Question about buprenorphine metabolism

[MolecularEuphoria]

Hey all,

Today before my usual suboxone dose I took a modafinil to help myself study. Within about 45 min to an hour I was noticeably high, which hasn't ever happened since I first starting taking suboxone. This was confusing (but awesome), and after reading more about what is known regarding modafinil's activity and metabolism, it is a cytochrome p450 3A4 inducer. This is the only thing I can think of that would logically make me feel the bupe more (buprenorphine -> norbuprenorphine, a MOR full agonist). This seems counter intuitive at first, and the only info about this ive found seems to be people (albeit with no biochemistry/pharmacology background) who think that a 3A4 inducer would make suboxone less effective due to the reduction in the amount of buprenorphine available, but from personal experience, this is NOT the case. My only other theory doesn't seem likely, but is it possible that it's speeding up metabolism of the naloxone leading me to feel a "clean" bupe high (which i definitely notice orally, subutex has significantly fewer side effects for me)?

Essentially what I really want to know is, when an enzyme is induced, does the product of the reaction with the ligand occur at a higher concentration relative to other metabolites, or does the reaction just occur faster with the same resulting concentrations? Is the buprenorphine just converting to norbuprenorphine faster or is there a higher concentration of norbuprenorphine relative to other metabolites, like the glucuronide/hydroxylated/w.e metabolites? This is kinda a general biochemistry question as much as a drug question, but i've been thinking about it all day and would love an answer lol.

p.s. Has anybody else noticed this or something similar from an interaction with a 3A4 inducer and bupe? Am I just creating all of this in my mind?

Thank ya!

 

[sekio]

Is the buprenorphine just converting to norbuprenorphine faster or is there a higher concentration of norbuprenorphine relative to other metabolites

Both - the enzyme that is responsible for turning bupe into norbupe (that enzyme only) is induced and that reaction goes faster. All the other metabolism (glucuronidation etc) occurs at the "normal" rate still. So concentrations of bupe go down faster and norbupe goes up faster and higher, because more is converted to norbupe, because the reaction is going faster.

It is known that provigil/nuvigil stimulates the enzyme that metabolized buprenorphine to norbuprenorphine.

Based on urine screens prior to nuvigil (150mg daily) use, my norbuprenorphine level was 71ng/L.

After three months of nuvigil use, my norbupe level has risen to 170 to 199ng/L. That is a consistent level, it the first month it was 185, the 3rd month was 199, and the second month was 172, so it doesn't seem to be exactly constant. This is from a 2mg / day dose (of bupe).

That's a pretty substantial rise. All urine screens have been conducted with 36 hours (+/- 3.5 hours) between last suboxone and 24 (+/- 4 hours) nuvigil dose.

see also this thread

So yeah, this is normal and independently confirmed. Hammilton points out that because there is more bupe being metabolised to norbupe when you take modafinil, that w/d from bupe sets in much quicker.

 

[MolecularEuphoria]

Thanks for your response!

This is very interesting, and a potentially great way to remove some of the "ceiling effect" of suboxone in users who want to get more short term out of their medication without using other opiates. Obviously I wouldn't recommend this to people who have battled difficult addictions and will end up doing this as often as possible, but as someone who is on suboxone because of an possession charge and probably didn't really "need" it (I'm doing as part of a comprehensive treatment plan I can show the courts when Im actually formally charged, as well as to appease my parents) this is beyond awesome. I will be experimenting with low dose modafinil to see if I can find a dose that doesn't cause a lot of activity (I hate stimulants and only take them when necessary to get work done) while still giving me the enzyme induction. I know alot of people who when put in similar situations as me iv their strips. It is a horrible habit, maybe even one of those people will see this thread and change their roa.

 

[Serotonin101]

If I remember correctly when I took St Johns wort with suboxone I felt the norbupe more. So yes, inducer should convert more bupe to norbupe more quickly and to higher levels. I believe this works with codeine to a degree as well.

 

[Hammilton]

If someone says to you that they took something and it made them feel the effects of some metabolite "more" I would skip right ahead.

It's not possible to really say from your one experience that you got higher because of the increased metabolism. It could be synergy, it could be that you absorbed it better for some reason, random biological changes, etc.

However, based on the studies I've seen and the results of my own urinalysis, I feel confident in saying that you would have had more nB floating around in your blood at some point.

The numbers I provided, and those in the studies I've seen haven't looked at changes in nB levels compared to B levels in the very short term. I don't know how rapidly you're getting nB into your brain. I can say that I'd be awfully shocked if you're experiencing the effects of the nB within an hour given that the metabolism is slow to begin with, even if you were to cut the half-life of B in half, that's still >24 hours.

The time course of nB:B levels in modafinil treated patients vs. controls would be interesting, for certain.

 

[MolecularEuphoria]

Well, regardless of the cause, I definitely noticed a large difference in subjective effects. It felt like I was on a full agonist, I had never heard of this combo doing anything before so I doubt it was placebo (but who knows the mind can do amazing things). I would say it took about an two hours for the effects to fully kick in, but even after 45 min I noticed something was different. I completely understand where you are coming from however, I am not arguing with your point in any way; I was just trying to find a theoretical basis for what was happening.

Also, does half life necessarily correlate with the time it takes subjective effect? I would think there are other factors at play here, but I am a lowly undergrad, certainly no expert.

Thanks for the replies guys, this is a hell of a forum!

 

[sekio]

Also, does half life necessarily correlate with the time it takes subjective effect?

Duration, yes. Time until onset, no.

 

[bingey]

Taking any stimulant in a low dose with or after an opiate gives a shorter more intense high , it's called a speedball.

sorry for polluting this classy thread with my junkie-wisdom-oneliner

 

[MolecularEuphoria]

Haha, while the "speedball effect" is definitely a possibility, I do not believe it to be a good explanation for what I've experienced. I have combined modafinil with other opiates and do not notice a subjectively different high from that combo, certainly no increase in the "opiate effects". I do not get any sort of high from modafinil, and in my experience, a speedball high is different from that of a pure opiate high (which is more along the lines of what I experienced). I have repeated this combo a few times since this thread was posted, and I have gotten similar results- leading me to believe this was not a fluke event.

But as people have pointed out, my possible explanation is NOT intended to be taken as a scientific truth. It is only the best guess of a undergrad biochem student. I would love to hear alternative theories, as well as to hear from people who have had similar experiences as there is a surprising(to me anyways) lack of anecdotal evidence regarding these type of drug combinations.

It would be extremely interesting to hear from somebody who has taken pure norbupe as well as this particular drug combo to see if there are subjective similarities. Without data from controlled double blind studies to determine the time course of bupe:norbupe in patients also on modafinil (as Hammilton suggested), as well as more information about what norbupe by itself does this will continue to be nothing but speculation.

Sekio, thank you very much for taking the time to answer my questions.