Let me preface (what's going to be an incredibly long post) with the fact that I know nothing about dopamine agonists or augmentation, except that the suffering it causes is more than I can bare. So first off, congrats to Kaarina, Jools, Elisse, Madlegs, Manerva and all those on here who tirelessly respond to those suffering from augmentation, whereas I look the other way...until today/tonight.
My ruminating began with the thought that there must be one DA that is least likely to cause augmentation. There is - Neupro - aka Rotigotine. Ok, good, I guess. But why? It's gotta have something to do with mode of action, right? Maybe? Neupro is what I call a broad spectrum DA. I made that term up, or rather I borrowed it from its use in regards to antibiotics. By broad spectrum I mean it somewhat evenly agonizes (but still favors D3) all five receptors - D1 thru D5. The worst in terms of augmentation is Prami which really is only an agonist at D2 and D3 but favors D3. Ropinerole is also an agonist at D4 and D5 as well as D2 and D3, but favors D3 as well.
Get to the point, right? As it turns out, augmentation, and maybe RLS in general, is really a tale of two cities/dopamine receptors. I always thought that all DAs do is beat the living crap out of our already lousy D3 receptors. Oh, DAs are so much more evil than that. They also upregulate our D1 receptors, which give off "excitatory" signals. I actually found an article which seems to indicate it really is not so much the down-regulation of our D3 receptors as it is the up-regulation of the D1 receptors that causes augmentation HELL. So picture this, not only are the good receptors all tuckered out by the DAs, but they also up-regulated the evil D1 receptors, which are now acting similar to a live wire applied to our spines. Who here ever heard of such a thing? Hmmm? Show of hands please? And here's the article that taught me this: sciencedirect.com/science/a...
And this confusing, but truly fascinating article too: frontiersin.org/articles/10... Btw, D3KO refers to mice that had their D3 receptors "knocked out."
So once again, I know what you're thinking - get to the frickin point. The point is, Neupro provides relief to RLS symptoms, but is less likely to cause augmentation because it does not up-regulate D1 receptors, it actually down-regulates them, just like it does to our D3 receptors. So maybe people should switch to Neupro and then taper down from there? The Neupro will get those D1 beasties under control a little bit. Maybe that combined with a little opiate and/or Gaba will alleviate some of that withdrawal hell. Also, if you want to avoid augmentation then be sure you have robust iron stores. Some of the articles I read indicate that augmentation is less likely to occur in people with normal Ferritin.
Last, but not least, someone figured this all out before me and may well be the next medical millionaire. He supposedly has a substance that will keep our D1 receptors at bay and thus augmentation as well, allowing people to stay on DAs longer and maybe have less symptoms when discontinued? I don't know. What do the DA experts on here think? earls.eu/blog/2021/5/9/the-....
Well folks, I have truly come full circle here on RLS-UK. I actually had the answer 6 years ago and didn't even know it. I truly am Little Miss Know it All healthunlocked.com/rlsuk/po...
Kaarina, do I win the longest (and most meaningless) post of the month award?
Hindsight is 20/20. We gotta do something for those in augmentation hell now, right? I'm not advocating for Neupro other than as a stepping stone to tapering off of the DAs. Speaking of hindsight, why not take two ferrous bis-glycinate tablets an hour before bed on an empty stomach, forget the Gaba, and call me in the morning. Xx
Elffin, ya gotta put the articles where your mouth is. I dare to disagree. These stats are great. ehealthme.com/ds/neupro/dru...
Give me Neupro over Prami, as a matter of fact, give me Neupro when I'm withdrawing from Prami. I'm telling you, I truly believe if someone switches to Neupro, which will then down-regulate the D1 receptors, and then tapers off of Neupro, rather than tapering off of Prami, they may suffer less. I'd give it a shot if I was on Prami and thinking about going off of it. I don't think my sensitive soul could stand the Prami withdrawal.
Yep. I've read the articles. The D1 receptor not only is over excited by the DAs but would appear to stay permanently damaged even after getting off Ropinirole/Pramipexole/Rotigitone. Dr B believes that's why pregabalin and gabapentin don't work for many who've been on DAs for years & suffered bad augmentation & withdrawal.There's a doctor in S. Carolina currently working on a drug ( I suspect Ecopipam) to see if it can stop the D1 receptors being over stimulated.
