this time i used "AI" to summarize the previous core arguments against the blind drive to use buprenorphine (a KOR-antagonist) for WED/RLS. this saved me time. while buprenorphine definitely helps, one should always be very aware of possible additional dangers when using this medication. thanks for your attention.
# Research Report: Kappa Opioid Receptor Blockers (KOR-antagonists) and Microglia-Mediated Inflammatory Responses
## Introduction
Microglia are the primary immune cells in the brain, playing a crucial role in the central nervous system's immune response. The kappa opioid receptor (KOR) is a protein that, when activated, can influence various physiological processes, including pain perception, mood, and immune responses. This report examines the relationship between KOR blockers and microglial activity, particularly in the context of inflammatory responses.
## Kappa Opioid Receptors and Microglia
KORs are not only expressed in neurons but also on non-neuronal cells, including microglia. Activation of KORs has been shown to suppress proinflammatory signaling mediated by immune cells, including microglia. Conversely, blocking KORs amplifies microglia-mediated inflammatory responses, as evidenced by increased levels of proinflammatory cytokines like IL-1β and IL-6 following the administration of an immune-activating agent, lipopolysaccharide (LPS).
## KOR Blockers and Inflammatory Diseases
The blockade of KORs has implications for the pathophysiology of depressive and anxiety disorders, where inflammation is increasingly implicated. The antagonistic actions of KOR blockers on microglia may detract from their therapeutic potential on neurons.
## KOR Activation and Neuroprotection
KOR activation enhances the interaction of β-arrestin2 with certain proteins, disrupting pro-inflammatory gene expression and protecting neurons from inflammation-induced neurotoxicity. This neuroprotective effect is particularly important in conditions like epilepsy, where inflammation plays a fundamental role in the origin and outcome of seizures.
## Microglial Polarization and KOR
Dynorphin, a natural KOR ligand, promotes microglial polarization toward an anti-inflammatory M2 phenotype, inhibiting the TLR4/NF-κB pathway. This polarization is crucial for resolving inflammation and repairing neuronal damage.
## Opioid Receptors and Microglial Activation
Opioid receptors, including KOR, have unique abilities to modulate microglial activation, regulating the secretion of cytokines and promoting the anti-inflammatory phenotype of activated microglia. This modulation is essential for protecting neuronal function and reducing seizures in conditions like epilepsy.
## KOR and Remyelination
In the context of autoimmune diseases like multiple sclerosis, KOR activation has been shown to promote oligodendrocyte-mediated remyelination, alleviating symptoms of experimental autoimmune encephalomyelitis (EAE).
## Conclusion
In summary, KOR blockers enhance microglia-mediated inflammatory responses, which can have implications for various neurological and psychiatric disorders. On the other hand, KOR activation has a protective role against inflammation-induced neurotoxicity by promoting anti-inflammatory microglial polarization and supporting remyelination. These findings suggest that KOR modulation could be a potential therapeutic strategy for treating inflammatory diseases of the central nervous system.
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snoemata
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Madlegs1, you gave me a chuckle out loud early this morning, after a very short (long?!?) night of walking around and sleeping very little....Thanks! Laughing is a good, non-drug way to combat RLS! OH, and you're no eejit!!! For me, as helpful as that comment was meant to be, it could've been in ancient Chinese slang!
Does this research differentiate between the typical higher doses used to treat opioid use disorders and/or chronic pain and the very low doses used for RLS?
Having suffered RLS for 70+ years (the last 20 being severe) I have found comparative peace with buprenorphine sub-lingual. As I have tried everything else on offer I am quite content to stay on BUP unless and until someone can give me a miraculous and safe alternative treatment which has been tried and tested.
I do not like being on buprenorphine (or indeed any opioid) but to me it is preferable to oxycodone. At my age I do not have the strength to parade around at night when I should be asleep and anyhow this could lead to a bad fall. Therefore, no matter what this report says I shall be continuing on BUP.
I feel that all other severe sufferers like me who have got to the end of the treatment list will also be glad to continue on BUP as at least there is some quality of life.
