Restless Legs Syndrome
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RLS and Dipyridamole study - Hope?

frontiersin.org/articles/10...

It is very technical in its language and I only understand about 1 in every 20 words in the study but is there something to be said for dipyridamole? My understanding is that it is a fairly safe drug used in the treatment of strokes - more so in the past than nowadays.

It inhibits platelet aggregation so would obviously not be good for anyone already on anti-coagulants etc.

Maybe some of the chemists/doctors/clever people on here could comment.

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It is a scientific paper bu Ferré and others, who alteady in a review on rls have discussed the implication of adenosine in rls. This seems a follow-up report on that line of research. I will read it and try to summarize it later in hopefully understandable English.

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I was so hoping you would get onto it LotteM.

I am already wondering about asking my very helpful GP if he would prescribe Dipyradamole so that I could conduct my own personal trial ...

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Good find, id!

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Where did you find this ID? Brilliant detective work . I’ve skimmed it and although very technical, it does show really encouraging, positive results.

6 of the 13 in the trial showed full response to the treatment ( though placebo effect is mentioned).

As the drugs are already out there, I agree that we could persuade our doctors to let us try them.

I think my MS neurologist might be up for this!

I’ll print it off, send it to her and see what she says.

Well done ID!

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I have tried to read it, but we do need someone who can translate it into simple words lol Good find tho ID. :)

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I am going to read this, I know of and have heard of this before. It is not new, that much I can say right away. :) I see Lotte says 13 people in the study? hmmmmmmmm, not nearly big enough for me. Anyone on blood thinners can NOT take this, that much I know.

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The drug itself actually dilates the blood vessels. This paper is made up of different quotes about this from several international doctors, and 2 of them I know pretty well, or know OF them and their work. It is supposed to help regulate the glutamergic system (glutamate) and also it seems to like the dopamine receptors, especially D3. That is the very simple explanation. I would say the jury is way out on this one, a study being quoted with 13 participants is not enough for me. It is basically a blood pressure drug in many aspects. But, you definitely cannot take aspirin with it, or anything that thins the blood, because it dilates the blood vessels so much. Have read Dr. Earley's comments on this before in 2009, so it is not something that has a lot of legs at all right now. That is what i am getting out of it, anyway, but good find, ID. :) We need all the info we can get, that is for sure! AND, the main focus on this, even though it SAYS RLS, is PLMD, which is fine, but that is what they were looking at, PLMD while sleeping.

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Thanks Nightdancer for your explanation. I did keep seeing them mentioning PLMD more so than RLS.

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Well done, nightdancer, also for the extra info re blood thinners that I suspect is not in the paper.

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I did put that in my opening post also.

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Sure thing, ID. Should have included you.

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me, me, me, me!

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You can’t take dipyridamole if you have any heart issues either. Just read about that.

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I have skimmed through the paper, after having kicked my hubby out of the bed and while waiting dor the tramadol to kick in.

The paper develops a long argument on the mechanisms in the brain involved in rls. It starts with the earlier finds of high levels of dopamine and glutamate found in the space in between the brain cells (=neurons). And it refers to earlier studies in which low iron (in diet during development) in mice results in fewer adenosine receptors (on the brain cells? Didn’t say; I have to search for that in the original paper).

Then follows a very long, difficult and complicated discussion of a cascade of changes and events in the brain that are or maybe implicated in rls. This cascade ends with the arguments that medicines aimed at stimulating the downregulated adenosine receptors are not a way to go, because stimulating these receptors directly causes slowed heart rates and increased blood pressure. Their alternative approach is, if I understand correctly, to aim for increasing adenosine, but not too much. They then focus on ENT1, a transporter of adenosine in the brain. And dipyridamole slows or stops this ENT1.

The problem is that it is questioned whether dipyridamole can sufficiently cross the blood-brain barrier, thus it may not get to the brain where it is needed in case of rls. It is tested in a study with mice or maybe mice cells (the mice ‘model’) and it does. And dipyridamole indeed increases the adenosine in the brain. They then say that they expect that the higher adenosine will activate the (in rls-ers reduced) adenosine receptors, which in turn hopefully will lower the (again in rls-ers) higher levels of dopamine and glutamate in the space in between the brain cells.

Thus, they gave dipyridamole to 13 patients not on other meds. Some responded, others partially or not. The results will be in a other paper published soon. Numbers are low as it was intended as an exploratory study; I get the impression they find the results promising enough to try and organise a full study.

