Extension vs. Enhancement (Regarding Benzodiazepine & Opiate/Opioid potentiation)

[lazyvegan]

Searched far and wide...

It is a well known fact that Benzodiazepine's and Opiates/Opioids "potentiate" each other, but my question is more specific.

Does the addition of a Benzo literally (and significantly) extend the actual time the opiate/opioid stays in one's body (effectively increasing it's half-life), and therefore extending one's 'high'? Or do they simply 'enhance' each other; strengthening the overall experience due to the increased synergy between the two alkaloids, while still adhering to their individual standard half-life's/durations?

I ask namely because I am currently in the process of migrating from various Opioids to Buprenorphine (Suboxone) once again. I am also prescribed Alprazolam (Xanax), which always leaves me feeling much better (not withdrawing) upon waking each morning, than without it (where I'd normally be in withdrawals). I've always assumed this was simply part of Alp's 'magic' (and to an extent it is), but lately I am starting to wonder if more likely the Benzo is literally extending the length of time the Opioids stay in my body, hence the reason I wake up not in withdrawals? Although this could just as easily simply be the effect of the Alp alone as well? So it's hard for me to say? And I have been unable to find a single reliable source that even refers to this interaction between these two alkaloids as anything beyond simple "potentiation".

I am also very well aware of the risk of precipitated withdrawals, and this is my primary reason for asking (having experienced them firsthand in the past). It is always a better idea to wait "too long" than "too little" in this situation (obviously), but I am curious if I should be factoring in any additional, specific ratio/percentage on top of my DOC's half-life when calculating the time between my last, full-agonist use and when I take my first Suboxone, due to the addition of my 4mg. per day Xanax script? Essentially, is the Xanax actually "extending" the time the opioids stay in my body, and if so, how much extra time should I account for this phenomenon when calculating a safe timeframe before taking my first Suboxone to avoid risking precipitated withdrawals?

And if it is the case that benzo's not only 'enhance', but indeed also (truly) 'extend' an opiate/opioids half-life, any links/refs to any legit, peer-reviewed articles, studies, or otherwise would be greatly appreciated!

The fact that they 'potentiate' each other is of course well know. The 'specifics' of how they 'potentiate' each other are however, not.

Thank you in advance my beloved Bluelighters!

Peace

LV

 

[nasir~]

Really good question(to me)!
I got the same response. When taking a benzo. it takes _a lot_ longer to get that opioide withdrawal.

 

[lazyvegan]

Indeed it would seem that way! But due to Alp's own unique properties, this could also perhaps be somewhat of a subjective experience? Hence the reason I'd be VERY curious to know if there have been any actual studies done where they measured specific blood-level variations, etc, over time, under each unique scenario?

 

[aced126]

Depends really, what you need to look up for each combination of opioid/benzodiazepine is the enzymes involved in their respective metabolisms. As an example, let's consider methadone taken along with diazepam. Methadone is metabolised by CYP3A4 (mainly), CYP2B6 and CYP2D6. Thus any drug which is also metabolised by one of these enzymes will act as a competitive inhibitor and extend the half life of methadone. Diazepam is metabolised by CYP3A4 to desmethyldiazepam (along with a few other enzymes but they are irrelevant as this is one of the major routes). Thus diazepam and methadone will both compete for 3A4 and extend each other's half lives.

Tbh, you can do this with any drug; the principle of enzyme inhibition is the same.

 

[lazyvegan]

Thanks aced! Exactly the kind of info I was seeking! My pharmacology knowledge extends to receptor affinity, etc, although I've been meaning to look into enzymes and their role in the scheme of things as well. So thanks for the heads up! I'll be looking into the respective enzymes associated with the metabolism of each then. And report back with any new information as soon as I have any. Thanks again!

Peace %)

 

[lazyvegan]

I had a few questions I was about to post, but they may be irrelevant if the following information I found is accurate.

