Open question #3: Why do Gabapentin/Pregabalin work?

[Frunobulax]

Hi again,

my next question is: Why do alpha-2-delta ligands (Gabapentin/Horizont, Lyrica/Pregabalin) work well for some WED cases? What kind of patients respond to these drugs?

It seems to me that these drugs are only effective for light or medium severe cases. I've never heard that a bad case of WED was treated with one of these drugs alone. Still, they do seem to work for some of us, and work reasonably well - while they do next to nothing for others (like me). The other classes of primary treatment options are effective for almost all of us, at least for a limited time (and if we can tolerate the side effects): L-Dopa, dopamine agonists and opioids. They have in common that the increase the (natural or artificial) dopamine level.

It is possible that only a specific subgroup of patients respond to the alpha2delta ligands. I would think that identifiying this group, and understanding why only this group responds to the treatment, would be a step forward to understanding the disease.

Regards, F.

[Rustsmith]

I came across this the other day on Medscape.

Gabapentin and pregabalin are structurally similar to gamma-aminobutyric acid (GABA), although they do not bind to GABA receptors. They are thought to exert their beneficial effects on neuropathic pain by binding to the α-2-delta subunit of voltage-dependant calcium channels. This leads to reduction of the influx of calcium into neurons throughout the central nervous system. This in turn may decrease the release of glutamate, norepinephrine, and substance P.

The researchers at Johns Hopkins are currently looking at the role of excess glutamate in the brains of WED patients and believe that this may be the reason why so many who are treated with DAs still have issues with insomnia.

This study also looked at the effective use of gabapentin in treating insomnia. http://www.ncbi.nlm.nih.gov/pubmed/20124884

Gabapentin is also used to treat neuropathy, so it should be effective in the treatment of cases of WED where there are painful sensations in addition to the need to move. Also for those WED cases where there is a comorbid condition such as migraine, fibromyalgia or chronic fatigue syndrome, gabapentin is a drug that can have a dual role.

So, I would agree with your premise that it may not be for everyone with WED, but that it certainly can help many. I know in my personal case it has helped with the insomnia aspect that remained after the DAs calmed my legs, arms and torso.

[ViewsAskew]

Long ago - maybe 5-8 years? - I remember one of the research doctors saying that it seemed people who had painful WED responded to the alpha 2 delta ligands much better than those who felt their sensations as electrical, crawling, creeping. IIRC, that was even in print somewhere (a search here might find our first references to it). Then, people started figuring out that even if it didn't help the sensations in the one group, it did help them sleep. That's what kicked off them looking at sleep, I believe.

So, I'd guess there are at a minimum of two primary actions taking place.

I can say that after we heard (here) that it was different between the two groups, there were several of us who found that to be true. Those of us it worked for indeed seemed to be the painful sensation-type and those it didn't work for as well (or not at all) seemed to be the creepy-crawly sensation type. Several years ago when I was at my first visit with Dr B, he gave me one of these drugs - I remember telling him in email the next day that it didn't reduce my methadone dose at all, but I slept through the night incredibly well. That was at a very low dose.

Others here have echoed that, too, which anecdotally supports the theory that they somehow change the brain chemistry so that we sleep, regardless of whether they help the sensations.

As an aside, I think they help a third category - people who actually have neuropathy that has been missed that occurs with WED, or people who have neuropathy that has been misdiagnosed as WED (I can think of two people off hand who were members here who were in this latter camp).

[Frunobulax]

The researchers at Johns Hopkins are currently looking at the role of excess glutamate in the brains of WED patients and believe that this may be the reason why so many who are treated with DAs still have issues with insomnia.

This study also looked at the effective use of gabapentin in treating insomnia. http://www.ncbi.nlm.nih.gov/pubmed/20124884

I know this connection, and Gabapentin is efficient for insomnia. Still, why does it calm our legs? Medication that helps us sleep is usually not effective for WED symptoms - especially antidepressants, which tend to exacerbate the symptoms.
Maybe this is similar to the action of Benzodiazepines, which are also primary sleep medication - yet they do help some of us. I'm probably in the other category - Gabapentin and Lyrica did not work well for me, and neither did Clonazepam (which seemed to have no leg-calming effect at all).

[Frunobulax]

Long ago - maybe 5-8 years? - I remember one of the research doctors saying that it seemed people who had painful WED responded to the alpha 2 delta ligands much better than those who felt their sensations as electrical, crawling, creeping. IIRC, that was even in print somewhere (a search here might find our first references to it). Then, people started figuring out that even if it didn't help the sensations in the one group, it did help them sleep. That's what kicked off them looking at sleep, I believe.

