"Less is More" buprenorphine

[kleinerkiffer]

and if it did let's say, is there knowledge out there that norbup would override the bup and not be blocked? ? I'm not saying there isn't facts that prove norbup would override everything on the receptor, I'm just asking everyone..

I just saw that the slow dissociation konstant of bupe is responsible for the blockage https://www.reddit.com/r/DrugNerds/comments/4v4dgu/crazy_buprenorphinenorbuprenorphine_facts_that/

slow off-rate/long residence time. Binding is pseudo-irreversible.

So imo norbupe shouldn't be able to override the bupe, but https://www.ncbi.nlm.nih.gov/pubmed/22469638

For the doses administered in this study, buprenorphine and fentanyl showed an additive interaction.

so maybe bupe and norbupe can have an additive interaction too

 

[kleinerkiffer]

i think less is more cuz some receptors are still open to let you feel the next dose, if you dose high every day your brain is just always full of bupe so you dont notice it.

The question is, how often is the receptor activated when bupe is bound. The intrinsic activity is around 0.4 iirc so bupe doesn't activate the receptor as much as say morphine. Due to the high dissociation constant it takes a while till bupe unbinds and goes back to the synaptic cleft. If bupe activates the receptor just once (most likely imo) and takes say 5 hours to unbind taking a high dose will activate say all 100 receptors once but it takes say 5 hours till the receptors can be activated again. But if you take a low dose you can stagger the effect by taking low doses a few times a day.

 

[kleinerkiffer]

I'll duplicate the thread and move one to Neuroscience and Pharmacology Discussion

 

[serotonin2A]

The question is, how often is the receptor activated when bupe is bound. The intrinsic activity is around 0.4 iirc so bupe doesn't activate the receptor as much as say morphine. Due to the high dissociation constant it takes a while till bupe unbinds and goes back to the synaptic cleft. If bupe activates the receptor just once (most likely imo) and takes say 5 hours to unbind taking a high dose will activate say all 100 receptors once but it takes say 5 hours till the receptors can be activated again. But if you take a low dose you can stagger the effect by taking low doses a few times a day.

The way you are describing receptors makes them sound like staple gun..you squeeze the trigger and it actuates, but nothing else will happen if you keep squeezing the trigger. Receptors don't work that way. The effect of an agonist is proportional to the length of time it remains bound to the receptor and not the number of association-dissociation cycles.

 

[kleinerkiffer]

^Thanks for the clarification!

So explaining it for an ionotropic receptor it would be: drug binds to receptor -> conformational change -> ion channel now open and permeable for ions -> open as long as drug is bound -> drug dissociates -> channel closes again ?
And how would you explain intrinsic activity ?
Partial agonists only open the ion channel say half as much as a full agonist ?

 

[EastCoast]

I would guess since obviously they don't work the same as full agonist I would assume like u said maybe they open half as much ? Or something along those lines..or maybe they just don't fully hit each receptor for them to even work in a complete functional order like full agonist? I'm just reaching here.

And that seems plausible, so basically as long as there binded to a particular receptor(s) there active.

But Can anyone also enlighten me or others , on how buprenorphine and it's very own Norbuprenorphine cause the less or more theory to actually be plausible as well. Because The theory is highly loved in many communities that less bupe causes the metabolized norbupe which is a full agonist to bind to the receptors and work as such. But from my research and understanding for a couple reasons the Norbupe doesn't even cross the BBB to make this possible, amd I do t even believe the norbupe can even override the buprenorphine if it did.