There do seem to be a few people who have switched from Ropinirole & Pramipexole to Rotigitone and haven't yet experienced augmentation but there are many more who have suffered augmentation quite quickly. Perhaps it depends on how damaged the D1 receptors were or how long they were on the previous DAs.
I am in the anti DA camp because I see so many thousands suffering horrendously on this site and others.
Yep, "you can't beat Mother Nature, you can only wipe her out." Just because "my" logic says down-regulate the D1 receptors with Neupro before tapering doesn't mean our finely tuned brains will respond accordingly. "Remove one card and the whole deck falls." Last cliche "it's not nice to fool mother nature." I read studies on Ecopipam and the results in terms of augmentation were neutral - meaning not significantly better than placebo. Plus, Ecopipam is a D1 antagonist. While it should at least provide some sort of short term relief because it is literally stopping the flow of the excitatory signal (think of melatonin antagonizing our D3 receptors and making our RLS worse) while it is in your system it is simultaneously up-regulating it which I would think in the long run would make withdrawal that much harder. Which makes me think that maybe Melatonin in the long run would up-regulate our D3 receptors. So painful in the process though and might not even work. Like you said, our dopamine receptors might be beyond up-regulating. Anyways, the point with Neupro is that it is a D1 Agonist, unlike Ecopipam which is a D1 Antagonist. In the short run it means that Neupro is probably less effective than Prami because it's prompting more excitatory signals at the same time it is prompting the calming D3 signals. In the long run however, the D1 receptors are at the very least not up-regulated and may very well be down-regulated meaning that augmentation/withdrawal should be much less common and severe with Neupro because augmentation/withdrawal syndrome is the tale of two evil scenarios. Neupro should only leave a person with one evil - down-regulated D3 receptors.
We need a natural, short-acting, D1 Agonist that could be taken during the day. It would be quite hard because while it is in your system it will make the RLS worse, but in the long run it will down-regulate the D1 receptors that were artificially up-regulated by certain DAs. Hey, I bet Melatonin is a D1 Agonist. Hold that thought Jools...
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Well, this article makes it sound like Melatonin is a D1 Agonist and as we know it is a D3 ANTAGONIST. Hah!!! Melatonin is a double whammy in terms of RLS. pubmed.ncbi.nlm.nih.gov/753....
I've had mild, infrequent RLS my whole life. Never even knew it had a name in my 20s and 30s. As I grew older it became more frequent, but not enough to send me to the doctor. In my early 40s I decided that melatonin would be a good supplement to take. You know, better sleep, fountain of youth, blah, blah, blah. My RLS became the devil incarnate and it took a full year for me to figure it out. The RLS was in my eyes, my finger nails. I would contort my body in alien fashion just for a second of relief while in bed, ultimately giving up. I don't think I slept for three nights until I went on the internet and did some research. That's when I read about the iron at night trick. It worked for the most part - meaning as long as I was taking .5mg of melatonin. When I raised the melatonin to 1 mg (and maybe even 3mg) I found I had to raise the iron. Such an idiot, you would think I would have made the connection. Then I read about how melatonin is bad for RLS on the internet. The day I stopped the melatonin is the day my RLS went quiet and I no longer took iron. It went really quiet. Like for two or three years quiet. Then it slowly crept back into my life and so did the iron. The point is, maybe the melatonin up-regulated (albeit temporarily) my dopamine transport system. It's just not a viable treatment for RLS...too much suffering, if it even was the melatonin that made my RLS go so quiet.
Yes thank you both so much for attempting to put pieces of the jigsaw together. It is a hydra headed disease, with leg/ body problems on one hand and excitatory nervous system dysfunction on the other, but both interrelated. We all desperately need some structured research, not only into drug/chemical reactions but also into diet and exercise routines such as food triggers and stretching and fascia stimulation. Also some epidemiology into who gets it and why. I can sort of envisage a kind of large, wholistic research questionnaire for many sufferers that takes into account all past, present, medical and environmental factors, but this would be a huge project. And then some sophisticated data analysis would be required on the results to point the way to a CURE. Am I dreaming or is there a medical researcher out there that would take this on?
Hope so but they need funding. We need a billionaire with severe RLS to put their wealth behind research. Wonder if Zuckerberg, Musk, Gates or Bezos have RLS?
