegretol Prolonged Release
• Topamax
• Trileptal
• Trobalt
• Vimpat
• Zarontin
• Zebinix
• Zonegran

 

I can say I'm genuinely curious to see what would happen if someone were to do that - although any other result that death would surprise me.

This is why you shouldn't let me run clinical trials.

 

I have been trying this drug (Keppra in France) for several months by varying the dosage between 250 mg and 3000 mg per day. No effect on my tinnitus, no side effects.

 

Has anyone tried Biviracetam which is similar to keppra but suppose to be very effective for epilepsy?

 

→ Effect of Antiepileptic Drug Levetiracetam on Cochlear Function

"Audiogenic seizures."

Maybe why some with reactive tinnitus get relief. I think 4-5 benefitted here.

Levetiracetam is also mentioned here for hyperacusis caused by irritable neural pathways:

(Source)

Levetiracetam could be worth a look!

 

Are you going to discuss this further with a provider? Being that reactivity is my debilitation factor, something like this is like dangling a possible amazing carrot in front of me, however I worry about side effects and the coming off of it eventually and what possible hell that could be. It would be even more helpful to know a general timeline for Dr. Shore's device. If its not available in the USA 4-6 months from now, that would further make me consider something like this more. It's crazy to read @Viking's post and a few others who basically reported reactivity/hyperacusis just vanished.

 

I suspect reactive tinnitus and noxacusis to share the same mechanism. I wanted to get on Keppra but was denied (for now). I will attach the full article here for anyone interested. Maybe I'll find the time to read it in the near future.

 

Thank you for sharing that full text, @StoneInFocus. I will add it to my documents that I am taking with me on September 15th to my Neuro appointment. I have been waiting 5 months for this appointment and he is apparently a great doctor with compassion, so am hoping to get a script and see results! If I can calm my reactivity, I’m a functioning adult again.

 

I think I figured out the reason why Keppra works for some people with hyperacusis and reactive tinnitus. Apologies in advance if this has already been said before in this thread.



If I understood it correctly, in the synapses located at the basolateral membrane of outer hair cells (OHCs), electrical activity via the activation of voltage-gated L-type calcium channels causes releases of glutamate through vesicles into the boutons of type II afferents. We know that normally, "glutamatergic synaptic transmission from OHCs [to type II afferent boutons] is weak. Individual OHCs release single vesicles with low probability so that summed excitation from the entire pool [do not know what Fuchs means by entire pool] of presynaptic OHCs is required for action potential initiation. Maximal stimulation [?] of an OHC had a one in four chance of releasing a single vesicle during maximal stimulation. Each vesicle causes a 4-mV depolarization [of the type II afferent] on average, thus requiring 7 or more concurrent vesicles for the type II afferent to reach the 25-mV threshold for action potential initiation."

But here's the curious thing. Paul Fuchs found out that the number and size of OHC synaptic ribbons increased after mice were exposed to damaging sound. Using a statistical model Paul Fuchs estimated that a global 20 % increase in OHC ribbon count observed in the noise-exposed mice is estimated to cause a 99 % increase in action potentials [of type II afferent neurons] in response to maximal stimulation of OHCs across the entire population of 1000 (virtual) type II afferents.

In short, if I understood it correctly, acoustic stimulation --> L-type calcium channels open --> calcium ions enter the outer hair cell --> OHC depolarizes --> glutamate is sent to type II afferents --> Type II afferents depolarize.

Now, in the case of acoustic damage, because of increased ribbon number and size, the same OHC depolarization makes it more likely for a type II neuron to fire. So that is a possible reason why normally non-painful sounds become painful to people with hearing damage.

Keppra, and also Nifedipine, block the influx of calcium ions through L-type calcium channels. So theoretically it should alleviate hearing disorders where type II neurons are the culprit, as is the case with noxacusis and maybe (reactive) tinnitus as well.

 

Very, very informative. Thank you for this.

I asked ChatGPT for some more examples of that type of medications, and some of the ones that popped up were Amlodipine, Verapamil, Diltiazem, Felodipine, Isradipine, Nimodipine, Lacidipine, Bepridil, and Efonidipine.

 

Wow. Thank you so much for that information @StoneInFocus. That alone should get you a Keppra script, and it angers me to no end that you were denied it. I would go back or to another neurologist with all your info and demand to try it. I have been advised by my psychiatrist and 2 investigative pharmacists to ask the neurologist to try Keppra as they all feel, based on research, it could very well provide relief to my reactivity.

I am trying to keep my hopes in check, but given my circumstances and how my reactivity presents, I think there is a good chance it may help reduce my reactivity. My cause of tinnitus and reactivity was an ear infection that went into inner right ear, causing immediate damage to hair cells which caused SSHL. Reactivity set in almost immediately and worsened as time went on. @Danny Boy (RIP) also had an ear infection that started his tinnitus and reactivity, and others who had success with it seemed to have cochlear damage, whether it was noise induced, infection, etc. I also find if fascinating that @Viking stated that his reactivity/hyperacusis did not come back even after weaning off Keppra. Someone wrote they had read reports of that happening to a few others too.

My appointment is next Friday the 15th. I will update here if I get a script, and I am going to be asking for brand name if insurance will cover it.

 

Interesting. What makes you believe that?

 

I initially had an appointment with my doctor this Monday, but we had to reschedule to next week. In the previous week I have sent him some articles, including the one about ribbon count and size after acoustic damage I attached here. I am hoping the doctor has read the articles and I can make a good case for Keppra, or maybe even a Nifedipine prescription now.

Best of luck with your appointment, looking forward to hear from you and I hope Keppra provides you good relief.