Hi Bantamdyno - I have not really found any trigger points. Sweet foods might be a trigger but not always. I can take coffee which has helped the symptoms to settle although for other reasons I do not drink coffee now. I think lifelong RLS does not necessarily have triggers - it just happens. Good Wishes
Mine is sweet things like ice cream and chocolate and also alcohol, so I have given the alcohol up completely. Also, now only drink decaf if I fancy a coffee or tea, but that is hardly ever. If I don't take my tablets on time especially my 1st dose at 6pm which is 600mg I suffer later on as often in bed by the time I take the next 600mg, I often have to take another 100mg and maybe/or a Dihydrocodeine to help me sleep.
Amen! You're spot on in describing how most of us feel in just wanting to get some results after years of struggling/suffering with RLS. I'm 64 and had a surprise fall last week, as I was walking around, exhausted and groggy, in the middle of the night. I decided to do some leg stretches, using the back if a couch as a sort of "barre". I swung my right leg up, lost my balance, and crashed headfirst onto to floor! Luckily our basement is carpeted; my first thought and utterance was, "God, help me!", followed by a quick, "God, please just take me, I'm so tired of this RLS!" Haha, I'm obviously still here, and only suffered a minor stiff neck. As I see a Nuerologist in less than a week, I'm sure hoping she'll prescribe Bupro.....
I have to echo the comments already posted on this thread. I appreciate that you are attempting to provide information to the forum about the risk of Buprenorphine, but as written, I cannot understand what your post is warning against. I wish I did because I am one of those who is using Buprenorphine and it has given me my life back. Though I am sure the intentions of your post are good, in it's present form, it has only succeeded in raising my level of anxiety. Rivers
All medications have side effects and a 'window' where their benefits outweigh the downsides (in most - for every medication there are people where the side effects are always greater than the benefit). If the benefits are substantial and the side effects felt as slight or delayed, people will probably want the benefit. But we dont want to be in an augmentation situation again.
Is there any suggestion that the inflammatory issues can be reduced by diet, anti-inflammatory supplements?
This is OP's second go around providing incoherent set of statements on the danger of buprenorphine. Like last time, he fails to make a distinction or point to what information is relevant to low-dose opioid prescription that most RLS patients take.
Hello all. In light of the conspicuous silence from snoemata in response to repeated requests for an explanation of their grave warnings of the risks of buprenorphine, I am prompted to respond in their stead in order to allay fears.
First of all, if you are taking buprenorphine, don't panic!
My credentials: I am a Harvard-trained physician with refractory RLS on buprenorphine transdermal (and no other meds). Not being a neuroscientist I can't profess to understand every detail of the apparently scientific research posted; but I am very experienced at reading, interpreting and evaluating scientific and medical literature, and I understand there is a wide range in quality of "research" plus great risk of false conclusions when making generalizations from isolated statements found on the internet. ( Especially those generated by an AI!)
In response to this post I have just spent about 3 hours sifting through and critically reading the scientific and medical literature on buprenorphine (BNP),
Nothing I found caused me alarm. On the contrary, I learned that BNP is a remarkable drug and probably superior to any other opioid for the treatment of chronic pain conditions or addiction.
I understand the desire to help others by warning of possible dangers but I wonder what qualifications snoemata has for posting medical advice and quoting scientific findings of unknown date, unknown publication, by unknown authors, with unknown reputability to the RLS community.? I have considerable doubt this individual has much understanding of the complex mechanism of action of buprenorphine or of the "pro-inflammatory effects of KOR antagonists on microglial cells" , nor of the applicability or validity of the information they posted. How many hours have they spent looking further into and vetting this data?
I could re-write the entire verbage (I won't give it the distinction of calling it research, or even fact) in plain language but there is no point, because there is no evidence that it is applicable to BNP. Or to humans. Or to the low doses we use for RLS. Or to the specific medical conditions each of us has.
But the main points are: buprenorphine is unlike any of the other opioids. It is acts on at least 4 different opioid receptors in the body. At some receptors it acts as an "agonist" and activates the receptor, while at others it acts as an "antagonist" and blocks the action of the receptor. (At the mu receptor it acts as a "partial" agonist, which does not diminish its analgesic effect but does reduce its adverse effects and risk of overdose death.) Each receptor, when activated, has different effects in the body and nervous system. The effect we are most familiar with is pain relief, mediated by the mu receptor. Another of the these opioid receptors is called the kappa-opioid receptor, or KOR., which is referenced in the warning post above. BNP acts as an antagonist at the KOR.
