Buprenorphine used w/ butalbital (barbiturate); possible antagonism? like naloxone?

[AlphaOdure]

In barbiturate overdoses, i know naloxone is used for supportive measures in clinical settings. Although it certainly doesn't resolve the situation. And I can't even seem to find any specific pharmacological reasons why its even used rather than "for good measure"... The only real information (and efficacy of its use) I can find on pubmed (& similar abstract & article sources) on naloxone in these potential incidences of barbiturate overdoses is when polydrug use (i.e., opiates/opioids, of course) is known or suspected. (correct me if i'm wrong on this). In fact several studies i've read (w/ mice & also dogs, i believe; but not humans to my recollection) show naloxone does not observably affect anesthetic doses of barbiturates. So one would assume this would be at least similarly true with sub-anesthetic, recreational, and/or maintenance use of barbiturates? Assuming these observations in non-human animals, particularly dogs, coincides with human use, at least to some extent?
.....OR Any subjective experiences on buprenorphine & butalbital (or other barbiturates???)... or even any neurological knowledge, facts, abstracts (which i obviously can't find somehow...)?

This gets to my main question/concern; which is this-
...The implications & possible interactions (or psychological antagonism to some extent--i am speaking of subjective effects, not literal neurological antagonism) of concurrent use of buprenorphine (suboxone formula) which I am prescribed 4mg/day (which i break up the 4mg into 4-5 doses/day; ROA usually being insufflation) with butalbital (a barbiturate, obviously) which I use daily, at around 1500mg-2000mg per day after several years of upwards titration due to tolerance (although, i typically use around ~1800mg/day; was using less when was trying concurrent use w/ baclofen to reduce my intake, but that is another story). Anyway... Since buprenorphine is very selective, competitive, & has a "ceiling effect" (i personally do not find any difference than a full 4 mg dose than >8mg dose)--i'm wondering about any knowledge, known abstracts, facts, personal or observed experiences, studies, speculation/hypotheses, etc on any similar impacts buprenorphine may have on the efficacy & pharmacological effect of of butalbital (or barbiturates in general).


I figured this would be the best place to go, since- 1) it is theoretical in nature, or at least i see it as such; and 2) in the OD forum, i see a lot of dumb shit posted like "oh, well, i spit out my suboxone so i don't get any of the naloxone into my body" <sigh> Anyway, apologies if this isn't appropriate for this forum, i've posted here often & it seemed to fit the guidelines (in my opinion at least) set by the sticky threads.

 

[sekio]

Butalbital binds to GABA-A
Buprenorphine binds mu, delta, kappa opioid receptors

= no interaction.

Just like bupe blocking neither alcohol nor benzodiazepines.

 

[AlphaOdure]

heh, I know. I'm quite aware of that- which is why i was somewhat confused on the matter- and also WHY it is STILL used (at least here in the US) for barbiturate overdose... even when opiate/opioid use is ruled out! ...hence my question; and asking of any information of buprenorphine's effects on GABA-a agonists.. particularly barbiturates. Since there is NO pharmacological information... at least I can find (neither on here or on google). Aside from: "well, barbiturates are sedatives like opioids, therefore naloxone is commonly used"... i mean, i understand not giving any sort of antagonist at barbiturate binding sites on GABA-a due to health concerns... (same hesitancy w/ BZP antagonists for overdoses or BZPs..); but naloxone use/interaction makes no sense??? Yet its still wide spread!

But, we're not doctors, or at least i'm assuming you're not (i'm not, at least); so its widespread clinical use must have some efficacy (naloxone, that is)... at least i'd assume so. Even if that efficacy is supportive in nature. Which ties into buprenorphine to some degree, which can act as an antagonist at mu opioidergic receptors in some situations. Due to very VERY low info on this matter, thought i'd ask in regards to both naloxone & buprenorphine (being a partial agonist w/ higher competitiveness & affinity) having an effect, or any effect at all, on drugs that bind to GABA-a via the barbiturate site.

 

[AlphaOdure]

Butalbital binds to GABA-A
Buprenorphine binds mu, delta, kappa opioid receptors

= no interaction.

Yes, as my above post states, i'm quite aware of this. Pretty much thought this was a given by my statements in my original post. And kappa agonism? Very low at best to my knowledge. Again, i'm for constructive criticism though if you have a source! :D

Just like bupe blocking neither alcohol nor benzodiazepines.

See my post above.. different binding sites; this could definitely play a role. & buprenorphine is used off label for alcohol abstinence. I don't the efficacy though... friend of a friend type of deal.

 

[sekio]

I have never heard of naloxone being used as a barbiturate antagonist. It seems like a very strange side effect that is only applicable with very high doses of naloxone.

