Bupe Buprenorphine potentiation: diltiazem

[AlphaOdure]

I tried posting on this topic in AD for some possible insight on the pharmacodynamics of this combination.. but to no avail! I am looking for any experience, any pharmacological insight, or any comments in general on this issue.

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Diltiazem Pharmacology:
This chemical is a selective calcium channel blocker of the benzothiazepine class. It is indicated (in the US) for the use of migraines & as a cardiovascular drug. It is also a vasodilator.**NOTE** Anecdotal/case studies have shown diltiazem can cause precipitated withdrawal symptoms in patients who use suboxone, apparently a result of hepatic interactions with nalaxone--however, I currently dose my suboxone via insufflation; causing higher bioavailability of buprenorphine & near non-existent bioavailability of nalaxone--however, nalaxone has higher bioavailability via sublingual ROA--and i am concerned b/c I am moving back to sublingual ROA in the near future.

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Here is my experience & deductions:
According to information found from a quick google search and skimming wikipedia, diltiazem is known to increase morphine induced analgesia (however, no other opioids of the non-morphinan class are mentioned). Roughly 5-20 minutes prior to taking my final, nighttime buprenorphine dose of 1 mg (i take a total of 4 mg daily) I usually take 180 mg - 360 mg diltiazem (in addition to 100 mg of diphenhydramine i also take concurrently, i have been taking diphenhydramine for roughly 5 years & I am pretty much tolerant to any potentative effect it has).

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I have been using diltiazem for roughly 3-4 weeks (as of today); and I have noticed the following opioidergic effects:
-- Significant increases in somnolence and/or sedation (i.e.- "nod")
-- Ataxia
-- Minor increase in euphoria
-- Increase in opioidergic induced histamine symptoms (which I personally enjoy)
-- Slight increase in anxiolytic effects
-- Slight increase in loss of inhibition
-- Hypotension / low BPM / low blood pressure

Other and/or ddditional observations that are non-opioidergic:
-- Decrease in buprenorphine's duration of action
-- But conversely less propentency to redose as often; perhaps good addition for tapering?

This is a known effect of this drug; its proposed to have a similar neuropharmacological profile as bupropion's impact on cessation of tobacco use (as well as stimulants, & to a lesser extent, other drugs.​

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-- Ceiling effect observed at >360 mg
-- Little to no effect noticed if taken after dosing buprenorphine
-- No effect if taken concurrently w/ bupe more than once a day

Does not seem to be tolerance related; b/c I was predosing with diltiazem before every bupe dose--4 times a day--for roughly 7-10 days & noticed little declining effects, even a higher doses, starting at day two; & on the last day of predosing 4x daily, I experienced no additional effects. I then went back to just predosing diltiazem at night; taking only 180 mg - 360 mg a day instead of taking 180 mg - 360 mg four times a day; the original potentiation​

-- Negative sexual side effects / decreased libido
-- Fatigue / lethargy lasting roughly ~20 hours from last dose of diltiazem

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I am assuming diltiazem's synergy w/ buprenorphine is related to its hepatic effects, being a known inhibitor of the CYP3A4 liver enzyme (among other CYP enzymes). CYP3A4 is one of the same hepatic enzymes that metabolize buprenorphine. I am assuming diltiazem causes increased levels of norbuprenorphine, which has more agonist activity at mu-opioid receptor sites—and i assume more metabolized buprenorphine results in less plasma levels of it--and buprenorphine happens to antagonize the agonist effects of norbuprenorphine. And thus, this causes the effects i've noticed. However, this hypothesis seems imply diltiazem has an inducing type effect on a shared CYP enzyme (inducing the enzyme's activity would create a higher metabolism rate, thus MORE norbuprenorphine); where as pharmacological literature clearly states diltiazem's action as an “inhibitor” on CYP3A4. So perhaps these effects occur from a different CYP interaction, or even a different mechanism--not related to hepatic activity--all together???

***Any experiences? Any thoughts? Any armchair chemists or pharmacologists have any info to share? Anyone prescribed both of these drugs & take them concurrently?***

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My pharmacological profile
-- Buprenorphine

suboxone formulation; 4 mg daily, 1 mg take 4x daily. ROA: insufflation​

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-- Diphenhydramine

400 mg - 600 mg daily; usually 100 mg ~10 minutes before dosing suboxone​

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-- Trazadone

50 mg ; taken at night -- roughly 0.5 - 3 hours before my final suboxone dose​

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-- Diltiazem

180 mg - 360 mg, once a day -- roughly ~5-20 minutes before taking my final, nightly suboxone dose​

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-- Butalbital

fioricet formulation; 1250 mg - 1500 mg daily; taken in increments of 75 mg - 125 mg at a time. Taken usually either ~1 hour after dosing buprenorphine or roughly ~2-3 hours before dosing bupe. My dosing regime of butalbital--relative to when I take bupe--is fairly erratic & can differ throughout the day.​

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[lorne667]

You say Anecdotal/case evidence indicates that Diltiazem precipitates WD??? That is literally impossible; I IV buprenorphine, giving me 100% BA of nalaxone, and it certainly doesn't put me into withdrawal! IDK where you got that information, it is blatantly false.

