Dipyridamole

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Rustsmith
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Re: Dipyridamole

Postby Rustsmith » Sun Feb 04, 2018 9:57 pm

My thought is that it might be an opioid alerting effect of the kratom starting to appear now rather than something from the THC or the gabapentin. Those two should both help induce sleep rather than interfere with it. It could be that the pramipexole, THC and gabapentin were all working to overcome the opioid alerting from the kratom. Now that the pramipexole is out of the picture, maybe the alerting from the kratom is starting to appear.

So, my suggestion would be to just change one thing at a time right now and drop (or reduce) the kratom rather than also stopping the THC and gabapentin as well.
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

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.

stjohnh
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Re: Dipyridamole

Postby stjohnh » Mon Feb 05, 2018 8:04 pm

Well I decided to follow Steve's recommendation last night, so I stopped the kratom but took the dipyridamole, THC and gabapentin as usual. I did have a better night's sleep, although still nowhere near as many hours as I usually got before I started the dipyridamole experiment. Urge to move symptoms were fairly well controlled.

I think tonight I will try cutting out the THC and just take the dipyridamole and gabapentin.

Even though I didn't get as many hours sleep as I did before the experiment, I still feel considerably different, hard to say exactly how but I feel more "normal."
Blessings,
Holland

Rustsmith
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Re: Dipyridamole

Postby Rustsmith » Mon Feb 05, 2018 9:21 pm

Feeling "normal" sounds like such an impossible dream. :D
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

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: Dipyridamole

Postby ViewsAskew » Wed Feb 07, 2018 5:00 am

stjohnh wrote:
Even though I didn't get as many hours sleep as I did before the experiment, I still feel considerably different, hard to say exactly how but I feel more "normal."


That is truly a dream for many of us. I may have control with all I do, but I haven't felt "like me" for at least 14 years.
Ann - Take what you need, leave the rest

Managing Your RLS

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.

badnights
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Re: Dipyridamole

Postby badnights » Wed Feb 07, 2018 6:37 am

Holland, I am not sure but perhaps your wakefulness after taking dipyridamole might be because your adenosine levels have become high enough to activate A2A receptors, which will slow down A1 receptor signalling thereby promoting glutamate release (p. 4, first para). That is, if the idea of the A1R-A2AR heterotetramer being a concentration-dependent switch is correct.

I did see a mention of cannabis, sort of. They say that certain cannabinoid receptors could be involved in the pathophysiology of WED/RLS, specifically heterotetramers of A2A receptors and CB1 receptors that (like the A1R-A2AR and A1R-D2R that they discuss at length) are in glutamatergic terminals in the striatum (p 8.). But they don't provide any more information than that. The reference is "in prep" so I expect more to be published on that at some point.

I finished the article but like Steve I would like to read it again. I didn't notice the thing about the frequency of electrical stimulation. It's nice how we each notice different things.

I don't believe they address the opioid connection, did I miss that too?
Beth - Wishing you all restful sleep tonight
WED/RLS AUGMENTATION:
viewtopic.php?f=5&t=6532&p=61601#p61601
Discussion Board Moderator's posts don't reflect the RLS Foundation's opinion & are not medical advice

stjohnh
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Re: Dipyridamole

Postby stjohnh » Wed Feb 07, 2018 2:59 pm

The real big obvious omissions for us RLS sufferers in the paper are no discussion of opioid mechanism of action or augmentation mechanism of action. I presume that the reason is that the authors either don't have a very good idea of how those things occur or, if they do, there is little experimental evidence to back up a theory.

I have now been off pramipexole for about a week, and have been off all RLS active medication except for dipyridamole for 2 days.

The good news is the dipyridamole at 375 mg is doing a good job at controlling urge to move. The bad news is I continue with serious inability to sleep. I'm generally getting about 2 hours sleep between 3 a.m. and 6 a.m.