In sum, jury still out on dipyridamole; we’ll have to for larger study. The reason why they looked at dipyridamole in the first place, is because of a series of earlier results and accumulated knowledge of what is going on or what has changed in a rls-brain. To me and as far as I know, that is new. Not simply because a medicine was observed by chance to happen to have a positive effect on rls.

Finally,I get the impression that in the paper PLMS is used to describe not only leg movements during sleep, but also during rest ans maybe also the urge to move. Shall try and email the author for clarification.

Disclaimer: I have done my utmost, but I am in bed and on my phone and well past midnight now. So please disregard the typos and the language errors. Also, I would like to have this ‘summary’ checked by either a colleague neurobiologist or, preferably, the author. Shall try if I have time and energy.

Sleep well!

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Thanks so much Lotte,

That is really useful and helpful for those of us who do not have a science background.

Sleep well also,

jools

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That's fantastic Lotte; thanks. Re the comments about it not being good for heart conditions and with blood thinners; I did try to allude to that in my opening post though possibly a bit obliquely.

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Just read your post more carefully and want to thank you very sincerely for the substantial effort you put into this (including all noted disclaimers!). You are tops Lotte, well done.

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Thank you so much. If effective it sounds as though I could take this drug for high blood pressure and RLS. That would be good.x

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My issue with this was also the blood/brain barrier. If the drug cannot get past that it is useless. I do not see much hope for this, and again I do not like such small short studies. A lot of assuming going on when you only have 13 test subjects and 5 of them are on a placebo.

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Hi nd, can I ask, what drugs are you on for your rls? Having looked into pregabalin more closely and now very scared of it, I feel like I am coming to the end of my tether.

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ID what are you concerned about taking pregabain..? Is it working for you right now. ?

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What is concerning you about pregabalin? EVERY drug has issues and we do not know until we try them if they will work for us or not. I can safely say that you could not find a drug for RLS that I have not tried. The ONLY thing that helps my RLS and keeps it under control 90% of the time are opiates. I also have severe chronic pain issues, 5 back surgeries and 3 neck surgeries, since the age of 14. So, my pain meds also are my RLS meds. Slow release morphine, short acting tramadol for breakthrough pain and RLS, Clonazepam which helps the other meds work better, and a sleep med , a very old fashioned one called Dalmane (Flurazepam) These meds I have been on for almost 19 years now. Never have upped the doses and in fact, my doctor and I have lowered the doses to keep with the CDC guidelines, whether we like it or not. Where have you been reading about Pregabalin and , again, what scares you about it. We can be cautious, but should not be "scared". I was on it for 2 months, and we quickly found out it did not help MY RLS or my Fibromyalgia, which is what it's original intention was when it came on the market.

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Thanks for that nightdancer. It is interesting to hear about the regimes of others.

I'm not sure why we should not be 'scared' - anyone who has been through the process of withdrawal from a d/a is likely to be scared of any medication that might involve going through something like that again.

I stupidly walked myself into a very difficult withdrawal by not informing myself about that drug.

Any man-made chemical formula has the potential to have unexpected outcome when ingested - different from the original intention. Where there is an extensive profit to be made, there is unfortunately a strong incentive to conceal or play down any negative outcomes that are not originally apparent. Thus, unless a drug has been around for a very long time - in excess of 50 years, it is difficult for anyone to be completely assured of its longterm impact on the human body.

Consequently, I would infinitely prefer to be on opiates/opioids, the outcome of which (opiates at least) have been observed for centuries. There are numerous studies confirming the ability of people to exist successfully on steady doses of opiates for very long periods - even lifetimes.

Unfortunately I suffer from opioid induced central sleep apnea and my consultant has advised me robustly not to take them. She is my sleep consultant and didn't even consider the option of a central sleep apnea mask. However, even if she was prepared to prescribe/advise one, I couldn't afford it. I am pretty sure my insurance policy wouldn't cover it and in Ireland such things are not provided to the likes of me by the state.

From my reading about pregabalin - when used for rls - it does seem to have a time limited usefulness. I haven't seen many people who are on it for more than a decade or so. Unlike opioids, it does not seem to be effective indefinitely. Thus it is likely to require to be discontinued at some stage.

Unfortunately there seems to be an immense body of pregabalin takers (many many on a lower dose than I am on now and for only a few months) out there who have suffered incredibly in their attempts to discontinue the drug. Most sound like very ordinary people who have taken the drug for established uses - the accounts I read were not people who had abused the drug. This is in stark contrast with the accounts I read before I started oxycontin or kratom.

In the case of both those drugs, the anecdotal accounts of difficulty in discontinuing them were characterised by people who had taken vast quantities of the drugs - far more than I was ever going to take - and for long periods.