Naloxone is not effective in counteracting depression due to barbiturates, tranquilizers, or other non-narcotic anesthetics or sedatives.

RXMED monograph for Narcan

Although many conflicting reports and opinions exist, high doses of naloxone may reverse the effects of some nonopioid CNS depressants. Benzodiazepine reversal has been reported after naloxone and may be related to GABA receptor effects, a nonspecific analeptic effect, or reversal of concomitantly released endogenous opiates. Barbiturate and alcohol reversal have also been reported after naloxone. Certain metabolic products of alcohol (isoquinolines) have opioid-like actions and may account for this interaction. Opioid-GABA receptor interactions could also explain barbiturate antagonism. Naloxone may also partially antagonize ketamine and N2O analgesia. The [minimum alveolar concentration] of potent inhalational agents is unaffected by naloxone. However, pretreatment of rats with naloxone does counteract halothane-induced depression of sympathetic nerve activity, but interestingly, not halothane-induced analgesia.

ref

 

[Epsilon Alpha]

Looks like antagonizing the mu and delta receptors enough actually stimulates respiration to me

 

[endotropic]

Looks like antagonizing the mu and delta receptors enough actually stimulates respiration to me

Or high doses of these depressants are causing a downstream release of endorphins?

 

[AlphaOdure]

I have never heard of naloxone being used as a barbiturate antagonist. It seems like a very strange side effect that is only applicable with very high doses of naloxone.

I didn't say it was directly a barbiturate antagonist (at barb binding sites/channels) on a pharmacological and neurological level. Which is what prompted my post... i.e., my confusion as to WHY its used (and/or looking for info as to WHY naloxone is used--here in the US at least--preferably w/ pharmacological explanations) and/or more specifically as to buprenorphine's relation to this, since it is more competitive and/or has higher affinity as a partial mu-opioidergic agonist.. which, in certain circumstances could cause similar effects (at least, i would make such a deduction...) as naloxone in relation to higher doses of butalbital (or other barbiturates). Thus, i'm sort of looking to concurrent naloxone & barbiturate overdose/over-use cases since there are NO references as to the neurological effects of concurrent bupe & barbiturate use.

Thanks for the references though (and the posts from your references), i'll read them over when I have a chance!

Looks like antagonizing the mu and delta receptors enough actually stimulates respiration to me

Definitely- Kappa agonists were ruled out ages ago as having typical, narcotic opioidergic effects (especially here in the US when they were ruled out as anesthetics due to their odd psychological effects on patient). As of recent (here in the US & in Northern Europe), the same issue is slowly being seen--although to a lesser extent than kappa agonists--w/ delta-opioid receptor agonists: Especially research drugs that are purely delta-opioid-agonists which have no or very-little-to-no affinity for other opioid receptors- especially the mu-opioid receptor system, which seems to provide completely different psychological effects than all the other opioidergic receptors (at least due to the studies done lately/recently on non mu-opioidergic agonists).

 

[AlphaOdure]

^^Wait @Epsilon Alpha.. i take that back in my most recent post: i've extensively read that AGONIZING & not antagonizing delta- and kappa- opioidergic receptors (w/o major activity at mu-opioidergic receptors) causes the opposite, unless you're put under anesthesia w/ kappa opioidergic agonists, even still; CNS stimulation, at least from the abstracts i've read, do not cause any (or very little) CNS depression; if anything they're neutral at best in affecting the CNS system, eh?

I will try to give up the sources if you want them!

<<EDIT>>
Okay... EA, here is a source that seems to state agonism of delta-opioid receptors does cause converse stimulation... do a "find" & type in "stimulation" (if you try to find delta... you'll get hundreds of results). I am short on time... so i only read part of it, i basically was only able to read the first results of "finding" the word "stimulation"--so again, this could be contradicted later on.. if you care to rad this fuckin' novel of a source, heh. This action of stimulation is also related to cAMP NTs (as i understood it, at least) and also, this sources states delta-opioid agonists affect Gi & Gs receptors as well (again, as i understood it.. & according to Wikipedia too. I certainly could be wrong on both statements if its contradicted later on in this source.. i am planning on reading it later in full when i have time)

http://pharmrev.aspetjournals.org/content/51/3/503.full

 

[AlphaOdure]

You noted from the Rxmed source the following:

Naloxone is not effective in counteracting depression due to barbiturates, tranquilizers, or other non-narcotic anesthetics or sedatives.