I currently don't have a clear plan on how to approach that. From the prior week when I was dropping the pramipexole, then kratom, then gabapentin, I'm thinking I should probably try at least a couple of more days of dipyridamole alone. The idea being that the multiple receptors involved in RLS may need further time to reset to my basal levels and respond to the dipyridamole. Additionally I should be confident on exactly how bad the sleep disturbance is before I start confounding the issue with the addition of other medications at other times and varying doses.

One puzzling factor I noticed was that the best sleeping nights I had were right at the start of dose reduction of pramipexole. The jump from 0.0625 mg of pramipexole to 0 mg of pramipexole was when I had the greatest worsening of insomnia. At this point I don't think there's any way of knowing whether the low dose of pramipexole was somehow helping the insomnia or whether that was just a matter of withdrawal. It is also puzzling to me that dropping the gabapentin seemed to have absolutely no effect on my insomnia.

I had the expected side effects of dipyridamole off and on for the first week: headache, occasional mild nausea, and occasional lightheadedness. They have all resolved.
Blessings,
Holland

badnights
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Re: Dipyridamole

Postby badnights » Wed Feb 07, 2018 4:53 pm

Maybe future papers will touch on augmentation simply because their work involves dopamine receptors, but their focus is directed specifically at adenosine-receptor heteromers in the striatum (and they mention spinal motoneurons as well, as the subject of an upcoming publication) so I don't imagine it's one of their goals to explain the opioid connection. Still, it's a huge step forward to link the dopamine, iron and glutamate together.

The insomnia you're experiencing is disappointing (more for you than us, I imagine). As I understand it, they thought that downregulated A1 receptors were responible for both the movements and the hyperarousal (but not the sensations?) and that dipyridamole would sort of bypass the downregulation by inhibiting removal of adenosine, letting it increase in the extracellular spaces. But the trick, as they say on p. 9, is to keep it below the threshold at which pre-synaptic A2A receptors become activated, because then you get the opposite effect of what you want - increased glutamate. But it's more complicated than that, because they talk about histaminergic and orexinergic systems affected by A2AR, and more importantly, because it might be relevant to you: activation of A2A might be blocked by dopamine... at least, they say that catalepsy induced by an A2AR agonist can be counteracted by a D2R agonist (top of p. 7). So maybe that tiny bit of pramipexole is necessary?

Or maybe you have to wait a bit longer, as you said, then try something like adding gabapentin back in.
Beth - Wishing you all restful sleep tonight
WED/RLS AUGMENTATION:
viewtopic.php?f=5&t=6532&p=61601#p61601
Discussion Board Moderator's posts don't reflect the RLS Foundation's opinion & are not medical advice

stjohnh
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Re: Dipyridamole

Postby stjohnh » Wed Feb 07, 2018 7:37 pm

Thanks Beth, I had not interpreted that section of the paper with as much understanding as you seem to have. I did get the impression that there might be a sweet spot in the dosing of dipyridamole. I think that's what you're saying. That too much might cause the same effect as too little. The last several nights I have been taking 375 mg of dipyridamole. At the time I had less sleeping trouble I was on a lower dose. My impression is that the urge to move was well controlled on the lower dose as well, perhaps I should try lowering the dose somewhat before starting other medications. The dosing used in the trial was 100 milligrams initially, increasing to 200 then 400 at 8 p.m. I don't know if all patients were titrated up to 400 mg if they could tolerate it.
Last edited by stjohnh on Wed Feb 07, 2018 7:57 pm, edited 1 time in total.
Blessings,
Holland

stjohnh
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Re: Dipyridamole

Postby stjohnh » Wed Feb 07, 2018 7:55 pm

Hmmm... As I think about my insomnia, the fact that I can't sleep at all until about 3am does fit with the theory that 375mg is too high and that it takes until 3am for the level to fall enough to allow me to sleep. Never in my life have I had this pattern of insomnia.
Blessings,
Holland