From: http://taimapedia.org/index.php?title=Opiate_Potentiation

Synergizers

As opposed to straight potentiation, these synergize with opiates to create an overall more intense experience.

(on that list) Benzodiazepines - Benzos can synergize well with opiates...

Would this mean, regardless of the information I have found so far regarding the specific enzymes responsible for the metabolism of various opiates/opioids, that the simple fact that Benzodiazepines "synergize" with, rather then "potentiate" opiates, would effectively rule out the possibility of a Benzo even having the ability to potentially extend the half-life of any given opiate/opioid due to competitive inhibition? Regardless of any other given enzyme interactions otherwise involved between either alkaloid?

It would seem (if this information is correct) that only alkaloids with the ability to 'potentiate' due to enzyme interactions, rather than 'synergize', would posses the ability to do so. Any thoughts?

[edit] Obviously this is likely not accurate information given 'aced's "Methadone/Diazepam" example above, but I just thought perhaps there might be more variables involved than simply the specific enzymes involved? And albeit insofar I have still yet to find any metabolizing enzymes shared between Alprazolam and Heroin/Morphine. The most accurate information I could find for Alp so far was this:

http://www.ncbi.nlm.nih.gov/pubmed/12196913

Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver by P4503A1 and P4503A4 respectively

Neither of which I have yet too be seen related to either Heroin or Morphine metabolism.

[Edit] I stand corrected. At least as far as it relates to Methadone: http://medicalxpress.com/news/2015-10-methadone-side-effects-efficacy-linked.html

Ok. More researching. Less posting. Got it!

Peace

 

[lazyvegan]

Well, from what I can tell, it seems Heroin is quickly metabolized into 3 separate compounds:

6-monoacetylmorphine (6-MAM), Morphine, (and the more or less inactive) 3-Monoacetylmorphine

The primary enzymes responsible are: a plasma enzyme; 'Pseudocholinesterase' (aka, Butyrylcholinesterase (BCHE), as well as 'Carboxylesterase 1' (hCE-1) and 'Carboxylesterase 2' (hCE-2), both liver enzymes. From what I can tell, the fact that these specific enzymes are the primary enzymes by which Heroin is metabolized is somewhat unique, in that it differs from most other opiates/opioids which are primarily metabolized by the P450 class of enzymes. And for this reason, I have a feeling I 'might' be missing something here?

However, again (as far as I can tell), although 'related', the Carboxylesterase enzymes and the P450 family are indeed two separate classes of enzymes: http://www.pharmacytimes.com/public...r2013/carboxylesterases-and-drug-interactions

The cytochrome P450 family of enzymes is responsible for the metabolism of numerous drugs and is involved in many drug interactions. Carboxylesterases (CEs) are another family of related enzymes that promote the hydrolysis of endogenous and exogenous compounds.

I guess my main concern would be considering this already being a somewhat abnormal mechanism of enzyme metabolism among opioids, the fact that they are even 'related' just concerns me. Can anyone enlighten me as to how the specific 'relation' between these two enzyme classes might/would influence their ability to interact/inhibit, etc, as it regards to my overall concern of extending Heroin's half-life with the addition of Alprazolam? Reward offered! (*see below)

Especially considering that Alprazolam is indeed metabolized by the enzymes P4503A1 and P4503A4, respectively.

So, am I missing anything here? Pharmacology, let alone Pharmacokinetics is not my forte'. But from what I can tell, although it goes against what would seem to be expected, there 'seems' to be no metabolizing enzymes shared between Heroin and Alprazolam. (besides the 'related' one's I mentioned). And (again, as far as I can tell), although it seems that Morphine as well isn't metabolized by any P450 enzymes either? Hypothetically? If it were? Would it otherwise be something to consider since Heroin does itself still metabolize into Morphine eventually anyways? Or is "too late" in the 'process' to be worth considering? Obviously the various "pathway's" and "phases" involved here don't make things much easier to comprehend for a pharmacokinetic-novice such as myself either.