I agree with you, kind of. In our lifetimes I don't think the cavalry is coming. We're our own best researchers. I think we all have figured out way more than the scientists up to this point in time. I would probably be in the looney bin right now but for what I read on an internet site about 15 years ago. Take me there Blueboat, take me there. You tell me why you think diet and exercise will help and then I will tell you why I think it might.
I’m way out of my medical depth here and deeply respectful of your posts on iron and dopamine receptors. You and Joolsg and Elffindoe certainly have the skills and capabilities to penetrate the mysteries of this disease, so far much more perceptive than the medical profession, ( with some notable exceptions). My concern is the quest for the silver bullet rather than a more holistic approach. The thing is that diet and exercise (necessarily the correct ones) do often seem to make a difference. There is plenty of evidence on this website for real advances through, for example, low oxalate, low glutamate diet, intense leg stretches, massage and fascia rolling, magnesium and other minerals. I am convinced that the solution ultimately lies in understanding the dysfunction of the muscular and metabolic systems alongside brain iron and receptors.
Yep, pretty much just looking for fast acting, simple, silver bullets. Just about any other annoying chronic condition I would follow your lead ie IBS, reflux, cystitis, psoriasis, but not RLS. It is the worst of these somewhat strange, not completely explained chronic conditions. I have IBS (pretty much controlled now), interstitial cystitis (no pain, just life altering frequency), chronic fatigue (atypical - I'm not confined to bed, I just resent feeling sleepy an hour after awakening), EOE, reflux, hiatal hernia, esophageal strictures. Whew, stay back, I might implode. None of these conditions hold a candle to the RLS. RLS is other-worldly. It has a life of it's own, it's alien, foreign, inhuman. I would rather be water-boarded. Get my point? I would probably kill if someone tried to take my ferrous bis-glycinate.
Hi Eitheror, I am afraid your posting is probably not the winner for being the longest post of the month award.🤣 It is definitely not meaningless. It has started a discussion which is good. 👍
Thanks Kaarina. I try hard not to be meaningless, in posts, or life in general. Dr. Clemens and his newly applied for Patent are on my radar now. earls.eu/blog/2021/5/9/the-.... This is the article from my above post. Later last night, after my post, I found an abstract (short ;)) from his Patent application:
"Abstract
The present invention provides methods of treating Restless Legs Syndrome (RLS) including administering to a subject an effective amount of a dopamine D.sub.1 receptor antagonist. Compositions and kits useful for treating RLS are also provided."
Is it just me, or is he trading short-term relief for long term hell which is just the opposite of what he hopes to accomplish??? I disagree with him so I contacted him last night via email and I want more of an explanation. I think we all deserve an explanation since his funding and livelihood are more or less coming off of our backs. First off, if he's right, and I'm wrong (which is very possible), then I'm not waiting for his patent and product to come to fruition. There's gotta be natural D1 antagonists out there already. But to me his logic is terribly flawed. I think in order to alleviate augmentation you need a D1 Agonist which Neupro contains. Prami is already basically a D1 Antagonist.
It sounds like there is a Yin and Yang system to our Dopamine Receptors. There are the calming ones like D3 and the excitatory ones like D1. I have to research more about D4 and D5. Anyways, they modulate one another and are supposed to keep things harmonious. We with RLS are born with lousy D3 receptors (smaller and fewer than the average bear) and our Yin/Yang is out of whack. But who knows, maybe we're really born with overactive D1 receptors that lead to lousy D3 receptors? I digress. We now know for sure (kind of) that DAs, like Prami and Ropinerole, will provide initial relief to RLS symptoms by whipping our lousy D3 receptors into a frenzy causing them in the short run to pump out ever more of the calming dopamine signal, but in the process "down-regulate" our pathetic D3 receptors even further and apparently giving the D1 receptors the opportunity to flourish. I don't understand how or why down-regulating our D3 receptors allows the D1 receptors to grow big and strong yet according to my first and second articles above, that is exactly what happens with Prami and Ropinerole.