That said, I find your post intriguing, but have no experience with any calcium channel blocker. Sorry!!!

 

[nAON]

@lorne - are you using generics of suboxone? Generics won't contain nax, I think only Suboxone/Subutex have it (may even just be one of those)

 

[Jabberwocky]

^subutex does not contain nalaxone. suboxone and it's generics do.

Alpha - if you supplied the case studies it would help deduce your answer.

 

[AlphaOdure]

You say Anecdotal/case evidence indicates that Diltiazem precipitates WD??? That is literally impossible; I IV buprenorphine, giving me 100% BA of nalaxone, and it certainly doesn't put me into withdrawal! IDK where you got that information, it is blatantly false.

Huh?? Thats besides the point--you're not taking diltiazem w/ buprenorphine.

And yes, i know formulations containing naloxone don't make much difference--buprenorphine has much higher affinity for mu opioid receptors than naloxone & is much more competitive at binding sites; rendering any antagonist effects small to non-existent. But i'm still concerned since there is another drug involved--especially one that is known to have significant hepatic/CYP impact.

Alpha - if you supplied the case studies it would help deduce your answer.

I will try & dig it up. But precipitated withdrawal from diltiazem use (which i've never experienced) was just one of the questions.. mostly interested in similar effects from others.. or experience w/ any other types of calcium channel blockers used to potentate opioids? B/c the effects do not seem to be hepatic, i've taken both CYP inhibitors & inducers w/ opioids... and diltiazem seems to be much different; and more potent. But then again, i'm not a pharmacologist or a chemist....

 

[AlphaOdure]

Oops, I completely misinterpreted diltiazem's interactions w/ naloxone, here is something from a page on suboxone drug interactions:

Diltiazem may have an adverse effect on naloxone.- Eur J Pharmacol 1996 Nov 28;316(1):7-14 -- Diltiazem inhibits naloxone-precipitated and spontaneous morphine withdrawal in rats. -- Kishioka S, Inoue N, Nishida S, Fukunaga Y, Yamamoto H
http://www.personalhealthzone.com/drug_interactions/buprenorphine.html

SO.. this means precipitated withdrawal caused by naloxone is inhibited by diltiazem in opioid tolerant individuals? Sort of meaningless w/ suboxone formula one would think, since naloxone's effects are rendered negligible b/c it is significantly less competitive at binding sites. Of course if this same effect is realized in humans, I guess this would be of use for IV users of buprenorphine/naloxone formulas; since naloxone does have some--albeit very little--effect using this ROA.

This is not the article/case report I originally read though; still trying to find it. But it said much of the same thing now that I think about it. Kind of hard to find any information, a google search with 'diltiazem, suboxone' brings up this thread & a similar thread i started in AD discussion as the top two hits.

 

[lorne667]

^^^ I know that was only one of your questions, I just wanted you to know that there was no way it could precip WD. You see, IV nalaxone is 100% BA, so it doesn't matter if it is inhibited or not, simply lowering it's metabolism isn't enough to have an effect if at 100% bupe already overpowers it. And even if there we're some adverse reactions, you would have nothing to worry about, as sublingual and nasal BA's are so much lower than IV. Basically, if Nalaxone isn't even active(or at least active enough to subtract from the experience) IV then it is irrelevant by any other MOA.

 

[AlphaOdure]

Okay, well guess we'll agree to disagree... hepatic or neurological interactions most certainly could cause a greater naloxone effect--especially if using 4 different drugs in addition to bupe; & especially if one of them is diltiazem. And not to mention if the ROA is IV, the hepatic metabolism is next to nil, relatively speaking--and IV suboxone does cause some naloxone effect in doses above 4mg/1mg-8mg/2mg (just do a quick search on BL, especially some threads & posts from jasoncrest).

Despite bupe's higher affinity & more competitive binding at mu-opioid receptors, injection of naloxone/bupe combinations still causes some naloxone-induced, opioid antagonist symptoms for the first ~0.5-1.5 hours after dosing (naloxone has a very short duration of action, especially in contrast to bupe) when used in doses >8mg/2mg (as I previously mentioned in this post). Although the antagonist effect is less pronounced in long-term and/or daily IV users of this formula at previously said doses.

