The key role of adenosine in restless legs syndrome.

[Arjiji]

A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome

Diego Garcia-Borreguero, MD, PhD, Celia Garcia-Malo, MD, Juan José Granizo, MD, and Sergi Ferré, MD, PhD

Sleep Research Institute, Madrid, Spain

Department of Clinical Epidemiology, Hospital Universitario Infanta Cristina,

Instituto de Investigaciones Sanitarias Puerta de Hierro, Madrid, Spain

Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program,

National Institutes of Health, Baltimore, Maryland, USA

ASTRACT:

Background: New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role.

Objective: The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment.

Methods: A 2-week double-blind, placebo-controlled crossover study assessed the eficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Seve rity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response.

Results: Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, ver sus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P <0.001).

Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%).

Conclusions: Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the eficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome.

© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

[Ebi1909]

Very good news! But as far as I understood, Dipyridamole isn't solely available. The only current drug I could find was Aggrenox (including Aspirin as well).

[Elffindoe in reply to Ebi1909]

Dipyridamole is available on it's own as used for anticoagulation.

Aggrenox is probably an even more potent anticoagulant because of the aspirin. I'm not sure it's advisable to take a potent anticoagulant when you don't need one.

[WideBody]

I am vey excited about this. I may need discuss this with my doctor. I think someone here is in a study on it.

[LotteM]

Thanks for posting Arjiji. It doesn't sound different from the previously published study. Also, I am a bit disappointed that - again - they tested only previously untreated patients and that the study lasted only two weeks.

We all know that RLS is difficult to treat and that we need new treatments especially for so-called 'refractory' RLS, that is patients who already tried and after a while failed treatment. And given that it is chronic (and I don't mention progressive) we need treatments that are both effective and safe and with only minimal side effects.

At least this is the first medicine that wasn't found effective by chance, but based on on-depth research into the workings of the brain and neurotransmitters of people with RLS.

Few people on here have tried dipyridamole, some with some success, others without. Ot is definitely not our silver bullet. But it does widen our treatment options.

[Hidden]

Hi Arjiji, sorry to hijack your post but in regards to the repetitive transcranial magnetic stimulation you underwent, what protocol did you use? Was it high frequency or low frequency? And I'm assuming it targeted the motor cortex?

Thanks in anticipation.

[Reb0013 in reply to Hidden]

following

[Elffindoe]

Thanks Arjiji, I had heard that it was intended to carry out full scale trials of Dipyridamole for effectiveness and safety. I'm not sure if this study counts as such.

In any event it still doesn't appear to have been approved for RLS.

I believe some people have tried it "off label" it's an approved anticoagulant.

They reported variable success.

[LanaCSR]

My neurologist has had me on dipyridamole (along with 2 other medicines) for RLS for about 2 years now, and I can tell you it works GREAT for me!! And before I found this neurologist I had been pretty much written off as a "difficult case" and my previous neurologist told me there wasn't anything else he could do for me and sent me to a pain management doctor to get on an opioid. After trying that route for about a year, the opioid just did the same thing every other medicine I had tried for RLS did, it worked well at first and then just started losing its effectiveness until it practically stopped working for me. Then I found my current neurologist who has me on dipyridamole, buprenorphine, and Horizant (a different form of gabapentin that I works for me). As an aside, I had tried regular gabapentin years prior and it caused such profound sleepiness and made me dizzy and I was bumping into walls and just could not tolerate it. Now I have found my current neurologist (thank goodness) who has had me on these same 3 meds for 2 years now, and I literally can tell as I take the dipyridamole in the evening (2 doses separated by 4 hours) that my RLS symptoms are starting to go away after the first dose and then by the time I take the second dose, my legs feel like a person without RLS all evening and through the night! It has worked better than any other medicine I have tried for RLS, and believe me I have tried them all since I was first diagnosed in 2012. Anyway, that is my story about dipyridamole. I realize I am being prescribed it off label, but it works for me. I pray it continues to work this well for me and that I can continue taking it for the rest of my life. If you have an opportunity to try this medicine, please ask your doctor about it. It is definitely worth a try, in my opinion. Good luck, my fellow RLS friends!

[ookla in reply to LanaCSR]

Have you tried taking the dipyridamole without the buprenorphine and Horizant? No offense, but I assume those two are doing most of the heavy lifting... maybe even just the buprenorphine.

[LanaCSR in reply to ookla]

For me it takes this magical combination of all 3 to work for me. When I just was taking the Horizant alone it didn't control my RLS. Same with the buprenorphine. It worked great at first and then started not working so well. As soon as the dipyridamole was added to the mix, my RLS was under control. And, as I said before, I can feel it working every evening as I take the first dose and then the second dose 4 hours (or more) later my legs feel like they did before I got RLS. Buprenorphine works fine for a lot of people by itself, but my RLS is extremely difficult to control, and buprenorphine alone doesn't control it. I expected to hear from a skeptic because we are all different and you don't know what it's like for me. But this works for me. I only told my story because of the post about the dipyridamole study and to show others that it truly does work in case someone might consider trying it.

[ookla in reply to LanaCSR]

I'm not a skeptic. I would love to try this. My only concern is that when someone is taking a few different medications, how do we know what's doing what? It would be very hard for someone to go to their doctor and say "I need these three medications." And for all we know, the dipy would work just fine all on its own. You say your symptoms went away after the dipy was added... so, again I ask, have you ever tried taking the dipy by itself? Maybe you don't need the other two?

[LanaCSR in reply to ookla]

I actually have RLS going on all day. So the buprenorphine keeps it at bay (for the most part) during the day. I actually have breakthrough symptoms when I skip a dose of buprenorphine. The dipyridamole can only be taken (the way my neurologist explained it) twice a day in the evening. So although it works wonders at night, it doesn't help my daytime symptoms because I can't take it earlier. *sigh* Great question, though!😍

[ookla in reply to LanaCSR]

I, too, have 24/7 RLS. I take tramadol every 4-6 hours to keep it at bay. I'm glad you've found a regiment that works for you, long may it last! Best of luck.

[LanaCSR in reply to ookla]

I tried tramadol for awhile, but it actually augmented on me, as well. Ugh! Isn't it weird how everybody is so different with RLS and how meds work differently for some than others? I feel like I've tried everything that's out there. I don't get 100% relief, but I get about 85% or more and if that's the best I'll ever get, I'm happy with that.

[Ebi1909 in reply to LanaCSR]

Source: ncbi.nlm.nih.gov/pmc/articl...

I recently found this figure, which shows why you seem to be fine with all three drugs.

[LanaCSR in reply to Ebi1909]

That is very interesting! Thank you for sharing this with me!!

[involuntarydancer in reply to ookla]

Anecdotally, RLS often seems to respond better to multiple treatments at a low dose than a single treatment at a higher dose. The outcome of multiple treatments seems to be more effective than the sum of its parts. The incredibly helpful diagram posted above maybe gives an indication of why this is. I think this is an important message for those who feel they are in the last chance saloon of treatments - eg when opioids seem to be failing after dopamine agonist augmentation and a2d ligands not proving effective. There is always hope and introducing one new med or tweaking the dose of existing ones can afford a few more years of coverage.

[involuntarydancer]

Based on the various anecdotal reports concerning the impact of dipyridamole on symptoms, it would appear that describing the role of adenosine as 'key' may be misplaced. It seems to be more contributory than key and treatments aimed at 'adenosine systems' seem to be complementary to other treatments rather than comprehensive in themselves. Perhaps, as Lotte's post also suggests, the outcome is different for sufferers who have not previously been treated.