Theories on Middle Ear Noxacusis and Potassium Channel Openers?

[haha ear go eeee]

I've been pondering potential trial drugs for primarily middle ear noxacusis, and I'm wondering if the upcoming potassium channel openers (like XEN1101 and BHV-7000) will help with it at all?

We know they will probably help inner ear noxacusis, but there hasn't been any studies done on the middle ear's response to potassium channel openers. Will they only work if the middle ear is responding to inner ear damage? Does there have to be noxacusis in both areas of the ear?

What does everyone think about this? Do you think we'll have the same amount of relief compared to someone with inner ear noxacusis? I'm very tempted to try out Epidiolex or high amounts of CBD isolate and see if opening those channels has any effects on my symptoms.

 

[MadeleineHope]

Great question!

Do you know why potassium channel openers might be helpful for inner ear hyperacusis?

(Sorry, not caught up to date with this!)

 

[haha ear go eeee]

Great question!

Do you know why potassium channel openers might be helpful for inner ear hyperacusis?

(Sorry, not caught up to date with this!)

It's all good! So there was a study published in 2015 found that opening the Kv7.2 and Kv7.3 potassium channels in mice "suppressed the type II fibre's response to hair cell damage". This was done by using the drug Retigabine (Trobalt). As we know, inner ear noxacusis most likely stems from those type II causing pain signals and being sensitized.

Multiple people on the Trobalt thread that tried it when it was available said that their tinnitus and hyperacusis symptoms were reduced, and in some cases completely disappeared. Of course, some people saw no benefit or got horrible new symptoms, this is speculated to be because it acted on Kv7.4 and Kv7.5 and not just those two channels involved in hyperacusis, so some people had their Kv7.2 and Kv7.3 channels affected more.

Of course, I personally believe only the Kv7.5 channel isn't meant to be opened, and that was causing the side effects. This is because XEN1101 and BHV-7000 act on Kv7.2, Kv7.3, and Kv7.4 without causing those same side effects. Meanwhile, Gabapentin (which affects Kv7.2, Kv7.3, and Kv7.5) can really help some people, or can cause visual snow.

I hope this clears everything up!

 

[Lucifer]

It's all good! So there was a study published in 2015 found that opening the Kv7.2 and Kv7.3 potassium channels in mice "suppressed the type II fibre's response to hair cell damage". This was done by using the drug Retigabine (Trobalt). As we know, inner ear noxacusis most likely stems from those type II causing pain signals and being sensitized.

Multiple people on the Trobalt thread that tried it when it was available said that their tinnitus and hyperacusis symptoms were reduced, and in some cases completely disappeared. Of course, some people saw no benefit or got horrible new symptoms, this is speculated to be because it acted on Kv7.4 and Kv7.5 and not just those two channels involved in hyperacusis, so some people had their Kv7.2 and Kv7.3 channels affected more.

Of course, I personally believe only the Kv7.5 channel isn't meant to be opened, and that was causing the side effects. This is because XEN1101 and BHV-7000 act on Kv7.2, Kv7.3, and Kv7.4 without causing those same side effects. Meanwhile, Gabapentin (which affects Kv7.2, Kv7.3, and Kv7.5) can really help some people, or can cause visual snow.

I hope this clears everything up! Let me know if you have any questions!

Whereabouts in the study does it specifically state that Kv7.2 and Kv7.3 were the potassium channels that were open? I can't seem to find it in the 2015 study. It only mentions potassium channels in general.

That's interesting regarding Gabapentin. I saw some users mention that Gabapentin helped with the burning pain from noxacusis. I didn't realise that it only opens up Kv7.2, Kv7.3 and Kv7.5. I always thought Kv7.4 might have opened as well with Gabapentin.

There is a good chance that we may only need Kv7.2 and Kv7.3 for tinnitus and hyperacusis/noxacusis so BHV-7000 or XEN1101 should help us.

 

[haha ear go eeee]

Whereabouts in the study does it specifically state that Kv7.2 and Kv7.3 were the potassium channels that were open? I can't seem to find it in the 2015 study. It only mentions potassium channels in general.

That's interesting regarding Gabapentin. I saw some users mention that Gabapentin helped with the burning pain from noxacusis. I didn't realise that it only opens up Kv7.2, Kv7.3 and Kv7.5. I always thought Kv7.4 might have opened as well with Gabapentin.