 

[adder]

In my opinion norbuprenorphine may have very little to do with the "less is more" theory. Keep in mind it's a secondary amine and a P-glycoprotein substrate, so generally at any dose the ratio of bupe:norbupe should be relatively higher in the brain than peripherally. Even if the affinity of both at MOP receptors is similar, norbupe appears to be weaker than bupe in mouse tests which may reflect its higher hydrophilicilty and not as read BBB penetration. The thing with a lower dose producing more "opioid-like" effect is that 1) at low doses kappa antagonism is probably relatively insignificant compared to partial mu agonism (effectiveness of buprenorphine in cocaine dependence at higher doses rather than at lower doses confirms it in a way), so there is none to weak stimulant effect, and 2) the "opioid-like" effect is apparent at low dose only if you didn't take a high dose or some time after you lowered your high dose - in the second case if you are at 8mg a day and then suddenly start taking 1-2mg a day, you'll shortly start feeling withdrawal and not more stoned "opioid-like" effect, so it's clearly a tolerance matter. I bet at higher doses kappa antagonism simply flattens classic morphine-like opioid effects by countering them with a stimulant effect, and also given that you get closer to a ceiling and basically have much of the previous doses still bound when you take a new dose, there is not as much of a kick compared to when you take a low dose every day when you don't accumulate as much buprenorphine and can feel more of a difference with each new dose.

That is to say in my opinion the classic opioid-like effect of a low-dose buprenorphine is most likely not exclusively to norbuprenorphine and rather mostly due partial mu agonistic effect of buprenorphine which has not reached a ceiling effect and is not effectively countered by more stimulant kappa antagonism. There is certainly something behind high-dose buprenorphine lowering craving for cocaine, and in my experience at some level when I keep increasing the dose, the effects mainly are increased anxiety and insomnia with little to none additional sedative/calming effect. I suppose different people want something a bit different from buprenorphine, I myself feel most okay when my dose is low enough to provide a weak calming effect, but high enough to make me alert and not sleepy. I also noticed that when buprenorphine caused pronounced opioid-like effect for me, I shortly craved it to be stronger and clearly it doesn't happen with this drug.

 

[EastCoast]

While a lot of this makes sense, the less is more theory is mostly based off of norbuprenorphine , because most say u get more "euphoria" -at really small doses

and this is based of at low doses the metabolized norbup is active and there is not enough bupe to knock it off, and people stand by this...which is fine but how scientifically? Like u mentioned norbupe is highly affinitive with PGP compound, and doesn't really penetrate the BBB, hence making it not really possible to bind to receptors and if it did, I'm sure there is still enough bupe to block it off..

what caught my attention was the kappa (KOR) u mentioned, because this is mentioned a lot in many readings I have done lately with norbuprenorphine .Though it's highly affinitive to Kappa, and should have an easy time binding to it wen available to do so, but it does not. Well it Does, but....at a very slow rate if at all, it barley penetrates the BBB.

This is is all pretty much stuff u said, anyway. So we don't seem to disagree, I'm just disagreeing to why most people stick with and use -"the less is more concept", next..

if your saying norbup is weaker then bupe, which I have heard too ( But idk, I hear more that it's stronger) but regardless if that's the case then it definitely is not true with norbupe, especially for fact it doesn't cross BBB at a strong enough rate

so basically ur saying bupe at low doses, effects the mu receptor more significantly then the K-opiod (kappa) , but why would that make it stronger?, because that's the argument that people say that low dose is actually more euphoric, etc, etc... ?

Im not saying that YOUR saying that, I'm just saying since u said that could be a reason why, why would something that insignificantly reacts with kappa for stimula/energy make it stronger... like wouldn't more attacking the mu and K make it that much stronger? Or no? Even tho it's a partial agonist, doesn't it still serve the same argument?

 

[adder]

I'm not a pharmacologist, so it looks quite confusing to me as well. Anyway, look up this article for a comparison of buprenorphine and norbuprenorphine, the EC50 values for norbupe compared to bupe alone suggest that effects from norbupe are rather secondary and given that EC50 is much higher for norbupe, its impact on overall effect may actually be more pronounced at higher doses. Norbupe has a higher intrinsic activity at MOP receptors than bupe, perhaps that's why many people say it's stronger, but really intrinsic activity alone is not an indicator of norbupe activity when it is formed as a metabolite of bupe. Still, I'm not saying norbupe has negligible impact on overall effects of bupe, when it's taken long-term, norbupe supposedly accumulates to an even bigger extent than bupe (I don't have a source for this at the moment though), I'm just guessing it's not really responsible for more classic opioid-like effect of low-dose buprenorphine.

