Bupe Norbupe Theory

[4meSM]

Aaah okay. So what exactly do they mean when they say norbuprenorphine inhibited P-gp? I always thought that meant is stopped P-gp from working. If norbupe inhibits it, wouldn't that mean norbupe could get through? Or if P-gp much more apparent and stronger in the blood-brain-barrier perhaps?

I think they introduce a known P-gp substrate, meaning a molecule which is know to be excreted from the cell by P-gp, and then they add different drugs (like norbupe) to observe if the standard substrate is able to get out (and if so, how much manages to get out compared to the control test).
If adding norbupe decreases or prevents the standard substrate from getting out of the cell then they conclude norbupe must be inhibiting P-gp.
Or something along those lines, it's not an in-vivo test or anything like that, I think they use some specific mutant cells (like dog cells with some human genes) to run those tests.
I know some stuff about enzymes but those kinds of studies are really not my forte , not too familiar with that particular model they use.

I read somewhere else that norbupe is a actually a P-gp substrate and it's thrown OUT of the brain, I mentioned it in my second post.
So that may be the reason why the study you shared said it's an inhibitor, not necessarily because it prevents P-gp from doing anything, but perhaps because P-gp is too busy getting norbupe out of the cell which means it wouldn't be able to also get the other standard substrate out (in short, it would prefer norbupe over other molecules).
But I would have to read the whole study, which I haven't lol.

BUT, norbupe might be able to cross the BBB to go INTO the brain via a different mechanism/transporter, I don't know but I think it's possible.

Anyway, seems like everyone agrees with low doses being better, if you want to get the most out of it.

 

[ryax]

Wow!! Thank you so much for the response, I appreciate it very much!

So theoretically, if one were to take a low enough dose of buprenorphine, the effects felt SHOULD be a combination of norbupe & bupe effects + metabolites? So buprenorphine in low doses would essentially be a pro-drug for a full agonist.

I wonder at what dose buprenorphine would antagonize it's own metabolite then. Thank you for sharing this. I've always wondered why lower doses seemed to feel much better, but I always assumed it had something to with the blood levels spiking up and down from the bupe doses, as I thought norbupe didn't really cross the blood brain barrier.

imo after being on bupe less than 2mg for around 2 years i gotta say that 1.5 to 2mg is my sweet spot sublingually. anymore than that can make the experience slightly better or worse depending on my mood.

However, doseages as low as 0.25mg are still absolutely felt

In the past, online it was widely regarded that after 4mg you stop getting as much norbuprenorphine.
this seems accurate to me.
but i think that bupe starts bothering itself at much lower doseages .

which is why overseas its dispersed in tablets of 0.1, 0.2 and 0.3 instead of 2 full MG . its also given every 4-8 hours like a regular opioid their .

so why is it here that we usually regard it as a 12 hour, or all day pill? probably because the doseages are leaving us with a lot of remaining other junk in our system to filter out because theyre so high.

One emergency room , when Bupe was becoming popular during the oxy pill mill days, said that they START people that coem in on standard of 16mg a day. Thats pretty insane to me considering i too was on 24mg and had absolute adverse reactions with no real positive reaction .

 

[Juniper Bruhmomentius]

Dosages of even 0.15mg can be felt. Prolly even lower. Bupre is some strong ass shit. The less the better with this drug I assume.

 

[ryax]

Dosages of even 0.15mg can be felt. Prolly even lower. Bupre is some strong ass shit. The less the better with this drug I assume.

the only reason to take more of this drug is to curve compulsion to take other drugs (or maybe help with ultra severe pain? im unsure. bupe has helped my pain a lot , but seems to helped more once i started to get to the lower doseages. i actually started on 24mg , 13 years ago lol) .
but those people have to realize they shouldn't stay on that high doseage even if its helping them for the time being
if you also notice, the bupe drugs that are formulated for pain, usually come in doseages as low as 100mcg similar to overseas, but those bupe based medications aren't covered by insurance.

BUPE IS A WEIRD DRUG... BUT................. if doctors explained EVERYTHING that is truely factual about Bupe (i.e. lower doseages have less side effects and higher therapeutic properties for some people) and that its extremely STRONG as strong as many other opiates I think people would lower their doses sooner and more willingly lower their dose and stop going back to their original DOC.

The makers of SUboxone refused to make a low dose tablet

I wonder why lol

 

[Fire&Water]

I use to have a Dr. in puerto vallarta that would throw me bags of Buprenex
vials were right around a third of a mg
Worked pretty decent for pain unless you used it more than once every few days ...

 

[Subdeep]

I asked this question as I am on bupe for maintenace, but it is no longer helping with cravings as I don't feel jack shit from it and this is unfortunate because it's effecting me mentally and making me crave heroin again daily. And methadone is not an option for me at the moment, so I'm trying to figure out the best way to utilize what I have and actually feel like my mind is satisfied. I have, in the past achieved very beautiful effects from bupe, so I know it's possible to feel good with this medication. but then again I also had a lower tolerance.