There is a good chance that we may only need Kv7.2 and Kv7.3 for tinnitus and hyperacusis/noxacusis so BHV-7000 or XEN1101 should help us.

Oh it's just in the Abstract section: "Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term "noxacusis" to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber's response to hair cell damage."

(Rereading your comment again, I have no idea where it mentions those specific channels though, that might be from another study.)

I'm not 100% sure, but I'm pretty sure it's just those three that are activated. Google's saying the same thing as well! If we need Kv7.4, maybe that's why Gabapentin's effects are so hit or miss?

I agree! It's a good thing those drugs also cover Kv7.4 just in case we do need it for noxacusis!

What do you think about potassium channel openers and their effects on middle ear noxacusis?

 

[MadeleineHope]

Thanks for the summary @haha ear go eeee! I suppose the question now is, assuming that the Norena model re: middle ear noxacusis is correct, where in that model would these potassium channels be involved? Would it be at the point where nociceptors are activated, for example? It seems like a thorough reading of this paper combined with some outside research would help, but honestly I'm just not in that headspace right now, haha.

 

[Lucifer]

Thanks for the summary @haha ear go eeee! I suppose the question now is, assuming that the Norena model re: middle ear noxacusis is correct, where in that model would these potassium channels be involved? Would it be at the point where nociceptors are activated, for example? It seems like a thorough reading of this paper combined with some outside research would help, but honestly I'm just not in that headspace right now, haha.

This is a good diagram from Biohaven presentation slides on the potassium channels and where they are on the body.

From the 2015 case study it was stated "Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term "noxacusis" to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber's response to hair cell damage."

They never stated which potassium channels were open to suppress the type II fiber's response to hair cell damage but I'm thinking they were referring to Kv7.2 & Kv7.3 where the synapses are on that diagram. Hyperacusus/noxacusis may be related to Kv7.4 as well but I feel like it's unlikely to be the case. We would know if we need Kv7.4 once BHV-7000 comes out first.

It's a shame we don't know the exact difference between the potassium channels that were open and by how much with Trobalt and BHV-7000/XEN1101.

 

[MadeleineHope]

Okay, so to help clarify, I found this today:

Apparently, Trobalt is a "positive allosteric modulator of the neuronal potassium channels KNCQ (Kv2 to 5). Under normal physiologic conditions, KNCQ channels help establish the neuronal resting membrane potential, by providing a continual hyperpolarizing influence. Retigabine increases the number of KNCQ channels open at rest, effectively limiting the overall excitability of neurons and facilitating their recovery from membrane depolarization."

Now I'm starting to remember things from a neurobio class, haha. Honestly, since potassium channels are so fundamental to neuronal function, & we can't pick & choose where exactly we want to limit neuronal excitability, these drugs are going to have very significant side effects either way :/

I also find it interesting that some people experienced visual snow with potassium channel opening, given that this is supposed to decrease, not increase, neuronal excitability. Does anyone know why this may be?

And just found this now too:

"In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2–5 channels, particularly heteromeric KCNQ2/3."

So it seems that Kv2 & Kv3 are affected the most, though there's an impact on the others as well.

EDIT:

Back with more research information to share! Haha. So apparently according to this study, "activation of Kv7 channels by retigabine, an activator for Kv7.2-5, reduces CGRP release." And we know that CGRP is an important player in the Norena model! So on this basis, I think it's possible for potassium channel openers to help with middle ear noxacusis too.

 

[haha ear go eeee]

Thanks for the summary @haha ear go eeee! I suppose the question now is, assuming that the Norena model re: middle ear noxacusis is correct, where in that model would these potassium channels be involved? Would it be at the point where nociceptors are activated, for example? It seems like a thorough reading of this paper combined with some outside research would help, but honestly I'm just not in that headspace right now, haha.

No worries! I think your theory is correct though, that would make the most sense. I'm not expecting a response back or anything, but I emailed Philippe Fournier and Arnaud Noreña and asked them if they had any progress with finding out if the middle ear responds to the inner ear and if they think potassium channel openers will have any effect on our symptoms.

Okay, so to help clarify, I found this today:

Apparently, Trobalt is a "positive allosteric modulator of the neuronal potassium channels KNCQ (Kv2 to 5). Under normal physiologic conditions, KNCQ channels help establish the neuronal resting membrane potential, by providing a continual hyperpolarizing influence. Retigabine increases the number of KNCQ channels open at rest, effectively limiting the overall excitability of neurons and facilitating their recovery from membrane depolarization."