This is interesting. The literature doesn't distinguish a lot between those two groups, does it?
And yes, I'm in the "electrical, creepy-crawly" group. But since I did fight insomnia before I had WED symptoms (for many years), I would guess that I'm also in the high-glutamate group. Now this is puzzling - isn't Gabapentin supposed to be effective for the high-glutamate patients?
But if I remember correctly it was rather hard to determine Glutamate levels in the brain, so it's probably not that easy to verify if I'm in this group?

Curious enough, my insomnia vanished whenever I took dopamine agonists. When I was on Ropinirole, I was wired all day long and had no trouble with sleepyness - until the time I took the Ropinirole in the evening, I would become very tired and sleepy after 20-30 minutes (and the sleepiness came much faster than the WED symptom relief). Later with Pramipexole I would experience daytime sleepyness, and an extra dose of Pramipexole would make me more tired. Which fits well to the different half-lifes of these drugs, Pramipexole has a longer time of action, explaining the increased daytime sleepyness.

But I've heard from a lot of other patients who do experience insomnia even with dopamine agonists. Is this, along with the glutamate levels, somehow correlated with the distinction between the "pain" and "electrical" WED group?

[ViewsAskew]

I am also in the creepy crawly group. And, when I first took DAs, they absolutely put me to sleep! And, I also have had insomnia symptoms since I was young - like a toddler - which was before I had WED, but I did have PLMS. I think you can't take PLMS out of the equation.

If I were doing a study, I'd start here. I'd collect very basic data on the following:
First, I'd find do a some type of study to find out how people describe it and norm the terms - for example, is pulling its own category or is it under painful or under electrical?

Then, I'd find out:
PLMS - yes or no or unknown (per sleep study or partner), and before or after WED onset
Type - based on the categories identified earlier
Insomnia without treatment - yes or no and onset
Insomnia with treatment - yes or no and with which treatments

And so on. We need to get really basic first. I honestly am not sure we understand some of these basic things. I wonder if we could get a small grant from the Foundation to pay for a website and instruments with which to capture and assess data? Or maybe we're ready to form our own non-profit .

[Rustsmith]

When my WED was mild (many years ago), I was in the creepy crawly group. But as the WED got more severe and spread to my torso and arms, the sensations completely disappeared. I went from "light sleep" to chronic sleep onset insomnia and my WED became daily urge to move issues that would start late in the afternoon. That is part of why it took six years for me to get a diagnosis. The doctors all tried to treat me for insomnia and it required a sleep doctor to figure out what was going on. I had no idea that the urge to move issues in my arms and torso were associated with RLS.

Once I started DAs, the urge to move disappeared and the insomnia lessened because WED, PLMS and UARS were not waking me up every 10 to 15 minutes at night. However, there were still enough sleep onset issues to present occasional problems. That is why my new doctor increased the gabapentin that I was taking from migraines from 600 mg/d to 900-1200. The gabapentin is allowing me to go to sleep "normally" on most nights and gives me 6-7 hrs of sleep each night. The only problem is that I started with low BP and the gabapentin has made it worse. Hopefully that improves with time.

So by Ann's categories:
PLMs without treatment - YES! even while attempting to sleep
Type - non-painful, urge to move only, genetic, idiopathic
Insomnia without treatment - YES!!!
Insomnia with gabapentin - Infrequent

As for information gathering - how about we create a forum here devoted to the data collection and then send an email blast to all members asking them to come by and complete the questionnaire. The Foundation could then offer the data to a researcher willing to process it. Granted, this probably biases the data to more severe WED cases, but is that such a bad thing in this case?

[ViewsAskew]

Sounds good to me. We might want to review my off the cuff categories to make sure I didn't forget anything. Starting at the very beginning, there are a couple other things that we likely should capture - your post reminded me.

First is the urge to move vs sensations. We need to ask if there is an urge to move - that alone would be important data. If many people with painful type say they have no urge, well, that's important. And, what about whether it's always been this way, for how long, and if it's changed. For many of us, it has changed. So, what are we gathering? Current state? Past state? Both/all? And, what about primary/ideopathic vs secondary? Is it important for this data to identify if the person knows of A) relatives with the disease, or has, B) conditions that are associated with the disease, and, C) when the symptoms started in relation to the other conditions? And, one more piece - age of onset. Then again, maybe I'm adding too much...