I truly appreciate everyone's input and responses. If anyone else has anything else to add, please feel free.

Have you tried NMDA receptor antagonists as a potentiator? A bump of ketamine works well, low dose dxm is ok too

 

[DeathIndustrial88]

Have you tried NMDA receptor antagonists as a potentiator? A bump of ketamine works well, low dose dxm is ok too

I have not had the pleasure of trying ketamine unfortunately, but dxm does help well! Only shortly though.

 

[DeathIndustrial88]

Is any sort of chemistry/synth discussion forbidden in this part of BL? If not, I have more to discuss.

 

[Subdeep]

I have not had the pleasure of trying ketamine unfortunately, but dxm does help well! Only shortly though.

Oh man thats a bummer, hopefully you get to try some good ol K soon. Have you tried nitrous oxide? Its another wonderful one but I guess the tolerance reset from it might be even shorter lasting then dxm since nitrous is like the crack of the NMDA family but it might be worth a shot since its a hell of a lot more easier to find then ketamine

The beauty of the nmda family is that they won't show up on most UA tests so we can mostly safely use them while on bupe maintenance

 

[DeathIndustrial88]

Oh man thats a bummer, hopefully you get to try some good ol K soon. Have you tried nitrous oxide? Its another wonderful one but I guess the tolerance reset from it might be even shorter lasting then dxm since nitrous is like the crack of the NMDA family but it might be worth a shot since its a hell of a lot more easier to find then ketamine

The beauty of the nmda family is that they won't show up on most UA tests so we can mostly safely use them while on bupe maintenance

I have not had nitrous either.
DXM is all I have experience with, but I have lots of experience with it.

Unfortunately, I don't have a plug for most things anymore.


I found DXM to only really have an affect on tolerance by doing 3rd plat & up doses. And then the tolerance reset doesn't last very long.
Actually I've found that it mostly resets the sedative aspects, but not necessarily the euphoria. For example, I can trip on dxm & take bupe on the come down or next day and while it's indeed much stronger, it's mostly a very boring sleepy experience. Like a nod, but with zero euphoria. Could be because bupes not a very euphoric opioid to begin with. Although I have had some pretty good euphoria from it a handful of times through out the years.

 

[Xorkoth]

Not sure where you live, but nitrous is sold in head shops and even some gas stations where I live. However I am not sure whether nitrous would really have a tolerance resetting effect for opioids. I don't really know, but it's so short acting, something tells me it wouldn't do that very well.

 

[JTemperance]

As much as I concur with the sentiment behind "Less Is More," there are some valid reasons to take not only 4mg daily but 8mg, 12mg, or more; it's not just a conspiracy by Big Pharma. I think at least some evidence suggests that higher dosages saturate a greater proportion of the opiate receptors -- 16mg doing this better than 8mg -- with the result that "cravings" are reduced, which is obviously desirable for an addiction drug. The very fact that you don't "feel" the bupe when you dose is a positive from this perspective, even though many of us find it to be a negative. A related benefit is the fact that at 8mg+ per day, buprenorphine's blockade effect will easily persist for a full day, which also helps avoid relapse (and isn't true of low doses).

 

[DeathIndustrial88]

@JTemperance Yeah, I actually find that not feeling my medicine makes cravings worse. And since my receptors were blocked, it actually caused me to start doing meth & other drugs.

But yeah, for some one coming off of a big habit, then I see where higher doses are useful.

 

[ryax]

I was doing some research today on Buccal Buprenorphine and Sublingual Buprenorphine
There seems to be QUITE the difference especialyl when taken daily
especially the difference of pure buprenorphine and norbuprenorphine as well as naloxone and norbuprenorphine being accumulated due to being swallowed sublingually

. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered agents may expose patients to higher concentrations of norbuprenorphine than buprenorphine due to swallowing of unabsorbed buprenorphine, whereas chronic dosing of the bilayered bioerodible mucoadhesive buccal formulation, which provides higher bioavailability and is efficiently absorbed across the buccal mucosa, results in higher buprenorphine concentrations than norbuprenorphine. These data support the hypothesis that exposure to norbuprenorphine, an active metabolite of buprenorphine, plays a role in the pathophysiology of OIC and that differences in norbuprenorphine exposure may explain the observed differences in constipation between SLBN and BBN.

Current knowledge of buprenorphine and its unique pharmacological profile - PubMed

Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ-opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review...

pubmed.ncbi.nlm.nih.gov

 

[Lorne???]

I hate to be the buzzkill, however Norbupe does not appreciably penetratre the central nervous system
.that is a FACT.

8mg buprenorphine sublingual or 1-2¿MG iv is the best dose

By the way for my peeps I am back, I lost my Dr though have a hookup now; am having to cut my dose in half though I will live (from 8mg clonazepam per day to 4mg)

And ftr, Valium is a rapid. Acting, short duration benzodiazepines... get over it people, Ativan last longer because it stays in the vascular compartment.