Now I'm starting to remember things from a neurobio class, haha. Honestly, since potassium channels are so fundamental to neuronal function, & we can't pick & choose where exactly we want to limit neuronal excitability, these drugs are going to have very significant side effects either way :/

I also find it interesting that some people experienced visual snow with potassium channel opening, given that this is supposed to decrease, not increase, neuronal excitability. Does anyone know why this may be?

And just found this now too:

"In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2–5 channels, particularly heteromeric KCNQ2/3."

So it seems that Kv2 & Kv3 are affected the most, though there's an impact on the others as well.

EDIT:

Back with more research information to share! Haha. So apparently according to this study, "activation of Kv7 channels by retigabine, an activator for Kv7.2-5, reduces CGRP release." And we know that CGRP is an important player in the Norena model! So on this basis, I think it's possible for potassium channel openers to help with middle ear noxacusis too.

It's unfortunate that we can't fully pick and choose yet, hopefully that'll come soon though!

I have absolutely no idea why it may cause visual snow in people. I'm guessing it's because of the Kv7.5 channel, maybe there's multiple pathways on what causes visual snow? I hope XEN1101/BHV-7000/Epidiolex don't cause it since they only seem to affect the channels we need.

Oh that makes me feel so much better! Didn't Wood suggest that CGRP may be causing a role in our noxacusis as well?

View attachment 55422

This is a good diagram from Biohaven presentation slides on the potassium channels and where they are on the body.

From the 2015 case study it was stated "Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term "noxacusis" to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber's response to hair cell damage."

They never stated which potassium channels were open to suppress the type II fiber's response to hair cell damage but I'm thinking they were referring to Kv7.2 & Kv7.3 where the synapses are on that diagram. Hyperacusus/noxacusis may be related to Kv7.4 as well but I feel like it's unlikely to be the case. We would know if we need Kv7.4 once BHV-7000 comes out first.

It's a shame we don't know the exact difference between the potassium channels that were open and by how much with Trobalt and BHV-7000/XEN1101.

Nice information! What's your best guess on when XEN1101 and BHV-7000 may come out?

 

[Josh59]

I'm wondering why the potassium channels would have a problem following shock/trauma to the eardrum, causing the tensor tympani muscle to vibrate?

 

[Lucifer]

What's your best guess on when XEN1101 and BHV-7000 may come out?

No idea but BHV-7000 is supposed to have its pivotal Phase 2/3 trial start in 2H 2023 and it may be quicker to come out due to Pfizer buying Biohaven but who knows.

XEN1101 has a study completion of June 2025 but may be earlier depending on if they can recruit patients fast and if they get FDA Fast Track and Breakthrough Therapy status.

And just found this now too:

"In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2–5 channels, particularly heteromeric KCNQ2/3."

So it seems that Kv2 & Kv3 are affected the most, though there's an impact on the others as well.

Thanks for finding that study on what potassium channels are opened by Trobalt. So both Trobalt and BHV-7000 have Kv7.2 and Kv7.3 being the most affected.

I'm not ruling out Kv7.4 being important for hyperacusis/noxacusis, but to hear some patients taking Trobalt having their hyperacusis/noxacusis reduce or gone has to be more likely to be Kv7.2 and Kv7.3 potassium channel related than Kv7.4. I still believe more in the theory of type II fibers being sensitised and once we open those Kv7.2 and Kv7.3 potassium channels, it should calm those synapses to reduce or get rid of hyperacusis/noxacusis.

 

[Lucifer]

I'm not expecting a response back or anything, but I emailed Philippe Fournier and Arnaud Noreña and asked them if they had any progress with finding out if the middle ear responds to the inner ear and if they think potassium channel openers will have any effect on our symptoms.

Did you get a reply from Norena on whether potassium channel openers might work with noxacusis?

Did you ask them specifically what Kv7 potassium channel openers might work with noxacusis?

 

[haha ear go eeee]

Did you get a reply from Norena on whether potassium channel openers might work with noxacusis?

Did you ask them specifically what Kv7 potassium channel openers might work with noxacusis?

I haven't heard back from them yet, makes sense though!

And no, but I will ask that in a follow up question!