So Dr. D1 (aka as Dr. Clemens) wants to give us a substance (a D1 ANTAGONIST to be exact) while we're taking Prami to extend the useful life of Prami and avoid augmentation???? I don't think so. Let's think about what would happen if we take a D1 Antagonist, with or without Prami. A D1 Antagonist, if it's a good one, should prevent the D1 receptors from churning out those excitatory signals. That sounds like a definite win for us with RLS....in the short run. We're low on the calming signals so lets lessen the excitatory ones as well. Now think about this, Prami + D1 Antagonist = less exciting signals, more calm ones - YAY - win win. Sorry, not yay, in the long-run it should (or could) up-regulate the D1 receptors and for certain down-regulate our pathetic D3 receptors. If that happens, that's bad, very bad, for augmentation - a bigger, better bad guy plus an ever weaker good guy??? What the hey? Doesn't the Doc realize there are no free lunches (except for ferrous bisglycinate). Dr. Clemens has some explaining to do.
I told him in my email last night that antagonizing the D1 receptors is exactly already the problem with Prami. And now he wants us to take Prami on steroids? Why do we want to add fuel to the fire?
I also told the good doctor that I think a D1 AGONIST is the way to go. In the short run it will make the Prami less effective because it's forcing the D1 receptors to pump out more of it's exciting signal, but in the long run will most definitely NOT up-regulate the D1s and maybe even down-regulate them a little. That's good, really good, we want somewhat weaker D1s. You see, that's exactly the way Neupro works - it is a somewhat less effective DA (in the short run) because it is not only an Agonist at D2 and D3, the way Prami is, but is also an Agonist at D1, D4 and D5. Don't get me wrong, Neupro, like Prami, tends to be more of an Agonist at D3 - meaning the substance preferentially goes to D3, but is still an agonist at the other receptor sites, albeit weaker. If it were equal across the board, then Neupro would provide no relief, it would maintain the equality (or in our case the inequality) of Yin and Yang, just at a higher level. RLSer's Yin/Yang is off to begin with as I stated - we need more of the light, happy Yin aka D3 receptor signal. Studies have shown that Neupro (which has mild D1 Agonist properties) makes augmentation and withdrawal symptoms much less likely. So let's give people taking Prami a D1 Agonist, right? Not a D1 Antagonist.
Got all that Kaarina? Do you agree? You wanted to be the Administrator...mwahaha :).
I really like all your thinking & research & theories. It’s what we so need. Night before last had the worst night ever, non stop movement, despite codeine & ferrous bisglycinate, muscles felt as if had run a marathon. Ridiculous to have to put up with! Never been on a DA, only Pregabalin in the past. What the h…. is going on. Had had 2 bananas earlier in the day & satsumas. But why on earth should they make it that bad? Please can I / we have some peaceful pleasant years before I expire!
I think the worsening of your RLS symptoms will be sporadic for you and is in someway related to your condition that we discussed in our last post. Have you thought about the turmeric that was mentioned in one of the articles I gave you. The article claims it is one of the few substances that might help your condition. Turmeric is, and has been for quite some time now, the latest greatest "it" substance for treating everything from toe nail fungus to dandruff to nerve conditions. It allegedly comes from it's anti-inflammatory properties. The other thing we talked about was calorie restriction because that is one of the few things that has been shown to increase the number and density of people's (not necessarily with RLS) dopamine receptors. As we all know, the RLS goes when standing and walking. What some people don't know is the reason why. When we stand and walk our brains release dopamine to balance us and coordinate movement. It doesn't matter how, or what part of the brain it comes from, the release of dopamine will relieve RLS. I was once standing while watching a movie because I had RLS. At one point I was leaning and I noticed that the RLS was not completely gone while leaning. I guess my brain wasn't sensing enough imbalance and wasn't releasing much dopamine. Anyways, the point of me telling you this is that I once read on here how a woman would fall asleep on her knees while bent over an ottoman. When you're on your knees that's quite a balancing act for the body and dopamine is released. Of course it's less of a balancing act being draped over an ottoman but it seemed to work for this one person. Sleep during the day if you can. You gotta keep moving forward...keep taking the iron, try taking three capsules with some vitamin C on an empty stomach before bed instead of two, keep taking the codeine at night. Ask the doctor if you can take two on bad nights. Try the turmeric. Try two days of severe calorie restriction, but be sure to get plenty of fluids. Make home made gelatin - use kosher gelatin from grass-fed cows and mix it with something delicious like green tea and a little sugar or sugar sub. I do this and then pour a teaspoon of cream over when I serve it. Buy the organic vegetable broth in grocery stores in large boxed containers and add some of your own vegetables. Blend celery and parsley and carrots and spring mix in a blender with a sorbet bar (add some coconut milk or coconut sorbet or half and half for fat - otherwise you won't absorb all the nutrients). These things are delicious, will provide several servings, and after two days you may find that your RLS is bearable for a few days. Then rinse and repeat :).
