Open question #6: Augmentation and disease progression

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Frunobulax
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Open question #6: Augmentation and disease progression

Post by Frunobulax »

Hi again,

not sure if I'll have a top 10 of WED questions soon, but I seem to be well underway :D

One thing that has always bothered me is the relationship between "augmentation" and "natural disease progression". I can't explain exactly why, but I feel uneasy about the distinction between natural progression and augmentation. After all, both have exactly the same manifestation - but augmentation is assumed if the symptoms get better after a few weeks being off the dopamine agonist medication. However, there are natural fluctuations in the symptom intensity, and most of us do have triggers that will significantly exacarbate symptom intensity. Is augmentation really different from a long-acting trigger? What if dopamine agonists and L-Dopa induce chemicals/neurotransmitters that cause WED symtoms, or deplete natural reservoirs of stuff our body needs to calm the legs? In other words - what if dopamine agonists and L-Dopa combine two actions on WED, one that calms the legs (possibly the dopamine) and something different that provokes WED? It wouldn't surprise me if this was the case, and that it takes days to weeks to recover from the WED-provoking stuff after stopping L-Dopa or dopamine agonists. These substances would have to be somewhat longer acting than the dopamine, which would explain why symptoms flare up as the L-Dopa or dopamine agonist dosage in the body is reduced.

Clearly dopamine agonists work different than natural dopamine, manifested by the large number of side effects that are not associated with dopamine. On the other hand, the highest augmentation rates come from L-Dopa, which is assumed to basically increase the natural dopamine level. But opioids, which are supposed to do exactly the same, are not associated with augmentation. What's the difference between these three substance classes?
  • L-Dopa is processed into dopamine, noradrenaline and adrenaline.
  • Dopamine agonists are supposed to activate some dopamine receptors.
  • Opioids increase the natural dopamine level and reduce the amount of GABA released.
Some people suspect that the active component of the dopamine agonist (the substance acting on the D2-type dopamine receptors) cause augmentation due to a downregulation of D2 receptors. I'm not sure if this is true. Why would both L-Dopa and dopamine agonists show augmentation, but not opiods if this was true? Downregulation of the D2-type receptors should happen with opioids as well. And downregulation is something that should pretty much happen for all of us, while clearly some of us are more susceptible to augmentation than others.

Of course, the question "why does augmentation occur" is only one side of the medal. The other side is "why does the disease progress [assumed naturally]"? Is it really a genetic/age thing that we can't influence, or is it possible that the remedies that we use somehow cause the disease to get progressively worse? I know about a few people who experienced a rapid progression of their symptons while being on dopamine agonists (me included), and symptoms did not rescind (much) after coming off dopamine agonists. Is is quite frequent that our body reacts more strongly to a substance after a prolonged time of exposure.

Let't compare WED to an allergy to a substance X. (Follow me here, after thinking about it for some time it seems to be a good analogy.) If I understood it correctly, what happens there is that the body starts production of antibodies to X, and this production gets more efficient over time. Therefore large quantities of X are required at first to set of an reaction, but with prolonged exposure or over the years it takes less and less of X to provoke a reaction - the body develops a higher sensibility to X ("sensitization"). We can calm down the reaction by stopping the exposure to X, or with medication that treats the symptoms (but does not prevent the antibody production).

Now, back to WED. Assume that a similar process is at work here: Something (whatever - let's call it X again, possibly synonymous for a lot of different quantities) offsets WED, and the body responds with pain or the urge to move, which relieves the urge. After some time, the body "learns" that movement is an efficient measure, and gets more sensitive - thus it will respond easier and easier to X. At the end, even small amounts of X cause severe WED symptoms. (Remember the speculation that WED sympotoms may not be a sensory thing, but kind of a safety valve for our body? What if we do not simply have an urge to move, but movement causes our body to produce substances that should help against the originating condition? This theory meshes well with what I'm developing here.)