badnights
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Re: Dipyridamole

Postby badnights » Thu Feb 08, 2018 12:53 am

I certainly might be reading it wrong, I'm not the sharpest pencil in the - umm, pen holder? - lately. But that's exactly the impression I got, that there must be a sweet spot. And maybe you're right, it's probably different for everyone.
Beth - Wishing you all restful sleep tonight
WED/RLS AUGMENTATION:
viewtopic.php?f=5&t=6532&p=61601#p61601
Discussion Board Moderator's posts don't reflect the RLS Foundation's opinion & are not medical advice

stjohnh
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Re: Dipyridamole

Postby stjohnh » Thu Feb 08, 2018 1:27 am

The authors may not have run across these problems with their subjects. Drug trial researchers ordinarily try to pick subjects that are not taking other medications to help avoid confounding variables. The article said the people with RLS were untreated, they did not specify whether they had never been treated. It is likely that the people that were used in their trial had mild to moderate RLS. Unlikely any of them had severe RLS.
Blessings,
Holland

badnights
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Re: Dipyridamole

Postby badnights » Thu Feb 08, 2018 6:57 am

Bingo. That's why none of them had the insomnia (unless the insomnia wasn't reported, which I doubt). I know they rarely pick severe cases - I tried to get into the glutamate trial at Johns Hopkins and was told I it would be too complicated to manage my withdrawal from a distance (too many meds, too severe, too far away - lots of points against me!)
Beth - Wishing you all restful sleep tonight
WED/RLS AUGMENTATION:
viewtopic.php?f=5&t=6532&p=61601#p61601
Discussion Board Moderator's posts don't reflect the RLS Foundation's opinion & are not medical advice

stjohnh
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Re: Dipyridamole

Postby stjohnh » Thu Feb 08, 2018 2:31 pm

Well, I had another bad sleep night but actually there is good news. I took 225 mg dipyridamole at about 6:30 last night, the other sleepless nights I had been taking 375 mg. I got about 3 hours sleep last night, however I started sleeping earlier in the evening. Besides the fact that my sleeping was slightly better I think the most important point is that my urge to move was still under excellent control with the significantly lower dose. That does lead credence to the theory that I was on a too high dose.

I think tonight what I'll do is take 75 mg dipyridamole at about 6 p.m. and if I do not have good control of my urge to move symptoms take another 75 mg around 9 pm. That has the advantage, compared to taking 150 mg at 6 p.m. that if 150 mg is still too much I do not have another nearly sleepless night to contend with.

I'm considering taking either 0.0625 mg pramipexole at midnight if I am still not asleep or perhaps 10 or 15 mg of THC or perhaps 100 mg gabapentin.
Blessings,
Holland

Polar Bear
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Re: Dipyridamole

Postby Polar Bear » Thu Feb 08, 2018 4:50 pm

Last night's dosage worked not too badly when reducing from 375mg to 225mg. Well done.
I'm wondering if there's a case for sticking with that 225mg dosage for few nights, see how that goes, and if it's good .... then reduce further.
i.e. bearing in mind any half life effects of the drug, checking each stage is steady before dropping further.

I understand that you probably want to move more quickly than this but going just a little slower might give a clearer picture. However, I'm willing to be told why moving faster is ok.
Betty
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stjohnh
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Re: Dipyridamole

Postby stjohnh » Thu Feb 08, 2018 5:18 pm

Betty, The 1/2 life for initial decline from peak for dipyridamole is 40 minutes. Terminal decline is 10 hours. So on the basis of half life the dose I took the night before last of 375 mg should be mostly gone by the time I took last night's dose of 225mg.

The fact that my urge to move was still controlled at 225 mg suggests that the 375 milligram dose was too high. The fact that my sleep improved only minimally suggests that the dose may still be too high at 225 mg.

I have now gone about a week with maximum sleep time of only 3 hours and I'm pretty sick of being completely exhausted from the time I wake up until the time I finally it go to sleep.

I agree there is a benefit to going a couple of days at 225 mg, however my patience is wearing very thin.
Blessings,
Holland


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