Thank you so much. I’d forgotten about the turmeric. Would it be too much trouble for you to remind me which article that was?I must try the calorie restriction. I find it really hard as when I’m tired I go into survival mode & Stoke the boiler, as I describe it, with anything going.
I also find my neuropathy, balance & shakiness is worse if I don’t have any sugar around ( hence the bananas ). The lack of myelin affecting function seems to be worse without sugar so it’s a catch 22. It could well be that that effect wears off after a few days when I got into another metabolic pathway.
I do try to sleep day time then need to have energy to look after my wee granddaughter after nursery.
I’m trying really hard not to take more codeine as I’m scared of addiction.
Thank you so much for your caring advice & input which you do in such a helpful & kind non ‘bossy’ way. Your tack suits me and I hope many others
oatext.com/Long-term-follow.... I would give this a shot. Turmeric has a good safety profile. Supposedly it's not great if you have reflux or stomach issues. Plus I recall reading that it is poorly absorbed and should be combined with pepper/piperone or once again maybe mix with quercetin in order to make it more bioavailable. I don't think you need to cut out sugar, many on here would disagree with me. I think if you understand the mechanics behind this calories restriction thing you might be more willing to play the game. Life can be divided into two categories, pleasurable things and annoying things. Pleasure comes with a price for the most part. Food is a dopamine agonist as well as sex, drugs and rock and roll. Done to excess they will down-regulate everyone's D3 receptors. We can't afford that. Then there are the annoying things like being hunger, exercising till you're gulping for air. These are the things that will up-regulate your receptors, regardless of your weight. Fat or thin, severe calorie restriction will up-regulate the D3 receptors. Obese people, who don't necessarily have RLS, were studied via Pet Scan. The scans showed that they had smaller and fewer D3 receptors, just like we with RLS, only they didn't have RLS, they just beat down their receptors themselves. It's a vicious circle because then once your receptors are beaten down you're more likely to eat even more. DON'T DO IT. Don't fall into this trap. I don't care if you drink a cup of apple juice with crackers 3x a day, try to keep your caloric intake below 900 for two days. Most people do that in preparation for a colonoscopy. If it provides no relief you can give it up or you can continue to restrict calories (please eat nutrient dense food though) and give your receptors a chance to up-regulate. A few people on here have gotten rid of their RLS symptoms using calorie restriction.
Yep that does the trick for me. You are a true scientist at heart. I take my hat off to you. I have a good feeling about the severe calorie restriction. 🌈. Please keep us posted.
And that fact about standing is fascinating isn’t it. There is no doubt it’s true. How often have I tried to do a puzzle sitting as I’m so fed up standing, & it’s impossible to stay still. Stand up & it becomes possible even if I have to fidget my feet. It’s all so weird
Take the iron, take the codeine, don't eat late into the night, lay down in bed, turn on the news, imagine yourself on a narrow mountain trail and you have to be very careful. I mean really imagine this. Or you're back in high school on the balance beams. You understand it all now. You know what stands the greatest chance of working. Do it all. Try to enjoy the insane game. Then write to me in the morning, "you know I love our little chats darling." That's a line from the movie, The Incredibles. It was on a constant loop in our house when my son was little. I bet your granddaughter would love it. Good night for now.
😘
Well i have read all this thread , I have never suffered with augmentation and hope i never will i am light weight anyway with trying to take meds. As i said i have never suffered with augmentation, BUT i know that people on here and other groups suffer badly from it and how much strength it takes to wean off it, so i have/do try to help those who are going through it. BUT regarding the science to it all, its all above my head. When someone posts on the D receptors etc etc and other in depth stuff i am lost. !! But i will leave all that science stuff to those who have a better understanding on how it works.. Thanks for your insight and lengthy post but its all good.
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The Illusory Truth Effect, or something like that
Too much Pramipexole.
Too much electrolytes?