As for kappa receptors, norbupe appears to be a partial kappa agonist while bupe is more like a silent antagonist or a very weak partial agonist, so their action there differs substantially. Also, norbupe has a substantially lower affinity to kappa receptors than bupe, so its impact on kappa-mediated effects is probably even lower than in case of mu receptors. My theory is that when kappa antagonism gets more pronounced at higher doses of buprenorphine it actually counteracts some effects of mu activation (even though activation of kappa receptors and dysphoria caused by it is countering euphoric effect from mu activation as well) - kappa inhibition elevates monoamine levels (including adrenaline and noradrenaline which are inhibited by mu agonists) and has a stimulant effect, if anxiety is reported as a side effect of bupe, it more often happens at higher doses and it's likely connected, for people with naturally high adrenaline/noradrenaline levels, anxiety intensifies when they take too much bupe. It's a bit like you took a dose of amphetamine along with heroin, it doesn't really make heroin weaker, but in some way makes it sedative and calming effect considerably weaker, though I realize it's not a perfect analogy.

I bet it's way more complex than that anyway.

 

[EastCoast]

Thank you adder, for sending articles and links, very informative

By the charts in that link it seems that they are about even, as they seem to go back and forth, but again those charts are binding, and by the read, well, yes, it does seem that buprenorphine may just be stronger even tho norbup is metabolized from bupe. Which is often rare to see.. so yes as u even stated, it's basically official but not yet fact, that norbupe has nothing to do with a possible dose of bupe being stronger at a lower dose vs higher...

First, okay u see I thought norbupe had a high affinity to kappa and was a partial agonist, which the partial part I think is true, correct? But instead it has a low affinity while bupe seems to have almost none (maybe that's where I got confused)...and it also seems even wen going back to the kappa receptors and (or) all receptors for that fact, norbupe is still a full agonist meaning in high doses only, it should or even must be more euphoric then bupe, but as of what we know so far, it's not as strong....like heroin vs fent...

but now it's time to drop norbupe out of the picture, as until I'm shown diffrently, it has little to nothing to do with " lower means more" theory...weather people are goin believe it or not, but like I was going say, even wen it comes to more then just kappa, mu, etc.. it still seems prominent as of now only, that low dose bupe is not in fact stronger then high dose bupe or even possibly more euphoric...

maybe a lower dose of bupe can hold its weight extremely well, and it may have similar or even the same effects of doses much higher , for example 3mg = 9mg etc.. but not in all cases, I realize habitual users coming off dope, including myself needed 8-12 mg on the first day of detox ..because my first dose was 6mg after a brutal run, and I was still sick after 1 hour n 20 mins, I had to up the dose and it wasent in my head...at all..

 

[serotonin2A]

^Thanks for the clarification!

So explaining it for an ionotropic receptor it would be: drug binds to receptor -> conformational change -> ion channel now open and permeable for ions -> open as long as drug is bound -> drug dissociates -> channel closes again ?
And how would you explain intrinsic activity ?
Partial agonists only open the ion channel say half as much as a full agonist ?

Channel state is binary (either open or closed). Partial agonists open the channel for a comparatively short time.

Your description of channel state omits desensitization states, which cause the channel to close before the drug dissociates. Also, there are two orthosteric binding sites.

So in general the different ionotropic states are:

drug binds to receptor, channel closed < -> second drug binds to receptor, channel closed < -> two drugs bound, channel open < -> two drugs bound, ion channel closed and desensitized < -> one drug bound, ion channel closed and desensitized < -> no drug bound, ion channel closed and desensitized

*****
More generally, norbuprenorphine cannot make a large contribution to the response to buprenorphine. Buprenorphine would obviously bind first, because it is the parent drug. Since buprenorphine has such a long residence time, it will block norbuprenorphine from binding.

However, norbuprenorphine is a minor peripheral metabolite, so the entire discussion is moot.

*****

In terms of the OP's question, some drugs have bell-shaped dose-response functions. Buprenorphine has multiple receptor targets, which tends to make dose-responses more complex.