BUT buprenorphine is not the only KOR antagonist. There are non-opioid KOR antagonists as well that many researchers are using to study the kappa-opioid receptor. In the verbage posted above there is no reference to BNP whatsoever so most likely the "research" was done using some other KOR blocker which makes it not applicable to our situation, especially because...
Buprenorphine is unique in that, unlike other opioids which target opioid receptors throughout the brain and spinal cord, BNP acts almost exclusively at the level of the spinal cord. This is one reason (there are several) that BNP has potent analgesic (and RLS-suppressant) effectswithoutthe usual opioid adverse effects: respiratory depression, euphoria and abuse potential. The "microglial cells" which the AI alleges are inflamed by KOR antagonists are brain cells but buprenorphine works primarily below the level of the brain.
Plus, the studies that I read which did involve BNP invariably used doses of BNP orders of magnitude greater than the doses we use to treat our RLS.
One study which looked at the effect of BNP on inflammation and healing from traumatic brain injury found no increase in inflammation or impairment in healing
So I am actually grateful to snoemata for starting this thread because it prompted me to read extensively about the drug I am taking, which I have found to be a really remarkable drug. I could go on and on about what is fascinating about it, but primarily what I learned is that of all the opioids, it is clearly the safest, with the fewest adverse effects. If it weren't for the fact that it is poorly absorbed by the oral route, and therefore can't be given in a convenient pill form, it would no doubt replace all the other long-acting opioids.
In short, I can't say without a doubt that there is no risk of "neuroinflammation" with the BNP we take, but I haven't found anything that indicates it does.
Great job Doctorplacebo. The only caveat I have stems from my personal experience and is probably unique. ,i apparently am allergic to this drug. This manifested itself in the eruption of hives all over my body. These were dealt with with massive doses of cortisone and lasted about two weeks.
Here’s an interesting phenomenon: I am reaching the end of 2 months in hospital and three weeks in rehab. I had two large life-threatening abcesses stretching from the top of the lumbar to the bottom of the sacrum. Twelve weeks of antibiotics has pretty much knocked them out. Here’s the kicker: not once in this long ordeal,has RLS reared its ugly head. Once the pain was controlled I slept like a baby for the first time in decades.
I was very moved by your detailed reply to my post. Not only for the invaluable medical advice but for the humanity that you have shown to me and to all of us RLS sufferers. I live in Canada where I have to say, my condition has been largely met by ignorance and/or indifference and if not open contempt. I say this, not out of anger but as a challenge to the Canadian medical profession. Come on Canada! For goodness sake look outside you Xenophobia, and your simplicity self agrandisment and do the research.
I apologize to you and to every other nationality present on health unlocked for turning this into a political rant but I do so only in hope of bringing about a change in attitude. I love my country but sometimes I am ashamed to be Canadian. My GP prescribed 6mg's of Premipexole for many years. Realizing (too late perhaps) that I was in trouble I was referred to a Neurologist specializing in in sleep disorders and RLS. He refused to treat me until I was off Pramipexole, advised me to go cold turkey, (what are you waiting for he said, I advise my patients to do this all the time?) and then ,after I foolishly followed his instructions, claimed that my devastating symptoms are largely imaginary. He is the best of the bunch, the rest of the profession are still prescribing DAs...!#*#!
On a brighter and more positive note, thank you for giving me the benefit of your medical expertise and for being so candid about your own experience. Thanks to you I am now in a much better position to cut through the BS and advocate for myself and for my fellow Canadian RLS sufferers.
I wish you all the very best with your own RLS challanges. I can't thank you enough for sharing this information with me.
Thank you so much for the clarification. The issue with AI it seems to me is whose intelligence are we talking about? If it includes the whole of human cognition we are in big trouble! As we all know there are real idiots out there!
I am currently taking 200mg of Tramadol and am concerned about augmentation. So I am trying to get a prescription for Buprenorphine. I am a bit concerned about what you said about it not working well in pill form.
I am also concerned that the prescription will probably include Nalaxone. The last time I tried it I only lasted about three weeks. The Nausea and constipation was pretty bad and depression was very discouraging.
Do you think that the Naloxone could have been part of the issue? I understand what it is for but I have no record of substance abuse so perhaps I should request BNP only? I may not get what I ask for but knowing more about it would help me make a case ....if indeed there is a problem with naloxone?