Now it get's interesting. It would appear that all WED medication does not interact with the underlying problem (the body being sensitive to X), but simply adresses the symptoms - similar to antiallergic medication not stopping the antibody production, but calming the symptoms instead. If it is true what I suspected above (that dopamine agonists and L-Dopa trigger WED), then patients taking this stuff would be pretty much screwed. Why? The dopamine agonists we're taking contain/produce both something provoking WED (X2) and a substance calming WED (say Y, possibly dopamine). By taking it daily we increase the sensibility to X and X2 over time (worsening WED). After some time, more dopamine agonists are required - either due to tolerance (Y does not work as well as before) or because the body reacts more strongly to the environmental X (we started the process, so there must have been something that caused WED that was not in the dopamine agonist). All right, we increase the dosage, and become even more sensible. What happens if we stop taking the dopamine agonist? After some time X2 leaves the body, giving us a bit of relief. Still, the increased sensibility to X remains for good, and our WED became permanently more severe.

There are some more similarities between WED and allergies: Like WED, allergies have a LOT of different triggers and a wide range of symptoms. Like WED, we do not always know why we react allergic to something. Like WED, allergies usually get progressively worse with age, but may get better on their own (by avoiding the substance causing the reaction).

Does this make sense to you? Note that some weird effects are explained here - why some people are more susceptible to augmentation than others (they react to X2 in the dopamine agonist, while other people don't), why some people augment and others don't, and why people augment much faster if they take up the drug a second time (they are already sensitizised to X2). What are the treatment options for WED, where is the glimmer of hope? With allergies, there is the possibility of desensitization. Is there something similar for WED? I guess we would need to find out why exactly we have the urge to move (see http://bb.rls.org/viewtopic.php?f=5&t=8928), and stop that.

In any case, if WED is really similar to allergies then we should consider the consequences:
(1) Avoid everything else that triggers your WED, as it may worsen your condition (sensitization).
(2) Avoid L-Dopa, dopamine agonists and everything else that may cause augmentation (sensitization again).
(3) All drugs used to calm WED symptoms will contribute to the progression, because with efficient treatment we do no longer realize what causes the WED symptoms. Throughout treatment we get gradually more sensitive, until our medication is no longer sufficient to control the symptoms - we need a higher dose or a different drug. The only "good" option we have is to find out what we're reacting to, and avoid it.

A closing remark: I am aware of the fact that I may be way off target with my musings. I simply tried to develop a theory, think it through and see where it leads me. Don't be surprised if I come up with a completely different (and contradictory) theory in my next post...

ViewsAskew
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Re: Open question #6: Augmentation and disease progression

Post by ViewsAskew »

I have to run and will read all soon - just read to the hypothesis that the DAs actually cause a problem. I completely think this is true. It's the ONLY conclusion when people such as myself augment in a week or less. And it was permanent. I had once or twice a month symptoms and in a week I had daily, nasty ones. OK, have to run, will read and digest more when I get back.\
Ann - Take what you need, leave the rest

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sleepdancer2
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Re: Open question #6: Augmentation and disease progression

Post by sleepdancer2 »

I too lack clarity on the augmentation vs disease progression issue. Spent years under the impression it was progression when it turned out to be augmentation. Augmented on both the L-Dopa and the DAs. Well, on the L-Dopa, maybe it was just considered side effects, I don't know. Can't begin to understand the science behind all this. Just so very glad to not be on those meds any longer, whatever the name they put on the misery they caused. After going off the meds my symptoms greatly subsided to what I'm figuring is the natural state of my disorder. In spite of the hell I've been through, Maybe I'm still one of the lucky ones. Below is a link to what my augmentation on DAs looked like.
https://www.youtube.com/watch?v=jE7WA_5c73c
My Augmentation Sleep Video: https://www.youtube.com/watch?v=jE7WA_5c73c

Rustsmith
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Re: Open question #6: Augmentation and disease progression

Post by Rustsmith »

I will throw a bit of a complication into your hypothesis using my own history. For many years I had what I would describe as mild WED. It was only a problem when I was on long airplane flights, of which I had many. I did not really notice a progression of the disease over the years, but I think that part of it might have been coping strategies and part a chronic case of jet lag due to monthly 8-12 hr time zone changes (and back). The jet lag was continually playing havoc with my circadian rhythm.