Anyway, this is getting a bit off topic.. no..? Not much going on here but two hardheaded individuals trying to have the last word. Which hopefully i've had.

 

[lorne667]

I hate to take the last word, but... Hepatic interactions are just that, inhibtion. Nalaxone has a horrible IV sublingual, like less than 10%. I'm sorry, but I can't let this go by; the fact is, no matter how much inhibition you affect, nalaxone has a BA of 10% or so oral. So your calcium channel blocker would have to make it 10 TIMES FUCKING STRONGER to even match IV; thus it is insane to think any effect. Yes, IV could make a difference, as you are getting 100% + the effects of diltiazem(though as you said, it skips a lot of metabolism that way). I myself have had physical effects from IV'ing too large of doses, but sublingual the BA is just too low. And I believe at doses 8mg and above, nalaxone could have an even more pronounced effect, but remember that 8mg bupe IV is close to 32mg bupe, and I am of the school that that high of a bupe dose is pointless, because if your not held BEFORE you reach that point, I don't think a partial-agonist wil cure DT anyway.

Forgive me, I enjoy debating, but more importantly I just need you to understand that no "hepatic reaction" is going to compensate for a ~90% loss of BA. Remeber, you asked about sublingual, so I am just answering off of that point.

(ANd I haven't really read the link you posted yet, but remember, buprenorphine itself will precipitate WD in opiate-dependent people...

 

[AlphaOdure]

Ok.. I don't think we're even disagreeing on much:

Forgive me, I enjoy debating

lol! As do I.. no need to ask my forgiveness.

I hate to take the last word, but... Hepatic interactions are just that, inhibtion.

No, hepatic interactions also include CYP inducers & CYP substrates. Drugs are metabolized by many different CYP enzymes; and a given drug can both concurrently induce & inhibit differing CYP enzymes.

no "hepatic reaction" is going to compensate for a ~90% loss of BA. Remeber, you asked about sublingual, so I am just answering off of that point.

Not trying to be a dick, honest question: do you have a background in organic chemistry or pharmacology to back up an objective statement such as this? Or are you basing this on your own experience? B/c MAOIs inhibit hepatic metabolism & can result in such dire effects as death if you engage in such risky behavior as eating cheese after taking your MAOI! Comparing MAOIs to CYP inhibitors may be an over simplification for an armchair pharmacologist such as myself, but i'm using this point to illustrate the fact that drugs that inhibit hepatic metabolization can fuck shit up. Although I'm sure MAOIs are far more potent in their hepatic inhibiting effect than (and acting on a more fundamental level than..) CYP inhibitors.

I haven't really read the link you posted yet, but remember, buprenorphine itself will precipitate WD in opiate-dependent people...

Yes I am aware of that, I mentioned this point in the post referencing the link. I know, annoying how 90% of recreational suboxone users think naloxone is responsible for precipitated withdrawal.. or how they think naloxone has any significant impact on suboxone's effects whatsoever aside from high IV doses. Buprenorphine is exponentially more competitive than, & has more affinity for, mu opioid binding sites (as well as delta- & kappa-) than naloxone.. rendering naloxone next-to-useless, (again, aside from high doses of suboxone doses via IV)...

So don't know why US doctors insist on peddling suboxone in place of subutex, or generic buprenorphine.. other than using naloxone as a scare tactic??

I am of the school that that high of a bupe dose is pointless, because if your not held BEFORE you reach that point, I don't think a partial-agonist wil cure DT anyway.

I've been on buprenorphine therapy for 4-5 years for a reason. Personally, I am not looking for a full-opioidergic type high. Opioid agonists...? Wont touch the stuff. Also why I refuse to IV bupe b/c I doubt i'd be able to control myself w/ it. I'm an addict, pure & simple. Plus I don't want my veins permanently scarred after a couple of years of IV'ing pills.

Just looking for something other than alcohol (and something that doesn't show up in a piss test; something not very addictive like carisoprodol--which i've had a problem with; etc) to use as a once-in-a-while recreational play-thing. And noticing the synergy of these two drugs after starting diltiazem, I merely sought any other experiences or knowledge on the matter!

 

[AlphaOdure]

Anyway lorn, we're getting off topic... again.. no need to actually read the source, I copied & pasted all the mentions of diltiazem & suboxone in that reference.. which, as I noted, actually INHIBITS naloxone-precipitated-withdrawal in opioid dependent mice, which seems sort of irrelevant since--as I and yourself previously noted--bupe is responsible for precipitated withdrawal, not naloxone. I am still looking for the original article, which was a case study. I am pretty sure it is referring to the same mechanism of action though--but i am not 100% certain. I will post a link & paste anything of relevance when i find it.

