Opioids tolerance to naloxone

[xxxyyy]

here in germany the strongest opioid not falling under the narcotics law (all substances falling under this law are a huge hassle to prescribe and thus seldomly are) is tilidine. it's a prodrug for nortilidine, which is roughly the potency of morphine, and back in the 70's when this new painkiller hit the market it instantly became very popular as a recreational drug and since the manufacturer wanted to prevent it falling under the previously mentioned law it added naloxone to it in a fixed ratio. so a pill containing 100mg tilidine will also contain 8mg naloxone etc. this off course limits its recreational potential. for once every ROA except oral is out of the question, and it also limits the amount one can take before the naloxone eliminates every and all effects.
sorry for the lengthy preamble, but i figured since this is a rather bizarre question, i'd explain why i'm asking it.
now i've been taking this substance on and off for a while, mostly for recreational purposes, but also recently for post-op pain.
and after browsing various german forums it seems i can take much more of this stuff and still have a decent high than most people.
i've never been physically addicted to opioids, but have abused them thoroughly on various occasions, from tramadol to fentanyl in strength, and once had a tolerance where i would take 2-4mgs of fentanyl a day orally. this however was eight years ago, and since then i've used opioids seldom and with large timespans in between (years rather than months).

so to finally get to the point, since naloxone is in chemical structure fairly similar to some opioid (oxymorphone if memory serves correctly) that my general tolerance to opioids also extends to naloxone? i mean, after two years completely without any opioids i had no problems IVing 2mg buprenorphine, which would OD most people instantly.

(if this question is utterly moronic please forgive me, as i am certainly a moron)

 

[Swimmingdancer]

A general tolerance to opioids does not extend to naloxone (it works on the opioid receptors in the opposite manner to opioids), but you might possibly develop a tolerance to naloxone itself if it is taken on a regular basis. This is one theory behind why many people are able to inject Suboxone when the nalaxone is supposed to put them into precipitated withdrawals if they do so, or at the very least counteract the effects of the buprenorphine - if they already take naloxone in their Suboxone every day, then perhaps they have built up a tolerance to it. Some studies have shown that rats given naloxone repeatedly develop a tolerance to it.

 

[Tripman]

The naloxone doesn't put them into precipitated withdrawals because Buprenorphine has a higher binding afinity than naloxone.

 

[Swimmingdancer]

^I know, I've heard that too, I was just explaining that I've read theories which suggested that it might also be due to a tolerance to naloxone. It wasn't my theory and I am making no assumption that it is correct, just thought it was worth mentioning. I can try to look for more info. Even if that theory is incorrect, there are still the studies which show a possible tolerance with repeated naloxone use.

EDIT: I checked one of the places I'd remembered reading it, Wikipedia, to look for the source and there is no inline citation, so I can only guess it is someone's "original research" (as they call it on Wikipedia), which makes it more dubious, especially when there are sources to support the idea that the ability to inject Suboxone is due to bupe's higher binding affinity (so it wouldn't make any difference whether someone was tolerant to naloxone or not).

Maybe it would be useful to find out the binding affinity for tilidine?

EDIT 2: If tilidine is a prodrug and its effects are due to metabolization in the liver and gut to its active metabolite nortilidine - then why would it be used by any other method than orally? To me it seems like using tilidine by other ROAs would greatly decrease its effects.

 

[xxxyyy]

tilidine has very little potency, and is considered a prodrug. it's rapidly turned via demethylation in the liver to nortilidine (a potent µ-agonist roughly the strength of morphine), which is then further metabolized to bisnortilidine, also an agonist with significantly weaker effects and with less receptor selectivity. from what i understand a third of the taken dosage is demethylated to nortilidin and a third of that is subsequently metabolized to bisnortilidine. apparently the enzymes CYP3A4 and CYP2C19 are responsible for the tilidin->nortilidin->bisnortilidin conversion.
this i all glommed from the german wiki page, as this stuff is only used in german speaking countries (and belgium i think).

so, tilidine will always be overriden by naloxone. and we all know unless you have a decently equipped lab and a doctorate in something like pharmacology or chemistry, it's nearly impossible to seperate the two. which is too bad, because from what i heard from old time users who got the stuff pre-naloxone, they say that a sufficient dose oral was up there with a good IV H shot in terms of euphoria and lasted longer.

the problem is not that i want to shoot it, the problem is that the naloxone prevents taking the dosages that induce this intense euphoria. maybe it's just nostalgia because the naloxone free version hasn't been on the market since the late 70s, and people tend to forget.
before i acquired a tolerance to the stuff 300mgs (which is already a lot more than most people can take before dread N fucks everything up) made me quite pleasantly high, i'd compare it to a 5-10mg dose of oxy for a completely opiate naive person..

 

[tricomb]

If its a prodrug then it's best taken orally, I think you might be expecting too much from a certain compound. I don't know, I haven't tried it nor do I have any strong desire to seek it.

 

[xxxyyy]

i think you're missing the point here man. i'm taking it for pain at the moment, and it's reasonably effective, but i was wondering why i could take so much more of it with its fixed ratio of naloxone than most people and still achieve a high.

also it's schedule I in the states so the chances, unless you come visit me, are rather slim that you ever get your hands on any.

i was just wondering if a repeated exposure to opiate agonists similar to naloxone in chemical structure could lead to a tolerance, i.e. a lessening of its antagonistic effects

edit: also, the first time i took this drug i already took more than most people can before the naloxone kicks in. maybe it's just my alcoholic liver working in overdrive, who knows.
does this same principle also extend to flumenazil?