Then when I retired and stopped traveling so much, my WED hit with a vengeance. It suddenly was in my arms and torso as well as my legs and insomnia due to WED replaced strange sleep hours due to jet lag. In fact, since the symptoms were no longer limited to my legs, it took six years to get a diagnosis and treatment even though I was seeing a neurologist for migraines during that entire time (and was complaining). If I had answered on of the augmentation questionnaires at that time, I would have been scored as probable augmentation even though I had never taken a DA.

So in my case, my WED naturally progressed from mild to severe all by itself and I believe that the progression was masked by jet lag and having my circadian rhythm continually out of phase.

However, with that said, it only took me about 9 months to start showing the signs of augmentation on pramipexole. I am still on a DA (Neupro) and hope to get a longer run out of this one.
Steve

https://www.mayoclinicproceedings.org/a ... 0/fulltext
Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

debbluebird
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Re: Open question #6: Augmentation and disease progression

Post by debbluebird »

Mine was augmentation, but the doctor, at the time didn't know about augmentation, and kept increasing my dose. So it just kept getting worse. He actually said, that he thought I had something else wrong with me, when he switched me from mirapex to requip. He couldn't understand why the requip didn't work. After months of hell, I finally got off the mirapex. Then they put me on Valium 40 mg plus four other drugs. I was a zombie.

ViewsAskew
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Re: Open question #6: Augmentation and disease progression

Post by ViewsAskew »

I think it is likely very difficult to distinguish between them.

One of the issues here is that we talk about triggers. Are DAs just triggers of sorts? We can't know, given how little we understand the body in relation to WED, if natural progression is always that, can we?

My mom has had the exact same level of WED for over 50 years. My sister's has been the same for 25 years. My grandmother's and both my uncle's, however, had gradually gotten worse.

Maybe the difference is gradual. Anytime the symptoms significantly increase in a short period (undefined) - can it be natural progression?

Then again, many auto immune disorders vary tremendously in how quickly or slowly they progress. Why? Is that "natural" too?
Ann - Take what you need, leave the rest

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jul2873
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Re: Open question #6: Augmentation and disease progression

Post by jul2873 »

I find the comparison of WED and allergies very interesting. I've had allergy-induced asthma for years. And I learned, years ago, that as soon as I start to get symptoms, I need to take my strongest medication and knock the symptoms right out. If I do that--if I am aggressive with medication at the first sign--I can usually stop an attack from developing and, in the long run, end up using much less medication. But if the symptoms get a good hold on me, then it can take days for them to finally recede.

I'm starting to think that my WED may work somewhat the same way. I've been using kratom (a mild opioid) to manage it, and for the last year and a half have been using very small doses frequently. The small doses would, usually, manage the symptoms for a few hours, but then the symptoms would return with their original power. Lately I've started using larger doses (two grams instead of one) before I go to bed, to really knock it out. I find that I'm still waking up around three hours later, but with only very mild symptoms or none at all. Anyway, I still take another two grams upon wakeup (unlike the one gram I used to take) and then go back to sleep and usually sleep until early morning, when I'll take a light dose if I am able to sleep in. The difference now is that I'm comfortable almost all the time. Before, strong symptoms would wake me out of a sound sleep; that hasn't happened now for weeks.

I do think WED is a moving target, and tonight or tomorrow the severity of my symptoms may return. But I'm enjoying the respite. And I take kratom now during the day if I know an activity--like a long car or plane ride--usually causes symptoms. I no longer wait for the symptoms to start. My whole goal now is to use however much kratom I need to prevent symptoms from developing at all--as much as I possibly can. My hope is that my legs will work like my lungs. The longer they are calm, the less likely it is that any symptoms will develop.

I am enjoying this discussion very much. Thanks to all who are participating.

