A collection of thoughts,speculations, and research on Bup.

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A collection of thoughts,speculations, and research on Bup.

Postby Solaris » Thu May 18, 2017 11:08 pm

alright, this is gonna be my little corner where im gonna try and post research papers (or links to the abstracts, to be precise, altho i do have access to the full studies, in case someone wants some more information about a specific one) focusing on buprenorphine. this is subsux, so if you want to find behavioural studies pointing out how much of a great drug this is as far as the social harm-reduction goes, look somewhere else.

(english is not my native language, so excuse my terrible grammar and werid errors here and there.)

what interest me is mostly post-marketing research focusing on in-vitro and/or in-vivo studies, to try and get a better understanding of the consequences of long term, high doses of buprenorphine on the brain and the endogenous opioid system. this is nowhere near complete, it can probably be considered a constant work in progress i guess, but it would still be a good start. i will also use this thread to post my considerations, thoughts, or answer any possible question people might have about those studies.

disclaimer: mind you, im no MEDIC, im just a chemist and my work is on unrelated fields, so dont take my opinions as MEDICAL ADVICE. (its not likely that your average sub prescriber knows more, but lets not go there... who dares question the amazing feat of getting a certification for passing an 8 hour online course so you can prescribe this narcotic to anyone.)

one last thing, i understand this is, by necessity, a somewhat "dry" and boring reading, having to do much with chemistry, pharmacodynamics, and concepts that mostly are still really only theoretical (that doesnt stop them selling those drugs tho, so i see no problem here.) and are open to various kind of speculations. hell, even the model of how modern antidepressant actually work is only "theoretical". this thread probably gonna require the reader to be familiar with at least the basic concepts of receptors, (mainly the opioid ones) their roles, what an agonist or antagonist is, and some basic neurochemistry. yep. i told ya its not gonna be fun...


lets start with something that i always found puzzling: many people reports buprenorphine "blocking" effect to be somewhat persistent even after stopping treatment, even after 3 weeks after the last dose, sometimes longer. the blocking effect im talking about is the fact that "normal" opiates feel somewhat different, less euphoric, and that tolerance after bupe treatment is sky high, requiring increased dosages to feel the effects that you could reach with half that amount before you started suboxone/subutex. now, they all gonna tell you that its the magic of buprenorphine, since its binds so tightly to all the receptors major types (mu delta kappa and nociceptin) that other opiate will simply have no places to bind to, bupe being king of the hill. that explanation works, if you are currently taking buprenorphine. but what about if you stopped weeks, or months ago? the drug is not in the blood anymore. there is no leftover buprenorphine occupying your receptors. there is nothing blocking anything. so why it happens?

well, apparently its becouse buprenorphine inhibits mu-receptor endocytosis on the surface of the cell, thus blocking the recycling of receptors and greatly increasing tolerance to all kind of normal opioid responses, including analgesia. keep in mind endocytosis is part of the mechanism by which tolerance AND dependence to opiods are mainly regulated. receptors needs to be internalized in the cell, and subsequently recycled to "reset" tolerance and dependence. (yes yes, a very crude semplification, but somewhat necessary here)
morphine and all other typical full agonist dont *trigger* endocytosis, but they dont persistently -inhibit- it for weeks after the drug is long gone from the body either...
i fear the amount of this kind of "desensitization" of the mu-receptor after buprenorphine is used is probably dependent on how long the drug has been taken, the dosage, and probably other factors.
the full study:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752300/

------------------------------

buprenorphine induces hypogonadism. does it need to be commented? sure, less so than methadone, but even the study warns: "the extent of hormonal changes associated with buprenorphine needs to be explored further in larger studies. Men receiving long term opioid replacement treatment, especially methadone treatment, should be screened for hypogonadism."

https://www.ncbi.nlm.nih.gov/pubmed/17971165

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this one study was a surprise to me.. sadly i can only link the abstract, but im gonna quote parts of the full study becouse i think its really "interesting":

https://www.ncbi.nlm.nih.gov/pubmed/10502307

in this particular assay, using guinea pig caudate membranes buprenorphine surprisingly acts as an antagonist at the mu receptor, not partial-agonist. this was so weird that they tried the test in rats too.

im going to quote a chunk of the full study, becouse those are the interesting bits:

"Additional experiments using selective assay conditions demonstrated that both etorphine and methadone stimulated [35S]-GTP-g-S binding primarily via activation of µ receptors, a finding consistent with most other pharmacological data. Surprisingly, buprenorphine, which is generally described as a partial µ agonist and k antagonist (Cowan, 1995), did not stimulate [35S]-GTP-g-S binding at all. This finding prompted us to test buprenorphine as an antagonist. As shown in Table III, buprenorphine antagonized µ-, d-, and k-stimulated [35S]-GTP-g-S binding, and was most potent at µ and k receptors, having a Ki value of about 0.08 nM. The µ antagonist effect of buprenorphine was confirmed in rat brain using autoradiography. Buprenorphine failed to stimulate [35S]GTP-g-S binding even in brain regions with a high density of µ receptors, such as the striasomes. Moreover, buprenorphine blocked DAMGO-stimulated [35S]GTP-g-S binding as effectively as CTAP. Our data replicate and extend these findings since we show that buprenorphine is a more potent µ antagonist under conditions where it acts as a partial agonist.These considerations indicate that although buprenorphine may demonstrate partial agonist activity under conditions of supraphysiological receptor expression, in native tissue it exhibits little or no agonist activity. Indeed, the results presented in Table III and Figure 4 demonstrate that the major action of buprenorphine is that of potent µ and k antagonism.

Previous reports demonstrate that a single administration of buprenorphine downregulates µ opioid receptors hours to days later.
The data presented here extend these observations: administration of a single dose of buprenorphine profoundly decreased µ and k2 receptor binding in rat brain and recovery of binding sites was slow and not complete even after 4 days.
Control experiments indicate that this is not due to residual buprenorphine in the membrane preparations.
Thus, in the rat buprenorphine appears to produce a long-lasting antagonism of µ receptors which likely involves receptor downregulation.

These observations are difficult to reconcile with observations in humans that buprenorphine has partial µ-like agonist activity and fails to precipitate withdrawal in patients physiologically dependent on methadone (Strain et al., 1992). On the other hand, the fact that buprenorphine blocks the agonist effects of hydromorphone (Walsh et al., 1995) and morphine (Teoh et al., 1994) is consistent with a µ-antagonist effect. Large doses of naloxone or naltrexone cannot precipitate a withdrawal syndrome in patients maintained on buprenorphine. This is consistent with the data reported here and elsewhere that buprenorphine apparently eliminates µ receptors for prolonged periods of time, since these receptors would therefore be unavailable for naloxone precipitated withdrawal.

The prominent µ receptor antagonist effects of buprenorphine observed here raise the possibility that some µ-like agonist effects of buprenorphine are not mediated by µ receptors. In this regard, it is noteworthy that buprenorphine has high affinity for certain subtypes of the k2 receptor, such as the k2a site. Additional research will be needed to resolve some of the paradoxical observations reported here."

eh? quite the read uh.. we all still waiting for the addictional research on this btw.

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(full study, so you can read it at your leisure)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682495/

short version (if we can even call this "short") is that with bupe, the mu-receptor binding of agonist like morphine or heroin was significantly reduced, an effect that persist after treatment. this might be considered a "positive" outcome for the short-term, but long term administration of buprenorphine will result in a marked attenuation of mu-receptor occupancy of the natural opioid enkephalin, ultimately resulting in a reduced released of Dopamine in the nucleus accumbens of the brain. the risk of long-term depressive symptoms (and thus relapse) seems to be finally getting some attention... and this is some damn serious stuff.


there's much more to say, specially about the role, and importance of kappa receptors and how buprenorphine extreme antagonism at those sites affects the brain, the worrying sign of neurological disturbances in long-term users trying to quit, etc. i guess il get to those things next time.

all thoughts, questions, speculations, insults, etc, are welcome :)
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Re: A collection of thoughts,speculations, and research on B

Postby Eyedotz » Sat May 20, 2017 9:04 pm

Good research and read man. It wasn't boring to me....after 13 years on sub, I feel my thought processes are somewhat different than pre-sub...I've also struggled with long term side effects like numbness (peripheral neuropathy) that still remain. I honestly think it's nerve damage from sub....it's getting better but it's a process. I also found it strange that all the years on sub, I did not sneeze once. Keep it up, it's nice to see some research. Nice to meet you, ~dotz
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13 Year Sub survivor - Jumped at .03mg after 9 month taper from 4-6mg.
JUMP DATE MARCH 18th, 2016

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Re: A collection of thoughts,speculations, and research on B

Postby Solaris » Sun May 21, 2017 12:39 am

hey Dotz. while it might be just a few days since i finally registered, i been a long-time lurker of this forum (6-7 months now) and your thread has been an incredible source of inspiration for me, specially while i was going thru the first weeks of my bupe jump.. without you even knowing, it helped me holding it togheter, and i bet im not the only one to say that :)