Moreover, many of the people discontinuing pregabalin were complaining of being left with permanent heightened anxiety.

I am no longer on 75 mg as I had been hoping that pregabalin could be the main drug to control my rls as I struggle to achieve a routine that allows me to continue working. I have titrated up very gradually and am now on 225mg daily. Unfortunately, while it does muffle my rls, I am still woken up twice in the night with rls every night and have to take something else to dull the symptoms so that I can get some sleep. I have been on 200mg for nearly 4 weeks so am fairly sure that I will need a larger dose for my rls.

In the meantime, I am not happy with my side effects on this drug. I am experiencing an unpleasant restlessness and seem to be becoming increasingly gloomy and miserable. I notice that I have difficulty with word recall, feel sort of 'drugged' during the daytime and am unsteady on my feet, particularly in the morning.

For all of the above reasons I do not think it is the drug for me. Now I am deeply concerned (as you do not like the word 'scared') that I will suffer difficulties withdrawing from it.

I am not unrealistic and I am not afraid of withdrawals. I have been through a few. Withdrawing from oxycontin was not a picnic - I didn't enjoy it and it took at least 6 weeks to recover from. Withdrawing from mirapexin was nothing less than a visit to hell which unfortunately for me lasted over four months. Withdrawing from kratom takes a maximum of two days of comparatively minor symptoms. However I would go through any of these withdrawals again if I knew I would get a few years of reasonable coverage of my rls.

But in the case of pregabalin, if I am unlucky, it could take me years to get down from my existing dose. I fervently hope that I manage to get off it much more quickly but a withdrawal of that length - accompanied by very unpleasant symptoms - appears to be far from unusual. Moreover, I may be left with permanent anxiety.

Thanks for your recommendation of rxlist.com. I have consulted that site previously in respect of various combinations I was using. I hope you are having a good night as I type.

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ID, what meds are you on now, if any, and what have you tried. Unless we know your history, we do not know how to try to help you. .........edit......... I looked at some of your posts and see you are on 75 mgs of pregabalin and use kratom? You would know by now if pregabalin is helping you or not. My best recommendation for "drug facts, interactions and side effects" is rxlist.com It is the most detailed site I have found for that purpose in 27 years.

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☺️

Calmed my legs! Not my mind, though 😏

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Fascinating study! I think this is an important take away...

"Confirmation of the therapeutic effect of dipyridamole in RLS would bring ENT1 inhibition as a new therapeutic approach for RLS, offering an alternative to dopaminergic drugs and, therefore, to their long-term complications, mainly augmentation."

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I visited my GP today for something wholly unconnected and in passing he asked about my rls. I mentioned dipyridamole (had to look it up - it wasn't sitting at the forefront of my brain) and it was barely out of my mouth when he was writing me a prescription for it - I hadn't asked for one at all. He said he considers it a very safe drug and thought it would be worth a try (he hates pregabalin which I am currently taking and so I slightly suspect his motives)! I'm not sure I'm going to get it but I am tempted ... Maybe I would be one of the slightly more than 50% who reported relief from symptoms - hope springs eternal!

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You can only try it and see.. Maybe it will work for you. I suppose do as usual, start at the lowest dose if you get tempted.

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Interesting, ID! If you will take it, please keep a diary of how you and your rls react. At best you start that lets say a week before, to have a good basis for comparison. And try not to change anything else at the same time.

Did your gp suggest to take the dipyridamole instead of your pregabalin?

Remember that the dipyridamole was tested with people with previously untreated rls, and not refractory rls. If you decide to give it a try I really hope it will work well and completely for you. At the same time I think that your expectations are at best kept low.

If joolsg can get it too, we already may have a N=2 for a study!

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He didn't suggest I come off pregabalin but I think he hopes I will. The more I read about pregabalin the more I would like to come off it myself.

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I hope it is not a "withdrawal" like Pramipexole. Good luck with it.

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Hey involuntarydancer. I like the "handle" it fits perfectly the RLS problem :-) Wanted to ask what you found helpful to relieve the symptoms when you were withdrawing from Pramixpexole? It has been almost a week and I had 1 unbelievable day with NO problems. I thought is was just about over. It came back with a vengeance, and has not let up. Tried 600mg Gabapentin and thought it was helping, but no. I am in a quandary as to what to do. Earliest apt. I could get at RLS Clinic is March. You have any suggestions >Thanks

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I feel your pain Billdel, and have little of solace to offer. When I was coming off pramipexole my consultant prescribed pregabalin but, as I learned by doing my own research, pregabalin - and gabapentin - will cut no ice against the awful symptoms that are experienced when coming off a dopamine agonist such as pramipexole. The only thing that works during the acute withdrawal phase is an opioid such as tramadol or oxycontin. I didn't have these when I was withdrawing. It is a truly miserable experience - I have never been through worse. If you can persuade your GP to prescribe tramadol, I would be inclined to do that. Otherwise it is a case of suffering through. I don't think anyone who gets through it regrets coming off the dopamine agonists though.