 

[xxxyyy]

apparently, mixed with some other first gen. antihistamine that was OTC back then, felt like heroin IV, or so i'm told.

also i've shot prodrugs before and got a pronounced if slightly delayed effect from them that exceeded its effect in the same oral dose.

 

[Swimmingdancer]

Tilidine will not "always be overridden by naloxone" (obviously, or they wouldn't put naloxone in tilidine pills). If you are taking the tilidine/naloxone orally, then the naloxone should not block the effects of the tilidine, because oral administration of naloxone only blocks opioid action on the intestinal receptors level, but has low systemic bioavailability due to marked first pass metabolism in the liver. Are you saying that you think if you take an extremely high dose of naloxone orally the little bit that isn't rapidly removed by the liver should be enough to block the tilidine? I don't think so, because you would also be taking a huge amount of tilidine, so the amount of naloxone that gets through would still be very small in comparison. Unless you are assuming that it might work differently if you have a very high tolerance to tilidine, but no tolerance to naloxone? I don't think it works that way. A tolerance to tilidine does not mean there is any less tilidine in your system when you take it, tolerance is just that your brain has adapted to tilidine so it creates less of a response. Oral tilidine should always overpower oral naloxone if I understand correctly.

 

[xxxyyy]

^ this i can definitely refute. it's about the fifth the strength of oral morphine, and i consider 200mgs oral morphine to be a good dosage, since it also it subjected to a high first pass effect by the liver. so i took 1000mgs of tilidine (an excessive dosage to most, but not me) the first time i ever took it, thinking it would compare to the equivalent of said dosage morphine. i ground up the pills, to destroy their time-release mechanism and dissolved them in a can of beer. all i got was unpleasant side effects like itchiness and insomnia from that dosage, not any sort of recreational high one would assume a 200mg oral dosage of morphine would bring even in an opioid tolerant person.
also, subutex and suboxone feel definitely different when shot IV. from subutex i get instant, massive euphoria, while suboxone takes a whole time longer than that to have any pronounced effects. too bad subutex isn't around anymore.
on a related subject, a recent study started in the city i live, and legalized in spite of massive opposition from the christian right, was the legalization of pure, medicinal grade IV diacetylmorphine as a substitution from street heroin administered twice daily by a doctor. it proved superior in every regard to methadone and suboxone in terms of harm reduction. i think it's an exceedingly good thing, even though methadone and suboxone are still the common practice. any thoughts?

edit: i find the maximum effective dosage to be 400mgs in me, which always contains a fixed sum of 32mgs naloxone. after browsing various german forums, i discovered this to be significantly higher than the average dosage of 200mgs, at which point for a lot of people the naloxone starts taking over and destroys the recreational effect from tilidine. which is why i asked the question in the first place

 

[Psychonauticunt]

on a related subject, a recent study started in the city i live, and legalized in spite of massive opposition from the christian right, was the legalization of pure, medicinal grade IV diacetylmorphine as a substitution from street heroin administered twice daily by a doctor. it proved superior in every regard to methadone and suboxone in terms of harm reduction. i think it's an exceedingly good thing, even though methadone and suboxone are still the common practice. any thoughts?

A clinic in my city does that, as far as I know. From what I seem to gather the results are generally very positive, so if it works, I don't really see why it should even be an issue. I'm sure buprenorphine has its uses, but unfortunately it seems to still be highly abusable, and in Finland it's the most commonly injected opioid - in fact, most people straight up start taking buprenorphine like any old opioid (and then end up using exclusively that, and oxycodone every now and again - most never see morphine or heroin, and stick to shooting bupe), get addicted, and from then on the story is pretty standard fare for IV opioid users. I don't know a single person that's kicked opioids with bupe, but I know lots of people whose first (and last) opioid of abuse was buprenorphine.
As for methadone, the results from my circle of friends are almost as grim - most people say they can stay off the smack, but that the methadone is possibly more addictive and harder to kick. They say it's an improvement and they become more functional on the methadone than they were scoring heroin off the street, but they're still severely dependent on a regular supply of a very potent full agonist.

Of course I understand that my own acquaintances are not necessarily a representative sample, but since from what I've read, the pure diamorphine seems superior, then I would obviously tend to favour that.

 

[xxxyyy]

i actually went to detox in the hospital where the study was started and briefly talked to the doctor whose initiative it was. massively erudite guy on all forms of addiction. the guy i shared a room with who had just switched to IV injections of diamorphine from methadone said it was what finally wanted to make him quit his massive benzo habit, which already had led to several seizures during WDs. he is the only first hand account i have of it and he said that each injection made him pleasantly high for a few hours, and the only drawback was that he had to go to the doctors office twice every day, as one concession that was made after the study and the subsequent legalization was that it would never leave the doctor's hands as these vials containing pure diamorphine were never supposed to hit the black market, as suboxone and methadone is commonly available on the street. i too have known some people whose opioid addiction was limited to suboxone purely. more so than with methadone probably.