Affecting CNS depression wasn't really what I asked- but i suppose it is one piece of the puzzle. I was asking about buprenorphine's impact on (or naloxone, by default, since there isn't much on the pharmacodynamics of concurrent buprenorphine & barbiturate use, especially in regards to functional/physiological antagonism) barbiturate's overall psychological & physiological effect & its possible reduction thereof (since it is commonly used in clinical settings with barbiturate overdoses). & to digress slightly to the first part of my paragraph here.. I suppose any sort of blocking effect could be applied in some measure to buprenorphine itself; at least in this one AREA, I am not addressing potentiation.. which i really don't feel any, anyway. But i don't use buprenorphine to get high, though.

I have never heard of naloxone being used as a barbiturate antagonist.

to reiterate in short... again, i never claimed it to be a neuropharmacological antagonist. Unless you meant this in the sense of subjective effects- i.e., antagonizing the psychological effects of barbiturates. In which case, this is why naloxone's widespread use in such instances confounds me; & its wide-standing clinical use must show at least some positive effectiveness? I assume?

 

[sekio]

Short answer: Don't worry about it. If you're really concerned, do some experimentation.

Long answer: All of the availiable evidence suggests that "normal" doses of opioid antagonists plus barbiturates don't produce effects much different from barbiturates alone. That is, there's no notable interaction at normal serum concentrations.
Buprenorphine ain't going to interact with your barbiturates in a negative way, assuming you're taking "normal doses". It will potentiate the sedative effects at best (like you'd expect from opi+barbs) or do nothing as a synergist at worst. I highly, highly doubt it will block or reduce any of the effects of normally dosed barbiturates.

I'm pretty sure if barbiturates and opioids interacted beyond simple synergy it would have been discovered & written up by now. Barbs and opis are old, old drugs.

In which case, this is why naloxone's widespread use in such instances confounds me; & its wide-standing clinical use must show at least some positive effectiveness? I assume?

Well, there's not really any other good barbiturate "antagonists" (flumazenil won't save you), so I think if you happened upon someone in OD you would try every last option availiable. And in the event of a polydrug overdose you don't lose anything. (naloxone has short t1/2)

 

[AlphaOdure]

I'm pretty sure if barbiturates and opioids interacted beyond simple synergy it would have been discovered & written up by now. Barbs and opis are old, old drugs.

Well, true in theory. But concurrent barbiturate & buprenorphine use would be a relatively new phenomena though. Buprenorphine is a relatively new opioid (first introduced in the 90's for pain if my memory serves me correctly? at least in the US.. I know bupe+naloxone is even never; circa 2000 or beyond, w/ the passage of the DAT act) which displays antagonist-like properties in opioid/opiate dependent individuals due to its competitive binding, relative to nearly all known full-agonist opioids/opiates--at least to my knowledge (correct me if i'm wrong), at mu-opioid receptors. This was part of my original reason for inquiry.

& furthermore, barbiturates have largely been absent (especially since 2000 & the DAT act when buprenorphine became largely used for addiction treatment) from the pharmaceutical market since the introduction of widespread buprenorphine use and/or prescribing. So, a novel-acting opioid: buprenorphine+barbiturates would be different than say, morphine+pentobarbital?


~ ~ ~


With that said- over time, i've noticed no negative synergy, if anything, slightly positive synergy.. as i take my buprenorphine mostly as prescribed (after protest over protest that there IS in fact a generic subutex, which my doctor denied, he finally switched me to the generic subutex tablet formula for monetary reasons. I take & am prescribed 4mg/day. i usually divide the 4mg into 3-4 doses. So i usually ingest between ~0.5mg-1.5mg every 4-6 hours, via insufflation usually).

I take about 2000mg of butalbital per day. I've been stable on that dosage for some time, & plan to stay stable at that dosage, then VERY slowly taper. Eventually I plan on tapering to 500mg-1000mg then slowly transitioning to higher dosages of etizolam (have solid source for it currently!)... Any views on this? I know it is thienodiazepine and wont fully resolve the w/d of a barbiturate! BUT... at those lower doses, plus given the barbiturate? its worth it. Plus thienodiazepines, particularly etizolam, have been shown (in barb-dependent-monkeys at least? heh) to sufficiently replace the "need" for barbiturates (probably much stronger ones than butalbital, btw) w/o any noticeable adverse effects?? Worth a shot!! Then i plan on slowly reducing the etizolam.

Well, there's not really any other good barbiturate "antagonists" (flumazenil won't save you)

True.. I guess it's sort of a "try-anything" approach, can't even really use flumazenil anyway if it DID work b/c it may put the user into seizure/convulsion (depending on his or hers dependency)...

I was just concerned.. since buprenorphine has higher affinity for mu-opioid receptors than naloxone..

 

[AlphaOdure]

PS- thanks for not closing this thread butalbital is widely used in the US (although perhaps not by many BL members)... so any information obtained via open threads is extremely helpful to me! Thanks Sekio