 

[MartinFn]

So well, Alpha and Lorne, diltiazem is a known inhibitor of CYP3A4, as you said, among a lot other inhibitors (ketoconazole, fluconazole, itraconazole etc., clarithromycin, erythromycin etc.). My question is if diltiazem potents opiods like fentanyl, heroin, oxycontin, and if it does, (of course just if you know, it's not the easiest question..) how much it potents, how strong inhibitor it is, for example in compare with ketoconazole, (which i think it's a strong inhibitor, so a very good potentiator.). It is prescribed for migraines and as a cardiovascular, as you said (Alpha). If it works as a potentiator, i suppose that the doses would be at 180-360mg, and takken about half an hour before you take the opiod (i've come to this conclusion from your posts, Alpha, and of course i might be wrong, i don't know..). I would be interesting to give me your lights, fellows...Also, i don't fuckin know anything, about the selective calcium channel blocker thing, and if it has something to do with opiate's potentiation, i have to do my homework about it, but this an other story...%)

PS:One more question, taking diltiazem (a cardiovascular med), has any risks about your health?8). Thanks...


MartinFn

 

[Coolwhip]

It could be extending your dose of bupe through enzyme inhibition.

But more likely, any difference in effects you feel are 1) synergistic 2) caused by increased brain blood flow 3) caused by its CCB action

 

[lorne667]

Ok..

Not trying to be a dick, honest question: do you have a background in organic chemistry or pharmacology to back up an objective statement such as this? Or are you basing this on your own experience? B/c MAOIs inhibit hepatic metabolism & can result in such dire effects as death if you engage in such risky behavior as eating cheese after taking your MAOI! Comparing MAOIs to CYP inhibitors may be an over simplification for an armchair pharmacologist such as myself, but i'm using this point to illustrate the fact that drugs that inhibit hepatic metabolization can fuck shit up. Although I'm sure MAOIs are far more potent in their hepatic inhibiting effect than (and acting on a more fundamental level than..) CYP inhibitors.

Dude, that part about the cheese had me laughing so hard!!! Ok, I get your point, I just can't believe that it could make a difference, but I get what your saying. Anyway, I was high as usual posting our "debate" , so I'm glad to see it come to a head!

and @ Martinfn: I haven't personally taken either substances you mention, but ketaconazole is known to be a strong inhibitor. I would take it an hour before, as opposed to just 30 minutes, as inibitors, in my experience take a minute to take effect then last a while. They upposedly last for days; I haven't noticed that, but a whole day of noticable effects, in any case.

(this has REALLY gone off-topic. I'm done being difficult; it's time you brought this back in!!!

 

[AlphaOdure]

My question is if diltiazem potents opiods like fentanyl, heroin, oxycontin, and if it does, (of course just if you know, it's not the easiest question..) how much it potents, how strong inhibitor it is, for example in compare with ketoconazole, (which i think it's a strong inhibitor, so a very good potentiator.). It is prescribed for migraines and as a cardiovascular, as you said (Alpha). If it works as a potentiator, i suppose that the doses would be at 180-360mg, and takken about half an hour before you take the opiod (i've come to this conclusion from your posts, Alpha, and of course i might be wrong, i don't know..).

If the effects I felt are a result of CYP inhibition (which I don't know, hence this thread), then its very likely it may potentate others--but this could cause some trouble w/ certain opioids which owe their neuroactivity to metabolism. Codeine needs to be metabolized into morphine to have any effect, therefore an inhibitor of this particular enzyme causes LESS opioidergic analgesia. One would want an INDUCER of the particular CYP enzyme in this instance.

I only take buprenorphine. I do not take any other opioids, nor do I plan to. So I couldn't report on any results. I have been on diltiazem in the past during my active addiction & do not recall any noticeable effects. Due to the high affinity of bupe's active metabolites, particularly norbupe, i'm akin to believe its a combination of bupe's hepatic complexity & diltiazem's CYP effects..

But, unfortunately, the pharmacodynamics of buprenorphine--and its active metabolites--are poorly understood and laxly reported on/investigated. Of course, this is of no surprise in an industry that spends billions developing drugs.. w/ no other purpose than to pump them through FDA for phase I and II trials as soon as possible, to make a profit. After that? No more research, no more inquisition into the pharmacology of the drug... UNLESS lawsuits happen to start piling up a couple of decades later.. and court cases are dependent upon pharmacological inquiry. ...So goes the free market when combined with medicine..