13 years uh.. i shiver at the thought. my experience was nowhere near as long, i been on it for 6 months with a max dose of 4mg a day, but the extremely sinister "quality" of my withdrawls, compared to the normal opiate wd's im well experienced in (sadly) is what really convinced me that this drug should hardly ever be used for long term maintenance, bar some exceptional cases, id say.
doctors have this idea of this being a safe, well tolerated drug with a mild withdrawl syndrome, becouse it "makes sense" to them, being a partial-agonist to the mu-receptors, instead of a full agonist. i fear this is not only wrong, but doesnt explain half of the peculiar properties and effects of this drug. buprenorphine is more of an antagonist than anything else, (an antagonist STRONGER than "pure" antagonist like naloxone and naltrexone, at that...) with an insanely long half life and a really slow kinetic interaction with thos receptors.
saying that an antagonist has no "intrinsic" activity, might be true, per-se, but its obviusly wrong when you consider the long-term changes and adaptations that antagonists cause. and buprenorphine is no exceptions.
shutting down your delta and kappa receptors (while the mu is still blocked, but minimally stimulated) 24/7, 365 days a year will result in massive up-regulation of those sites, and thanks to a cascading effect, it does affect dopamine and other neurotransmitters too. the implications are still quite unclear, as far as long term goes.
my personal opinion is that the kappa receptor plays a bigger role in buprenoprhine effects than assumed.. its binding affinity for the kappa is the higest im aware of out of the entire class of antagonists, and bupe wd's to me felt more similar to hardcore psychiatric drugs than full blown "typical" (short-acting) opioids/opiates detoxes. and just like you mention, there's the whole neurological aspect, something i often hear reported by people who have been exposed to bupe for years. those are really worrying issues that the medical community just seems to.. gloss over.
i fear that the short term benefits of being put on this drug chronically, are really, really NOT WORTH the price people will be asked to pay when they want to get off.. as many find out too late.

edit: to clarify, possibly thanks to my relatively short time on it, and my relatively low dose, the worst of the physical part of the detox for me was the insomnia, the restless legs, and the inability to eat for a good month and a half after my jump. those in itself were not intense, but protracted for sure.
what made the bupe detox quite different than my other detoxes (all short acting opiates) and makes me compare it to psychiatric drugs in general, was the mental aspect.
i never suffered from such dark, intense, and heavy depression before. my anxiety was out of scale, and my tolerance to stress on par with that of a scared goldfish. this all had a distinct "chemically induced" quality to it, and took me a good few months to start feeling like my old self again. now, i have shat and puked and shivered on a H cold turkey before (a few times lol, and not just diamorphine..) but more or less by the end of the first week, i was basically over and done with most of it. my bupe detox instead was quite different, and not in a good way, let me tell ya..
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Re: A collection of thoughts,speculations, and research on B

Postby cheeps » Sun May 21, 2017 11:13 am

Keep it coming...there was a time last year I shoved my nose in these studies but since I'm so not a chemist, it was hard for me to really get it.

One thing I did get was that the kappa receptors are responsible for the mental SHIT. How all the rest coincides, he'll, I don't know. Ratch got me started on it as he once said he had episodes of Depression. I might be able to dig up the thread that had comments in it.
10 yrs on methadone
Meth free 10/08
Back surgery 5/12/14
Knee surgery 9/19/14
Oxy free 12/06/14
2017 taper in progress
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Re: A collection of thoughts,speculations, and research on B

Postby A7dream » Mon May 22, 2017 11:33 am

Solaris wrote:what made the bupe detox quite different than my other detoxes (all short acting opiates) and makes me compare it to psychiatric drugs in general, was the mental aspect.
i never suffered from such dark, intense, and heavy depression before. my anxiety was out of scale, and my tolerance to stress on par with that of a scared goldfish. this all had a distinct "chemically induced" quality to it, and took me a good few months to start feeling like my old self again. now, i have shat and puked and shivered on a H cold turkey before (a few times lol, and not just diamorphine..) but more or less by the end of the first week, i was basically over and done with most of it. my bupe detox instead was quite different, and not in a good way, let me tell ya..


You couldn't have explained it any better, and goldfish! is exactly what I've been in the state of off and on since this taper. I just a lot longer to say what you cut to the chase and said. I hate this drug more than anything, I don't feel I'll ever be anywhere near the person I used to be. I get disgusted when I hear someone is just started on it, I wanna go pickett in front of the manufacturer building for 30 days straight or more, if it would get someone's attention and gain more of a crowd, idk how the hell they've used this shit over in Europe .
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Re: A collection of thoughts,speculations, and research on B

Postby cheeps » Tue May 23, 2017 8:57 am

Now more than ever I believe the brain folks are getting closer to helping us heal...I've done something similar to this about seven years ago and while I haven't been to these particular treatment facilities, I think they are the present and future of healing the noggin.

If anyone does this or knows of it...tell us more.

https://neurostar.com/
10 yrs on methadone
Meth free 10/08
Back surgery 5/12/14
Knee surgery 9/19/14
Oxy free 12/06/14
2017 taper in progress
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