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PostPosted: Sun Mar 22, 2015 9:03 pm 
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Buprenorphine is a complicated and often misunderstood drug.
It has a stronger effect at lower doses and as dose increases a ceiling effect on respiration. A lower effect at higher dose?
Bupe is said to be both stronger than morphine and only a partial agonist that does not stimulate the receptor as much as morphine. Which is it?

These things seem contradictory. After many years of rigorous, dedicated, tireless trial and personal error, I present my findings and theories on the enigma of bupe...

Buprenorphine is a partial agonist at Mu receptors and is metabolised into norbuprenorphine by CYP450 enzyme in the liver. Norbupe is a full agonist at Mu receptors so has stronger subjective feeling than bupe. But norbupe is also conjugated in the liver by a second enzyme. Conjugated means it has a simple sugar attached to it which makes the molecule polar. Polar molecules don't cross the blood brain barrier so even though norbupe is technically stronger than bupe it can't get into the brain and so has very little effect.

The thing is, CYP450 enzymes are not only present in the liver. They are also present in the cytoplasm of many other cells in the body including the mucus membrane in the mouth. Conjugated norbupe is basically lost but unconjugated norbupe is a very strong full agonist that may be responsible for the much of the good feeling after taking bupe.

So taking your subutex under the tongue, some of it gets metabolised into a full Mu agonist norbupe and is not conjugated. The conjugating enzyme are only present in the liver. So this unconjugated norbupe can cross the blood brain barrier and this feels good. I have read many people say that sublingual bupe FEELS better subjectively than shooting bupe. Well maybe this is why... Some of it is converted to nonpolar unconjugated full agonist norbupe when you take it sublingually..

Many people will tell you there is no rush when shooting bupe but over time it starts to feel good... Maybe this is because bupe has to be converted to norbupe before it feels good.

This also explains why bupe feels better at lower doses because bupe is a competitive partial antagonist for it's own full agonist metabolite norbupe. Also why lower doses are stronger and high doses have a ceiling effect on respiratory depression. Higher doses of bupe are blockading the unbound full agonist norbupe metabolite.

here are some pharmacology papers for reference. You can google these titles to read the abstracts.

Comparison of Pharmacological Activities of Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a Potent Opioid Agonist

Kinetics of Respiratory Depression in Rats Induced by Buprenorphine and its Metabolite, Norbuprenorphine

When trying to find good information about Norbupe one comes across conflicting papers. Many papers fail to differentiate between conjugated bupe which can't cross the blood brain barrier and unconjugated bupe which can cross the blood brain barrier.
In my experience taking CYP450 inducers increases the subjective full agonist feeling of bupe. Maybe because more unconjugated nor bupe is metabolised.

If this is all true, it is the best reason NOT to shoot your bupe. Something many of us have found out ourselves. It just feels better if you take it sublingually or snort it. About the same either way.

You say injecting means 100% bioavailability but if buprenorphine is competing with unconjugated norbupe then the important thing is the ratio of bupe and uncon norbupe.

I can only say that in my experience bangin bupe is like bangin mineral water. There is no rush or feeling at all. 15 mins later a nice feeling comes but it is never as strong as if I had just put it under my tongue.

I suspect that the crucial thing is that when you take it sublingually there is high local concentration of bupe in the mucosal cells of the mouth and more of it is converted to uncon norbupe. A high local concentration may be important for uncon norbupe to be made by the enzymes in the mouth. If you shoot it it gets spread out in the whole body and diluted to very low concentration. Many enzyme reactions are proportional to the concentration of the substrate.

I have seen a simple study comparing bupe and it's metabolites for injected bupe and sublingual bupe.

Buprenorphine, a powerful mixed agonist-antagonist analgesic which shows promise of providing maintenance pharmacotherapy for heroin addicts, is metabolized in male human subjects to norbuprenorphine and to conjugated buprenorphine and norbuprenorphine. Following subcutaneous, sublingual, and oral buprenorphine administration to a single subject, total metabolite excretion in urine was 2, 13.4, and 12.1%, respectively.

As you can see injecting means a lower ratio of full agonist norbupe and higher ratio partial agonist bupe. So if I am right about all this then the only thing that matters is the ratio of unconjugated norbupe and buprenorphine. Taking it sublingually has six or seven times as much norbupe than injecting!

Another study was using % of metabolites to predict weather patients would stay in treatment. They found patients who had higher metabolites were more likely to stay in treatment. If uncon norbupe is the main reason bupe feels good then it is no surprise people with low levels of metabolite dropped out of treatment. Patients with high levels of norbupe stayed in treatment because they felt better and craving went away.

Basically I am thinking that bupe is really like codeine. A prodrug which has very little action itself but it's unconjugated metabolite is the main cause of the Mu agonism.

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Fond Du Lac Psychiatry
Dr. Jeffrey Junig, M.D., Ph.D.

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  • Asst Clinical Professor, Medical College of Wisconsin

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