[Frunobulax]

We need to get really basic first. I honestly am not sure we understand some of these basic things. I wonder if we could get a small grant from the Foundation to pay for a website and instruments with which to capture and assess data? Or maybe we're ready to form our own non-profit .

My thoughts exactly, and one reason for my "open questions" series is to distinguish between things that we already know (but haven't written them down), things that we don't know but aren't that relevant, and the things that we don't know and which would appear to be relevant.

As for the evaluation, I would guess that the hard part is designing a good questionnaire, which captures the essential things without taking hours to complete
I know somebody running a small company that does evaluations and questionnaires. If we really want to do this, I could ask him how much it would cost to set up an online questionnaire.

And yes, I do think that the Foundation should be a part of the data gathering - the contents of the questionnaire should be checked with some medical advisors. I wondered why they did a survey gathering the IRLS score - what's this going to accomplish? If you want to describe the clothes a person wears, why do you ask only about the color, but not about the material, the design, the age and the condition?

[Frunobulax]

And, what about primary/ideopathic vs secondary? Is it important for this data to identify if the person knows of A) relatives with the disease, or has, B) conditions that are associated with the disease, and, C) when the symptoms started in relation to the other conditions?

I do think we should ask about relatives (probably first and second degree), but I'm not sure if there is something like ideopathic WED - perhaps we just don't know all the conditions causing WED?
And I would think that the "ideopathic = people with relatives having WED" theory is a load of crap. After all, there is a genetic disposition for a most non-infectuous diseases. If a disease (say diabetis) is hereditary and triggers WED, then it is not surprising that the relatives of a diabetis/WED patient have diabetis and WED too. For our "ideopathic" cases, the fact that it runs in families just tells us that it is like any other hereditary disease (and is probably not caused by environmental conditions, lifestyle or nutrition).

[ViewsAskew]

I do online questionnaires for work sometimes. There are free tools we can use. The person you know likely knows of them, too. It's not hard and the free tools allow you to do most basic stuff (and some more complex stuff).

In terms of the Foundation, it seems to me that we can approach this in two ways. The first way would be to submit it as research project and see if we get funded. We'd need a project plan, etc. The other is to do it on our own and then send them the results - I do not think we can do this casually and expect them to contribute or help.

Frunobulax, I am not sure which survey you are talking about...I guess I need to pay more attention to the Foundation's website. I honestly am not there that often - I'm here instead!

[Frunobulax]

I do online questionnaires for work sometimes. There are free tools we can use. The person you know likely knows of them, too. It's not hard and the free tools allow you to do most basic stuff (and some more complex stuff).

Well, I guess there are free tools and commercial tools, the commercial ones having more functionality. It is quite possible that the free tools are sufficient for us.

In terms of the Foundation, it seems to me that we can approach this in two ways. The first way would be to submit it as research project and see if we get funded. We'd need a project plan, etc. The other is to do it on our own and then send them the results - I do not think we can do this casually and expect them to contribute or help.

If we want to have meaningful data, we need to have a large base of people taking the survey. Even though this board has some members, I'm afraid we need more. So having this backed by the Foundation would help - and including scientists from the advisory board would give the necessary medical credibility. But I'd suggest to nail down the contents of the survey first, before we worry too much about funding and organization - I figure we should be able to convince the foundation that this is worthwile if we want to have a chance to conduct this

Frunobulax, I am not sure which survey you are talking about...I guess I need to pay more attention to the Foundation's website. I honestly am not there that often - I'm here instead!

I've got an email inviting me to an online questionnaire, which was simply an IRLS score test. I thought this may have been because I'm a new member, but since I've got another email reminding me that the time to take it ends soon (and at a time when I had already completed it), I figured it was not personalized. No idea if there was something on the web site.

[ViewsAskew]

[quote="Frunobulax"

I've got an email inviting me to an online questionnaire, which was simply an IRLS score test. I thought this may have been because I'm a new member, but since I've got another email reminding me that the time to take it ends soon (and at a time when I had already completed it), I figured it was not personalized. No idea if there was something on the web site.[/quote]

Huh. My membership lasped recently....could be something that went to members?

[Rustsmith]

I suspect that you are correct that the email only went to members. There appears to be an effort to revise the IRLS questionnaire a little bit to help clarify the wording of the questions and to help provide a bit of guidance for picking the answers consistently. The changes were not major, but will probably help improve consistency.

[Polar Bear]

I also got a questionnaire - maybe a couple of months ago.
Even though I completed it another was received a few weeks later.