Clarification needed please Ellfindoe, Joolsg and others

[67Waterman]

I still struggle with the fact that RLS absolutely responds to Ropinirole, which is a dopamine-receptor agonist, but then we are told no to that, and are advised to take Gabapentin, which is an anticonvulsant medication. Stupid question but is that telling me that lack of dopamine causes the nerves to twitch, so we are now treating the latter rather than the former? I am sure it is more complicated than that. With thanks, Sally

[LotteM]

No, there is no lack of dopamine in people with RLS. Actually too much dopamine in the sending side (=presynaptic) of the nerve cells in a part of the brain.

Dopamine agonists activate the dopamine receptors, whereas gabapentin and pregabalin increase the accessibility of the nerve cells in a more general way.

I hope this helps to clarify.

[67Waterman in reply to LotteM]

You do realise that I will need ven diagrammes. Sadly you are talking to the uninitiated. Sincerely, Sally

[LotteM in reply to 67Waterman]

Sorry. Shall try again later and better. But it IS difficult and even far from fully understood by scientists who research the RLS brain.

But I hope you got the message that there is no lack of dopamine.

[Joolsg]

The experts are still working on exactly what causes the problems we have but faulty uptake of dopamine by our dopamine receptors is suspected. And we need iron in our brains to facilitate that uptake. One day I intend to study the dopamine pathway more fully!

Lotte is a scientist and understands far more than I do...

[67Waterman in reply to Joolsg]

Perhaps someone could just spend their time producing my wonderful old drug Ropinirole (which I miss) without the augmentation ... I would be so happy! (Smile).

[Joolsg in reply to 67Waterman]

I know. It was miraculous before the dreaded Augmentation & hellish withdrawal. A doctor in S. Carolina is working on that as I write. Hes trialing a drug that counteracts the over stimulation of the D1 receptors. There's hope. If the same funding was spent on RLS drug trials as on multiple Sclerosis, we'd have several new drugs by now!

[Hidden in reply to Joolsg]

Ecopipam for RLS is going nowhere fast. It should NOT be added to DAs as the good doctor suggests. It will just supercharge the DAs and make them all the more a nightmare. I don't know how anyone can get anything so wrong. Ecopipam is a D1 "antagonist." Great for RLS in the short run because it will block those excitatory signals, but in the long run will make them gargantuan in combination with the DAs all while the calming D2/D3 receptors are "agonized" and hence shrunk.

Ecopipam is on the fast track for Tourette's Syndrome. clinicaltrials.gov/ct2/show... Every couple years there is a new clinical trial and there is one going on right now for Tourettes. The one clinical trial for RLS concluded with somewhat blah results. If you read the one paragraph describing how it works in the article you will see they believe that Tourettes is caused by overexcited D1s (kind of like us, post DAs) and that Ecopipam will block those signals. I have no doubt it's great for Tourette's...in the short run. I hope in the long run it does not worsen the condition. There are no free lunches.

What post DA sufferers need is just the opposite - a D1 Agonist. We need to take those babies down. That's why I like Neupro - it is an equal time agonizer. It may make it less effective in the short run when compared to Prami, but in the long run, as we know, results in less cases of augmentation and DAWS. A friend's boyfriend has been on 2mg Neupro for decades. He has RLS but his big complaint is PLMD. He told me he has 8mg patches that he cuts up and will sometimes slap another 2mg patch on if it's particularly bad. I believe he did about 40 sessions of transcranial magnetic something. He said it worked but then wore off. For the past 7 weeks he has been wearing this watch like device that vibrates and has different settings. He called me over to their house just to tell me about it. After the first week he was able to stop the patches and sleep through the night. The point of this long story is not to propose this watch thing but to point out that he had zero withdrawal upon discontinuing the neupro patches and I don't think it's the watch that's doing it. He has run out of the patches in the past, for weeks at a time, when switching doctors and never suffered withdrawal, just a return to his normal annoying PLMD. If he were taking prami for his PLMD I think it would be a different story. One person does not a clinical trial make. I've noticed that at 8mg daily people have come on here and complained of augmentation from the Neupro. At lower doses it just seems to lose it's effectiveness and when discontinued people go back to their baseline RLS, or maybe a little worse, but I haven't seen anyone complain of DAWS. Now if those people are on SSRIs during and after they stop the Neupro they will be in hell until they stop the SSRI.