And as much as I truly enjoy this kind of research, I really would like to migrate to Suboxone ASAP, so any help is truly appreciated if there is something I have overlooked here. If it weren't for Buprenorphine's pesky, unrivaled affinity for the 'mu' receptor and the risk of (very un-fun) precipitated w/d's, it would be a non-issue. And if only I had enough bulk Kratom already on hand (it's on it's way) I'd likely just skip the Suboxone altogether, as Kratom, at least for me, is nearly identical (if not better) in it's effects in this regard. (Although even then, 7-hydromitragynine, one of Kratom's 'very' minor alkaloids still has some affinity for 'mu'. And as insignificant as it truly may be? That's an experiment for another time if considering using Kratom to 'pass the time' before taking Suboxone at least).

Or even a measly day's supply of (the recently now Sch. IV) 'Tramadol', being somewhat of an "atypical" opioid, and (to my understanding) specifically binding only to certain μ-opioid receptors which Buprenorphine does not, could therefore also be taken while preventing any affinity 'clashes' (again, please correct me if I am wrong). But in this case, Tramadol could therefore also safely be taken in the 'waiting time' needed (to 'tide' you over) before one could safely take their first Suboxone dose without the risk of p/w's. And the Tramadol (considering it's sub-par agonist effects) could of course still easily be potentiated, potentially possibly making this even a desirable possibility? But unfortunately, I have neither at the moment. But I do have both a 4mg Xanax and 0.2 Clonodine script, which in my opinion, are still the next best things to have on hand anyways in this situation anyways.

I'd also be curious if taking a small amount of Dextromethorphan Hbr (or any NMDA-antagonist for that matter) could possibly be of any help? As they claim to prevent the development of tolerance towards opiates/opioids? "If" the effects would be obtained fast enough? Could they potentially 'flush' out any remaining alkaloids bouncing around, effectively shortening the necessary waiting/suffering time required before consuming my first Sub dose? (Again, "if" I'm even understanding this correctly and "if" this would even be a realistic possibility in the first place?). Although perhaps drinking a ton of Cranberry Juice might help by acidifying my urine, and therefore also speeding up the elimination of the remaining alkaloids from my body? And in the process also reducing the time required before safely taking my first Sub dose? (OT: This was a trick I learned the 'hard way' (so to speak) many years ago, as the labrat and author of the first ever reported/published trip-report on Memantine, both here, on Erowid, as well as in The Entheogen Review itself.]

"Memantine - First Time - A few words of caution...!": http://www.bluelight.org/vb/archive/index.php/t-132616.html

Good read if you ever get the time. But off topic, getting we are...

However, if anyone could possibly enlighten me as it pertains any of the specific questions/concerns I have expressed above (specifically the "relationship" between the P450 and Carboxylesterase enzyme classes as they pertain to the subject at hand), you will hereby be eternally blessed with pure, uncut, unadulterated, shear awesomeness, along with a 'no-strings-attached' lifetime supply of FREE Space and Time! [*some restrictions apply]

And what the hell? A free copy of my new album too: Spundaze - "Bounce Your Reality Check Pt. 1": https://spundaze.bandcamp.com

Peace

And thank you!

LV

 

[aced126]

Would this mean, regardless of the information I have found so far regarding the specific enzymes responsible for the metabolism of various opiates/opioids, that the simple fact that Benzodiazepines "synergize" with, rather then "potentiate" opiates, would effectively rule out the possibility of a Benzo even having the ability to potentially extend the half-life of any given opiate/opioid due to competitive inhibition? Regardless of any other given enzyme interactions otherwise involved between either alkaloid? (1)

It would seem (if this information is correct) that only alkaloids with the ability to 'potentiate' due to enzyme interactions, rather than 'synergize', would posses the ability to do so. Any thoughts?