Hi Welschrispy. I don't want to replace the advice of your doctor, but as we all know, our doctors rarely have the knowledge or understanding of RLS and RLS meds that we RLS patients have, given that we have "skin in the game."
So I will post a few things I have learned by reading and talking to a respected anesthesiologist pain specialist, and experienced personally, about naloxone/ buprenorphine combos.
When I started on the buprenorphine path (because methadone seemed to be causing me depression and brain fog) I did research on the different BNP formulations and pushed to get the "monodrug" as they call it. After some very rocky times I am now happy with what I am taking, the 7-day BNP patch (generic). More about why I like it later.
The problem is, the naloxone thing, in the US at least (I am in the US), became politicized when it became good PR to appear to be concerned about the welfare of opioid addicts and overdose deaths. Someone decided that by adding the opioid-blocker naloxone (Narcan), to the formulation it would prevent fatal ODs if someone took the sublingual tablets, ground them up , and injected them to get high (something we RLS patients do all the time, haha). The oral naloxone (NXN) supposedly was not absorbed through the gut and therefore wouldn't interfere with the opioid's action but would prevent respiratory depression (and death), as well as the desired euphoria, if injected intravenously. In the US, when Suboxone (the combo drug) appeared, the FDA actually took the monodrug (Subutex) off the market, which is a shame.
If you are in the UK there are several generic formulations of buprenorphine monodrug available, but in the US there is only the patch and an oral film called Belbucca which is not available generic and is extremely expensive.
Anyway, further research has shown that NXN is in fact absorbed to some degree through the gut and therefore does interfere with the action of the opioid, and has other problems associated with it, but this knowledge has not changed the way it is prescribed. An anesthesiologist I spoke with , who specialized in pain management, was adamant about avoiding the combo preparations. For one thing he said it was impossible to get off them once started (I'm not sure why, but I trust his expertise) and that it could interfere with other opioid analgesics one might need for surgery or trauma.
Welschrispy, I do not know if the NXN was responsible for your nausea, constipation and depression. If anything it should decrease constipation. The N and depression could well be due to the NXN interefering with the BNP or simply to your own particular reaction to it. BNP is supposed to be less likely to cause depression than methadone, and there is research in the works actually considering BNP as a possible antidepressant (!), so IDK.
But, If I were you I would definitely request the monodrug. Explain to your doctor that you are NOT a drug addict and therefore don't need an extra drug muddling up your treatment, that you already had a bad reaction to the BNP/NXN combo, and throw in that you are concerned about destruction of your teeth (see below). If you need a scientific article to print and take to your doctor showing that the BNP/NXN combo drug has risks I can dig it up for you.
Which monodrug?
Sublingual tablets and the oral film have been associated with instances of severe tooth decay but this may be only in higher doses and people with poor oral hygiene (sorry to stereotype but all the studies were done with opioid addicts). Although probably not a big risk for us, if you use one of those you need to take special care with dental hygiene which just adds to the hassle factor of dealing with this #!$% disease. Also, I am very sensitive to small fluctuations in opioid level, and I don't know if the daily dosing gives as even a level as the patch. I know that on methadone I was aware of the daily ups and downs--not good for me.
The patch is the most hassle-free formulation. You put the patch on and pretty much forget about it for a week. That is the biggest benefit for me: For a whole week I can forget that I am dependent on opioids and feel like a normal person rather than being reminded every time I take a dose that I am opioid-dependent. And I don't have to worry about missing a dose and going into opioid withdrawal and rebound RLS (been there. Horrible. ) The psychological benefit of the patch is huge (for me) and not considered anywhere in the literature or by prescribers, even my own doctor who is an RLS opioid specialist.
The downside to the patch: it is hard to make small or frequent dose adjustments, the rate of absorption of the drug through the skin may be affected by external factors such as exposure to heat and intense sun (you have to be careful about hot baths and showers), swimming is not recommended, and there is a small chance of skin irritation.
Sorry about another long-winded post, but there are just so many subtle details to consider; and after all, it is literally our life we are talking about.
Thank you so much for this explanation. I must admit that though the post was unintelligible, I was worried. I suppose that might be because like so many on here site, I have been led down the garden path before with RLS remedies and the thought that it might be happening again was disheartening. Buprenorphine has be a game changer for me. Again, thanks so much. Rivers
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