Please note that once you are over the acute withdrawal period gabapentin/pregabalin may well be useful in treating your rls which should settle down a lot. How are your serum ferritin levels.

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Thanks for the reply. As you know, it truly is a struggle. I have no idea where in the withdrawal phase I am other than 7 days. I have a Rx for Oxycotin-acetaminophen 10-325, that was for my neck surgery. Never used it and tried 2, at 6 hour intervals earlier and it didn't seem to do much. Maybe need different combination or stronger dosage. Waiting for my Dr. whose wife has RLS big time, to return my call. He is a sharp guy, but not into RLS and I am trying to figure out what to ask him for when he calls. I am sure he will help but I am not sure what I need. Your suggestion of Tramadol, which I am not familiar with or oxycontin is a good a good start. Thank you. Any thoughts you may have on this situation would be appreciated.

I hope you have found a good solution to your situation.

You mentioned something in a previous message that I am not familiar with. What is a relaxis pad?

You ask about my Fe. Checked it last week and all #'s are mid range. I was hoping it was low. Taking an iron supplement has always helped in the past but that was not "withdrawal"? And, I really hoped to get into IV iron as a long term solution.

Thanks again.

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Regarding iron, it is very unlikely to help with the withdrawals but I have a (totally unproven) suspicion that having higher serum ferritin levels might move the process along a bit. Have you looked at the Johns Hopkins website? They have a very good section devoted to rls - their doctors are among the best in the world. There are some interesting short videos, especially by Dr. Christopher Early. They favour getting serum ferritin over 100. Also rlshelp.org - Dr. Buchfuhrer's website (another rls expert). He has a patient's question page which repays perusal. Many on here have had their questions answered by the seemingly untiring and exceedingly generous Dr. B. His name is up in lights in rls communities across the world.

When I was withdrawing from pramipexole, I spent a lot of time looking at (pacing back and forth in front of) these websites.

The relaxis pad is a medical device aimed specifically at rls. It is a mechanical pad you lay on your bed which vibrates. The theory is that it provides a counterstimulation which causes the brain to switch off the rls symptoms. There are some videos on youtube about it including one with Dr. Buchfuhrer who endorses it for mild to moderate rls. It won't help with withdrawals and is eye-wateringly expensive. It is definitely not a silver bullet, it isn't even reliable against the rls, but it is another weapon in the arsenal. For some reason I find it more useful when I take a nap in the afternoon (which is currently a rare event) and rls strikes than at night time. If it was MUCH cheaper, I would recommend it as a non-pharmaceutical option (or if you are Bill Gates) but as it is, it is insufficiently reliable to justify the cost. It is soothing however so if money is no object ...

Regarding your oxycontin, if your tablets are 5mg then I think it is unlikely that one tablet at a time would be enough for pramipexole withdrawal. Please note I am not recommending you to embark on high doses of opioids. I am only recording what I believe to be the case. I would imagine it could take 2, 3 or even 4 of those 5mg tablets to make an impact on your symptoms at the moment. BUT if you do decide to try that I would suspect it would be better to work up to that dose over at least a day or two because you don't want to take too many chances with opioids. Maybe you could try taking two together tonight? Also I wouldn't take them for more than a few days at a time unless you want the joys of opioid withdrawal to follow hard on the heels of your d/a withdrawal. Withdrawing from oxycontin is no joke either with, ironically, restless leg type symptoms as one of the worst elements.

Best of luck, Bill

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Thanks ID, this is a lot of good info. which I will follow up on. I am familiar with Dr. Earley's video's on Iron. That is what interested me in the Iron IV option. Glad to know about Dr. Buchfuhrer. Sounds like he may be in Germany. May skip the relaxis pad for now. Reminds me, however, of something my Pharmacist suggested. He said to put a warm heating pad on the floor and lie on it with you very lowest back/butt on it. He said that is where all the nerves extend down into the legs and it "may" calm the symptoms at a neutral location. And, it seemed to work when my symptoms were at their worse, in withdrawal. I hate to say it, because it will come back to bite me, but I have had minimal problems yesterday and today. And as I mentioned my 60 hrs depletion of the Pramip. is up. Wow, maybe its all pulling together. That would be a first for me and RLS.

Thanks for the good info.

Bill

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