[edit] Obviously this is likely not accurate information given 'aced's "Methadone/Diazepam" example above, but I just thought perhaps there might be more variables involved than simply the specific enzymes involved? And albeit insofar I have still yet to find any metabolizing enzymes shared between Alprazolam and Heroin/Morphine. The most accurate information I could find for Alp so far was this (2):

http://www.ncbi.nlm.nih.gov/pubmed/12196913



Neither of which I have yet too be seen related to either Heroin or Morphine metabolism.

[Edit] I stand corrected. At least as far as it relates to Methadone: http://medicalxpress.com/news/2015-10-methadone-side-effects-efficacy-linked.html

Ok. More researching. Less posting. Got it!

Peace

(1) Both can happen. You can take two drugs which will inhibit each other’s metabolism as well as synergise along with each other. For example, MDMA and amphetamine taken at a club. Synergistic effects are normally a lot more subjective than enzyme inhibition, which is something which can be quantified even.
(2) Yes, alprazolam is metabolised by CYP3A1 and CYP3A4 (CYP and P450 are interchangeable). Morphine and heroin could both be metabolised by 3A4 (N-demethylation) to a small extent. However with morphine (and heroin once the acetyl groups are cleaved off, I’ll talk about this later), the main way it’ll be excreted is by conjugation to glucuronic acid (glucuronosylation). This severly increases polarity of the molecule. Polar molecules cannot cross the membrane of the collecting duct and pass back into the bloodstream when being excreted in the kidneys. Once conjugation happens, the molecule will be excreted very quickly, and no other modifications to the molecule are likely to be made.

Well, from what I can tell, it seems Heroin is quickly metabolized into 3 separate compounds:

6-monoacetylmorphine (6-MAM), Morphine, (and the more or less inactive) 3-Monoacetylmorphine

The primary enzymes responsible are: a plasma enzyme; 'Pseudocholinesterase' (aka, Butyrylcholinesterase (BCHE), as well as 'Carboxylesterase 1' (hCE-1) and 'Carboxylesterase 2' (hCE-2), both liver enzymes. From what I can tell, the fact that these specific enzymes are the primary enzymes by which Heroin is metabolized is somewhat unique, in that it differs from most other opiates/opioids which are primarily metabolized by the P450 class of enzymes. And for this reason, I have a feeling I 'might' be missing something here? (3)

However, again (as far as I can tell), although 'related', the Carboxylesterase enzymes and the P450 family are indeed two separate classes of enzymes: http://www.pharmacytimes.com/public...r2013/carboxylesterases-and-drug-interactions



I guess my main concern would be considering this already being a somewhat abnormal mechanism of enzyme metabolism among opioids, the fact that they are even 'related' just concerns me. Can anyone enlighten me as to how the specific 'relation' between these two enzyme classes might/would influence their ability to interact/inhibit (4), etc, as it regards to my overall concern of extending Heroin's half-life with the addition of Alprazolam? Reward offered! (*see below)

Especially considering that Alprazolam is indeed metabolized by the enzymes P4503A1 and P4503A4, respectively.

So, am I missing anything here? Pharmacology, let alone Pharmacokinetics is not my forte'. But from what I can tell, although it goes against what would seem to be expected, there 'seems' to be no metabolizing enzymes shared between Heroin and Alprazolam (5). (besides the 'related' one's I mentioned). And (again, as far as I can tell), although it seems that Morphine as well isn't metabolized by any P450 enzymes either? Hypothetically? If it were? Would it otherwise be something to consider since Heroin does itself still metabolize into Morphine eventually anyways? Or is "too late" in the 'process' to be worth considering? Obviously the various "pathway's" and "phases" involved here don't make things much easier to comprehend for a pharmacokinetic-novice such as myself either.