 

Unfortunately I could not get a prescription for Keppra. The doctor said Keppra was 'expensive', a new drug and he had not really prescribed it for his patients before I believe. The doctor told me to try Pregabalin or Carbamazepine for two weeks, I opted for the latter.

I asked him if Keppra or Ivabradine are on the table if these two drugs were to fail,
but I could not get a clear yes or no out of him.

I am not really sure to what extent the doctor had read my articles, but it seemed like the article about the HCN2 channel and tinnitus caught his attention.

The doctor told me to stop the 0.5 mg Clonazepam without tapering off.

Considering the safety of Keppra and Carbamazepine, I considered the former to be the safest of the two. I am really spooked about the potential side effects of the latter.

It's really interesting that a psychiatrist and these investigative pharmacists advised you to ask for Keppra. Did they provide you with any articles? Why couldn't the psychiatrist prescribe you Keppra in this case?

 

Wow, your doctor said Keppra is a new drug?

Keppra has been around for a verrrry long time as one of the first go to anti-seizure medications.

My psychiatrist cannot prescribe it to me because it is not used off-label for any type of mood disorders, anxiety, etc like other anti-seizures are.

The investigative pharmacist told me that he and the others consider Keppra the “oldie but goodie” and with its safety profile and its mechanism on calcium channels it’s what they would recommend. My pychiatrist told me he came across Keppra being used successfully in some cases but again, he cannot prescribe.

 

I do not know where you have done your research, but after reading a lot of user reviews on drugs.com, I´ve come to the totally opposite conclusion. Actually, I don´t think I´ve ever read such many horrifying reviews on a drug as I have with Keppra.

There are some things you should know about Tegretol as well. It is a GABA agonist. The only other drug I know of to be just that is barbiturates. A bit scary. No wonder it worked so well on my benzo withdrawal.

As I´ve said before, it´s also such a strong inducer of the CYP 3A4 enzyme, that not only will it affect the metabolism of other drugs, it kind of trips its own foot as well ("auto induction"). After 2-3 weeks on the drug, the serum concentration of the drug will decrease by ⅔ and you will have to up dose to remain a "steady state". It has a really long half-life though.This is from what I have read and understood. I might be wrong.

As you know, it helped me with my tinnitus and noxacusis more than any drug I´ve ever tried (over a short span) and I am sure it will help you as well, but I really question its viability.

Part of my claims comes from this article (PDF).

It´s worth trying, as I think, like me, you are desperate for relief.

By the way, I experienced no side effects. Only interaction problems.

 

Carbamazepine scares me because, according to Wikipedia, it is a possible serotonin reuptake inhibitor. Carbamazepine might also be ototoxic.

I have never read anything about Keppra causing adverse effects that last permanently, unlike Carbamazepine or SSRIs.

"Of the 99 [trigeminal neuralgia] patients who had a good initial response [to carbamazepine, CBZ], 19 developed late resistance in that the pain recurred and did not then respond to CBZ. In these cases, resistance developed 2 months to 10 years (mean 4 years) after commencing treatment."

I'm not too worried about developing tolerance for now. My first objective is to find something that can alleviate the pain at all, and then subsequently translate that to a long-term treatment strategy.

The doctor told me to take Carbamazepine 100 mg two times per day for two weeks. I've started yesterday. Maybe I'll ask the clinic if I can take a higher dose next week if I don't suffer from any serious side effects the following days nor notice much effect on my noxacusis.

How is your benzo withdrawal doing?

 

I have been on SSRI for 25 years. Nothing to be scared of.

There is something called "Keppra Rage". Just does not sit well with the inhibitory effect we try to achieve. It is also to my knowledge the only antiepileptic with no off-label prescriptions. And even for its indication it gets a lousy score.

Benzo withdrawal is killing me.

I started Oxcarbazepine again today 150 mg twice a day. I will evaluate after a month.

Maybe we should start a new thread called "Tinnitus, Noxacusis and Anti-Epileptics"

 

Yes, I've heard about that phenomenon as well. As I'm already prone to anger outbursts I can only imagine the terror I'm going to inflict on this forum when on Keppra Luckily I'm on Carbamazepine then.

I wish you the best man. Hoping you find the strength to ride it out.

If you make one, I'll post a nice comment there If I have good results from the Carbamazepine, I'll make a separate thread for that in the hyperacusis subforum.

 

My neurologist had no issue writing me a script for Keppra. I'm picking it up this afternoon, and I will start with the first dose tonight. I'm starting on a low dose, 250 mg twice a day, and will up it in a week or so.

Now, just praying with all of me that it actually works against my reactivity.

 

Well done @ErikaS.

 

That's so exciting! Please let us know how it goes!

You have reactive tinnitus, eh? Any signs of loudness hyperacusis or noxacusis?

 

I hope it goes well for you @ErikaS - I have my fingers crossed!

Let us know how it goes.

 

Thank you! I will definitely share updates.

No loudness hyperacusis or noxacusis, but I’ve definitely developed negative emotional responses to certain sounds that agitate/spike my tinnitus. And yes, reactive/sound sensitive tinnitus to the max. I told the neurologist it’s like sound keeps my tinnitus alive.

 

This is day 3 of 250 mg of Keppra twice a day.

Right now my main and most debilitating tinnitus sound is worse.

My ultra high frequency electric sound where I had my sudden hearing loss in the right ear from ear infection that falls anywhere from 12 kHz to 15 kHz is very prominent, sensitive, and intrusive in both ears. This is my most debilitating sound especially when reactive, so I am nervous and discouraged being 3 days in on a drug that has literally done the opposite for others. I want to believe there is a chance that things could just be acclimating and get better, but I’m not aware of anyone on Tinnitus Talk who is still active and who has taken Keppra to discuss these concerns with.

So yeah, so far, increased sensitivity and intrusiveness.