Sorry off topic I just get sick if that nonsense

 

[DeathIndustrial88]

I was doing some research today on Buccal Buprenorphine and Sublingual Buprenorphine
There seems to be QUITE the difference especialyl when taken daily
especially the difference of pure buprenorphine and norbuprenorphine as well as naloxone and norbuprenorphine being accumulated due to being swallowed sublingually

. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered agents may expose patients to higher concentrations of norbuprenorphine than buprenorphine due to swallowing of unabsorbed buprenorphine, whereas chronic dosing of the bilayered bioerodible mucoadhesive buccal formulation, which provides higher bioavailability and is efficiently absorbed across the buccal mucosa, results in higher buprenorphine concentrations than norbuprenorphine. These data support the hypothesis that exposure to norbuprenorphine, an active metabolite of buprenorphine, plays a role in the pathophysiology of OIC and that differences in norbuprenorphine exposure may explain the observed differences in constipation between SLBN and BBN.

Current knowledge of buprenorphine and its unique pharmacological profile - PubMed

Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ-opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review...

pubmed.ncbi.nlm.nih.gov

Thanks!
So swallowing buprenorphine should lead to higher norbuprenorphine concentrations.
But why isn't oral buprenorphine all the rage then?

"It was agreed that buprenorphine clearly behaves as a full μ-opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event."

This is interesting. If buprenorphine doesn't activate receptors all the way, then why do they say it "clearly behaves" as a full agonist for analgesia?
By behaves, they certainly don't mean that it is a full agonist? And you can only activate so much with bupe. Wouldn't this mean higher and higher doses should help pain? And if it's not fully activating the receptors, then how is it stopping pain? It's been my experience that bupe doesn't offer much pain relief. At least not for moderate-severe pain.

"No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them."
Wait... what? lol Bupe definitely blocks other opioids & definitely causes PWD from some as well.

 

[ryax]

Thanks!
So swallowing buprenorphine should lead to higher norbuprenorphine concentrations.
But why isn't oral buprenorphine all the rage then?

"It was agreed that buprenorphine clearly behaves as a full μ-opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event."

This is interesting. If buprenorphine doesn't activate receptors all the way, then why do they say it "clearly behaves" as a full agonist for analgesia?
By behaves, they certainly don't mean that it is a full agonist? And you can only activate so much with bupe. Wouldn't this mean higher and higher doses should help pain? And if it's not fully activating the receptors, then how is it stopping pain? It's been my experience that bupe doesn't offer much pain relief. At least not for moderate-severe pain.

"No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them."
Wait... what? lol Bupe definitely blocks other opioids & definitely causes PWD from some as well.

in sublingual formulations both buprenorphine and norbuprenorphine are signifigantly higher quantities
than the buccal buildup

with buccal, you're getting more buprenorphine
with sublingual, you're getting more buprenorphine AND norbuprenorphine. with buccal you're getting LESS, and LESS naloxone is swallowed and less Buprenorphine is accidently swallowed . Buprenorphine when swallowed is present in larger amounts than if you just did it sublingually *ESPECIALLY when dosed chronically, and when your sublingual dose is accidently swallowed

@lorne the central nervous system? you mean the blood brain barrier. Norbupe & bupe definitely crosses the BBB. in amounts larger than 4mg it has trouble getting through . norbupe is what causes the motility in your gut when you take buprenorphine. and even if the amounts passing are SMALL, bupe is a potent chemical. hope i explained that properly.

Norbuprenorphine-3-glucuronide​

passes in very small amounts, which is another norbupe metabolite produced by buprenorphine


im not a scientist though, just someone who takes bupe & read the report that i posted above.

 

[ryax]

also just because something doesn't cross the BBB to get you high doesn't mean it doesn't play a role in the overall effect

 

[Subdeep]

also just because something doesn't cross the BBB to get you high doesn't mean it doesn't play a role in the overall effect

Like what happens with gabapentin and gaba supplements, right? I think there are receptors in the gut for those though.

 

[Xorkoth]

I hate to be the buzzkill, however Norbupe does not appreciably penetratre the central nervous system
.that is a FACT.

8mg buprenorphine sublingual or 1-2¿MG iv is the best dose

By the way for my peeps I am back, I lost my Dr though have a hookup now; am having to cut my dose in half though I will live (from 8mg clonazepam per day to 4mg)

And ftr, Valium is a rapid. Acting, short duration benzodiazepines... get over it people, Ativan last longer because it stays in the vascular compartment.

Sorry off topic I just get sick if that nonsense

Where are getting this information from? People have posted links to studies regarding norbuprenorphine's binding affinity in this thread. And diazepam is well documented as having an extremely long half-life. True, its duration of perceptible effect is shorter than its half life, but it is not shorter than lorazepam, not by a longshot.