And as much as I truly enjoy this kind of research, I really would like to migrate to Suboxone ASAP, so any help is truly appreciated if there is something I have overlooked here. If it weren't for Buprenorphine's pesky, unrivaled affinity for the 'mu' receptor and the risk of (very un-fun) precipitated w/d's, it would be a non-issue. And if only I had enough bulk Kratom already on hand (it's on it's way) I'd likely just skip the Suboxone altogether, as Kratom, at least for me, is nearly identical (if not better) in it's effects in this regard. (Although even then, 7-hydromitragynine, one of Kratom's 'very' minor alkaloids still has some affinity for 'mu'. And as insignificant as it truly may be? That's an experiment for another time if considering using Kratom to 'pass the time' before taking Suboxone at least).

Or even a measly day's supply of (the recently now Sch. IV) 'Tramadol', being somewhat of an "atypical" opioid, and (to my understanding) specifically binding only to certain μ-opioid receptors which Buprenorphine does not, could therefore also be taken while preventing any affinity 'clashes' (again, please correct me if I am wrong). But in this case, Tramadol could therefore also safely be taken in the 'waiting time' needed (to 'tide' you over) before one could safely take their first Suboxone dose without the risk of p/w's. And the Tramadol (considering it's sub-par agonist effects) could of course still easily be potentiated, potentially possibly making this even a desirable possibility? (6) But unfortunately, I have neither at the moment. But I do have both a 4mg Xanax and 0.2 Clonodine script, which in my opinion, are still the next best things to have on hand anyways in this situation anyways.

I'd also be curious if taking a small amount of Dextromethorphan Hbr (or any NMDA-antagonist for that matter) could possibly be of any help? As they claim to prevent the development of tolerance towards opiates/opioids? "If" the effects would be obtained fast enough? Could they potentially 'flush' out any remaining alkaloids bouncing around, effectively shortening the necessary waiting/suffering time required before consuming my first Sub dose? (Again, "if" I'm even understanding this correctly and "if" this would even be a realistic possibility in the first place?). Although perhaps drinking a ton of Cranberry Juice might help by acidifying my urine, and therefore also speeding up the elimination of the remaining alkaloids from my body? And in the process also reducing the time required before safely taking my first Sub dose? (OT: This was a trick I learned the 'hard way' (so to speak) many years ago, as the labrat and author of the first ever reported/published trip-report on Memantine, both here, on Erowid, as well as in The Entheogen Review itself.]

(7)

"Memantine - First Time - A few words of caution...!": http://www.bluelight.org/vb/archive/index.php/t-132616.html

Good read if you ever get the time. But off topic, getting we are...

However, if anyone could possibly enlighten me as it pertains any of the specific questions/concerns I have expressed above (specifically the "relationship" between the P450 and Carboxylesterase enzyme classes as they pertain to the subject at hand), you will hereby be eternally blessed with pure, uncut, unadulterated, shear awesomeness, along with a 'no-strings-attached' lifetime supply of FREE Space and Time! [*some restrictions apply]

And what the hell? A free copy of my new album too: Spundaze - "Bounce Your Reality Check Pt. 1": https://spundaze.bandcamp.com

Peace

And thank you!