Anyways, the problem with taking a D1 agonist is that it will make your legs go crazy... in the short-run. And I personally would never take the prescription ones. I recently posted about Berberine which is supposedly a natural D1 agonist. I cannot recommend it, however, I am trying it in combination with a flavonoid to make it more bioavailable. I take it in the morning and do not care for the way it makes me feel about 45 minutes later. Low level buzz all over my body, but not RLS. Some people might actually like it. I count the minutes for when it will end which is about 3 hours. I haven't noticed any improvement in my RLS and possibly even a worsening. I'm not post DA so I wouldn't expect it to help my RLS, even in the long run. I'm taking it more for my recently elevated LDL.

[LanaCSR in reply to Joolsg]

Joolsg, do you know the name of the doctor in South Carolina?

[Joolsg in reply to LanaCSR]

Sorry it's East Carolina University. Professor Stefan Clements. He's targeting D1 receptors and I suspect he's looking at Ecopipam. It was in the Fall 2020 edition of Nightwalkets magazine. I'm sure the US foundation will report any results.

[Elffindoe]

The latest model of RLS is that there is a series of factors which lead to RLS.

What seems to be the main differences between people with RLS and those who don't have it can be -

People with RLS have a failure in transporting iron from the blood into the brain across what is known as the blood brainnbarrier (BBB).

People with RLS have less D2 receptor sites in dopaminergic neurons in sensory motor nerves.

The first failure can lead to a condition called Brain Iron Deficiency.

BID in turn, causes a reduction in the activity of a neurotransmitter called "adenosine".

This leads to TWO problems

1) Excessive levels of dopamine, a neurotransmitter.

2) Excessive levels of glutamate, another transmitter.

The excess dopamine can lead to sensory-motor symptoms and PLMD.

The excess glutamate can lead to PLMD and "hyperarousal".

In addition, despite high levels of dopamine, the lack of D2 receptors can lead to RLS symptoms.

The first treatment for RLS historically was opium.

More recently however was Dopamine, presumably discovered, when treating people with Parkinsin's Disease.

Levidopa is VERY effective in relieving RLS symptoms within 15 mins.

It works presumably because it creates more stimulation of the lesser number of D2 recoptors.

It was then discovered that dopamine receptor agonists (DAs) can directly stimulate D2_ receptors.

The DAs are miraculously effective at treating RLS as you know. Unfortunately, they also have a major complication, augmentation.

A more recent treatment for RLS is the gabapentinoids, gabapentin and pregabalin.

These work by reducing glutamate levels, i.e. the other aspect of RLS.

Because these reduce nerve sensitivity they have a general calming effect on RLS, nerve pain and epilepsy.

Another approach to RLS is to correct the BID using iron therapy.

A more recent development is the experimental use of dipyridamole, which increases adenosine.

There is a good diagram of this.

I hope this gives you a wider perspective on RLS.

[LotteM in reply to Elffindoe]

One minor correction of Elffindoes reply. DAs seem to target the D3 receptors, thus not (so much) the D2 ones that are reduced in people with RLS.

Aaarggggghhhh. Complicated. And not yet fully understood even by RLS specialist scientists.

[Elffindoe in reply to LotteM]

Thank Lotte.

Confusing somewhat. I seem to recall D3 and D4 receptors are "D2 like".

D5 receptors are "D1 like".

Or vice versa!

[LotteM in reply to Elffindoe]

Don't know, Elffindoe, I tend to forget the (for me) less relevant details.

[Elffindoe in reply to LotteM]

I was just showing off!

[67Waterman in reply to Elffindoe]

So bad and yet so funny!

[WideBody in reply to Elffindoe]

Elffindoe, you said there was a good diagram of this? Do you have a link?

[Elffindoe in reply to WideBody]

Not on this device.

I'll see if I can rediscover it.

[Elffindoe in reply to WideBody]

It's in this article

sciencedirect.com/science/a...

[67Waterman in reply to Elffindoe]

And I came across this last night .... some of what Ellfindoe was saying above but in speech from the Mayo Clinic:

youtube.com/watch?v=Qh7rbW5...(Not working as expected?)

[Woody4 in reply to Elffindoe]

My question is why can I have 2 episodes, a year apart, when I was 10-12. And not have another for over 50 years.

[Virginic]

Thank you! Immensely complicated but you have made it comprehensible here. No wonder it’s such a difficult condition to treat. My husband’s condition is worsening, he’s 75 now. Still hoping something very effective emerges to treat him and all RLS sufferers in the next few years.

[Elffindoe in reply to Virginic]

Yes please let's all hope so too!