Mary

Frunobulax
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Re: Open question #6: Augmentation and disease progression

Post by Frunobulax »

Rustsmith wrote:I will throw a bit of a complication into your hypothesis using my own history. For many years I had what I would describe as mild WED. It was only a problem when I was on long airplane flights, of which I had many. I did not really notice a progression of the disease over the years, but I think that part of it might have been coping strategies and part a chronic case of jet lag due to monthly 8-12 hr time zone changes (and back). The jet lag was continually playing havoc with my circadian rhythm.

Then when I retired and stopped traveling so much, my WED hit with a vengeance. It suddenly was in my arms and torso as well as my legs and insomnia due to WED replaced strange sleep hours due to jet lag. In fact, since the symptoms were no longer limited to my legs, it took six years to get a diagnosis and treatment even though I was seeing a neurologist for migraines during that entire time (and was complaining). If I had answered on of the augmentation questionnaires at that time, I would have been scored as probable augmentation even though I had never taken a DA.

So in my case, my WED naturally progressed from mild to severe all by itself and I believe that the progression was masked by jet lag and having my circadian rhythm continually out of phase.

However, with that said, it only took me about 9 months to start showing the signs of augmentation on pramipexole. I am still on a DA (Neupro) and hope to get a longer run out of this one.


Well, I guess there is no easy explaination - but then, there are no settled theories that would explain the weird tricks the disease plays with us...
The fact is, symptoms remains stable for a long time or may worsen markedly in a very short time. In some cases symptoms get less severe with time. All this sounds very similar to allergies if you ask me, even if the symptoms (and probably the mechanics of the disease) are completely different.

To put it in a nutshell: Allergies are a reaction of the immune system to a "perceived danger" (immune system produces antibodies), even though the offending substance is rather harmless. With WED, we may be looking at something similar here - for some reason our brain requires us to move as a reaction to something that in reality doesn't require a reaction. And with time our brain seems to get more sensible to this something, and of course there may be a lot of possible "somethings".

Rustsmith
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Re: Open question #6: Augmentation and disease progression

Post by Rustsmith »

There are a few details in your allergy analysis that are not quite correct. However, if we continue to look at the allergy as an analog, there may be some reason why WED exists. With allergies, the Immunoglobulin E (IgE) system malfunctions and attacks allergens instead of the parasites that it was originally intended to protect us from. Other autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and maybe even diabetes also have some ties to the immune system being misdirected.

Since we know that WED has a genetic component, like the autoimmune diseases, and that WED effects a large part of the population, there has to be some reason why the original genetic defect survived. Cystic fibrosis is thought to be the most studied genetic disease. One of the things that the study of CF found was that it originally developed because it provided protection from typhoid. The original individuals with CF survived exposure to typhoid and were able to reproduce before the CF killed them. Since WED is much more widespread, there has to be some reason why. The original defect also has to be quite old since WED is found in equal proportions in just about all racial groups.
Steve

https://www.mayoclinicproceedings.org/a ... 0/fulltext
Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

ViewsAskew
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Re: Open question #6: Augmentation and disease progression

Post by ViewsAskew »

Dr Rye hypothesized that WED encouraged our ancestors to hunt more frequently for red meat. Unable to sleep, why not go kill a bison? Eating the red meat would increase the iron. The fact that we can function on lack of sleep is an advantage in itself. And, if you are better fed, you have an advantage.
Ann - Take what you need, leave the rest

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Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

Frunobulax
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Re: Open question #6: Augmentation and disease progression

Post by Frunobulax »

ViewsAskew wrote:Dr Rye hypothesized that WED encouraged our ancestors to hunt more frequently for red meat. Unable to sleep, why not go kill a bison? Eating the red meat would increase the iron. The fact that we can function on lack of sleep is an advantage in itself. And, if you are better fed, you have an advantage.


I don't know, I would guess that both severe allergies and WED are malfunctions of our body, and that people like us should be happy that we are living in the 21st century, since our life expectancy may have been very limited a few hundred years earlier :?

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