LV

(3) Heroin has 2 ester groups within its molecule. Our body has very specific enzymes for ester hydrolysis which follow a similar sort of reaction mechanism with each other (https://en.wikipedia.org/wiki/Catalytic_triad). Whenever there is this sort of bond in a molecule, an ester bond, or an amide bond (which is stronger and harder to hydrolyse), normally the first sort of reaction will be to hydrolyse this bond. The result is a great increase in polarity.
A lot of drugs which have ester bonds will have very short half lives because once they are hydrolysed, the drug isn’t active anymore. For example, consider Ritalin and cocaine. In the case of heroin, once hydrolysed, the molecule is still active in itself, and still has a decent degree of lipophilicity (opposite of polarity) so it will need to undergo further metabolism to its respective glucuronide derivatives as with morphine.
(4) The 2 enzymes are not really related. It is just that in morphine and heroin, their chemical structure means that they can be metabolised in that way. If say morphine-6-G or morphine-3-G wasn’t polar enough, then N-demethylation via say 3A4 would be required.
In the example of heroin, it just happens to be that there are 2 very easily modified ester groups within the molecule, and so that metabolic reaction is going to take place first.
(5) No, not to any significant degree really. It just so happens by chance that certain modifications can be made to morphine and heroin that happen before any sort of modification by the P450 system can be made (apart from maybe a small proportion being N-demethylated).
(6) If you’re a heroin user, I’d be wary about using tramadol to avoid withdrawals. Due to the opioid tolerance you have likely built, the doses of tramadol required to avoid withdrawals will likely be in a range where you’re at risk of seizing (tramadol can precipitate seizures or serotonin syndrome at high doses).
(7) NMDA antagonists can reverse opioid tolerance I believe but I know very little of this topic so I’ll let others answer it. However, the mechanism by which this is achieved is unrelated to metabolic enzymes, nor can they “flush” out any remaining alkaloids lol.
If you’re just waiting for your suboxone dose, just keep on using whatever opioid you can to avoid withdrawals I guess. If not, then benzos should make wds bearable at least.

 

[dopamimetic]

Somehow I don't believe that the usual benzodiazepines do alter enzymatic degradation of opioids or other drugs to a significant level. The effects you feel are entirely due do their primary action, as GABA positive allosteric modulators that is. There's some reasons why opioid users tend to like benzos, and as long as tolerance isn't too high they are probably able to suppress withdrawal entirely, but only as long as they are active (by countering the excess neuronal excitation) and eventually one becomes addicted to them too.

The situation with NMDA antagonists is a bit different. They are indeed readily capable of inhibiting or even reversing tolerance to opioids (and dopaminergics by the way) and can kick you off an opioid habit with ease. This is something many people have a hard time to believe that it's possible (which I can understand), but it is - we have enough personal reports and well, I can confirm it too. Memantine, being a rather weak antagonist in comparison, but one with an endless half live, can even be strong enough.

Don't give that linked warning above about memantine too much weight. You're not supposed to take 100mg of a medication you don't know yet when one should titrate up from 5mg/d and the regular dose is 20mg/d - also it doesn't require that much effort to look up the half life of 70-100h. But maybe we should be thankful for this report (one of the only memantine reports that made it to e.g. erowid by the way) because of this the substance is still quite unknown, and for one of the only prescribe able NMDA antagonists this is remarkable. Memantine is usually well-tolerated, just look at the amazingly short list of side effects (and this with a med that's usually used in the elderly!). I've stopped to recommend it to opiate addicts btw, people should research by themselves and if they don't want to believe maybe it's better this way. I don't want memantine to get scheduled. And addicts using it would be a fast track to this, unfortunately. There's a reason too why addicts are addicts (usually. I don't like preconceptions, but just too many addicts left me puzzled etc.. overdoses would happen too readily and too soon, when you give them a potent tolerance-lowering agent.)

Well, I can't say whether it's dependent on genetics etc. and especially how the NMDA antagonism behaves when you already have tolerance. But there is evidence for that it works. Just be careful with the dosage, I do tolerate 60mg/d and this is an amount that has been used in studies too, but it's nothing you should do without really knowing the substance. Start with 10mg, and if you tolerate it, move on to 20mg.

Another substance we have some good experience reports with is the even OTC available dextromethorphan. Yeah, cough medicine can bring you off opioids. This one is more trippy and has some side effects that may range from interesting to scary, but it's a potent NMDA antagonist and can and does work.

I don't speak about easing withdrawals or 'keeping your mind distracted' as it's usually criticized. I don't understand it fully yet, but NMDA antagonism does completely reverse opioid tolerance sometimes, removing every single symptom and - be careful about that! - even make respiratory depression from your once regular dose a real danger!