Opioids Theories / Question ...

[DeathIndustrial88]

So... this has been on my mind for awhile now.
I've noticed that whenever I take breaks from buprenorphine to use full agonists, I almost notice what feels like withdrawals, even though the full agonist effects are present. Spent 2 weeks on hydrocodone & it bored me to tears. I felt them & enjoyed them some days, but other days I felt "off" & felt like I had a weird "black cloud" hanging over my head. Even had anxiety. It was almost like taking tapentadol. I know they were real pills. When I went back on my bupe, I almost enjoyed it because the effects were more pronounced & relaxing than hydrocodone. Does hydrocodone have really strong kappa agonism or something? I found it odd that a full agonist seemed just as boring, if not more so, than a partial agonist.

This isn't the first time I've experienced this on hydrocodone either, btw.

So I have a question. Buprenorphine is so potent that at 8-16-24mg, it can cover all of your opioid receptors. When you use a full agonist, you only have a small % of your receptors covered at a time, right? So is it theoretically possible that some one who is use to having 50% of their opioid receptors covered with a partial agonist, could have withdrawals even while using full agonists? If a person stops to use a full agonist & that full agonist is only covering 5% of your receptors, aren't those other 45% still crying out to be partially agonized? If not, why not?

Also, is there any research on what discontinuing kappa receptor antagonists can do? Is there such thing as "kappa receptor antagonist withdrawal"... ? And would this cause some kind of rebound cascade of kappa receptor activation that can lead to dysphoria, anxiety, etc... ?

Just looking for thoughts. As far as I know, I haven't seen anyone else posit these questions...

 

[Opana313]

My question is..are you cycling your bupe..like being sick for a day or 2 then jump on the full agonist wagon?

Reason I ask is because I did the EXACT thing for 5 years except I wouldn't really wait at all besides 8 hours of sleep(if I ever got enough). Basically I needed something every morning for sure, sooo wasting DOC or not, its happening...once I got bupe down to less than 2mg once daily(morning). I could feel things much better. Euphoriclly speaking.

Then as I got my dose down to just snorting. .5mg(this seemed like ages and without tryptamines and lysergamides, I probably would had failed and gone back up , or fearee it would never end)THEN I found i was usually always dysphoric and felt like shit until things even out.. now im drug free, besides anything that will make me trip my face off.

 

[DeathIndustrial88]

My question is..are you cycling your bupe..like being sick for a day or 2 then jump on the full agonist wagon?

Reason I ask is because I did the EXACT thing for 5 years except I wouldn't really wait at all besides 8 hours of sleep(if I ever got enough). Basically I needed something every morning for sure, sooo wasting DOC or not, its happening...once I got bupe down to less than 2mg once daily(morning). I could feel things much better. Euphoriclly speaking.

Then as I got my dose down to just snorting. .5mg(this seemed like ages and without tryptamines and lysergamides, I probably would had failed and gone back up , or fearee it would never end)THEN I found i was usually always dysphoric and felt like shit until things even out.. now im drug free, besides anything that will make me trip my face off.

I usually wait a day or two before I do it. And if I know I'll be doing it, I usually start to lower my doses ahead of time a bit.

But I stayed on the hydros for 2 weeks & still noticed up until the very end that I just didn't feel completely satisfied on hydrocodone at all. Which is odd to me, being that it's a full agonist & should be more 'enjoyable' than bupe. Ironically when I jumped back on the bupe, I got more of an "opioid" like effect from the bupe (as in warm body rushes, feeling floaty, chatty & then noddy).

I know the hydrocodone were real because they came from the pharmacy though.

Thanks for the response at least. No one ever answers my questions on here anyway, so I dunno why I bother to ask or try to start any discussion.

 

[Allylbenzene]

...whenever I take breaks from buprenorphine to use full agonists, I almost notice what feels like withdrawals, even though the full agonist effects are present.

I reckon TLR4 might be involved. It plays a key role in opioid-related issues:

Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway
— 10.3389/fimmu.2020.01455

Further, representative members of clinically relevant opioids such as morphine, oxycodone, buprenorphine, methadone, pethidine/meperidine, and fentanyl showed efficacy in driving TLR4 signalling in a TLR4 overexpressing cell line
— 10.1016/j.bbi.2022.02.001

While the role of the immune system, specifically, Toll-like receptor 4 (TLR4) in drug-induced reward is becoming increasingly appreciated...
— 10.1016/j.bbi.2017.08.021

One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at TLR4
— 10.1177/17448069241227922

Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction.
— 10.3389/fphar.2020.603445

...structurally diverse opioids (including the clinically relevant agonists morphine, fentanyl, remifentanil, methadone, oxycodone, buprenorphine, meperidine and antagonists naloxone and naltrexone) interact with TLR4
— 10.1177/0310057X211063891

The most well-known TLR4 blockers are naloxone and naltrexone besides the multiple OTC options. Blocking TLR4 helps to reduce opioid-related issues:

Several TLR4 antagonists and glial modulators shown to reduce opioid-induced tolerance, hyperalgesia and allodynia preclinically are clinically available...
— 10.1177/0310057X211063891

I reckon that blocking TLR4 could be worth trying in your situation. I wrote this practical overview on how to address opioid-induced TLR4 issues. It doesnt rely on any experimental or expensive items, it's 100% OTC.

Imo anyone using opioids long-term would benefit from a TLR4 antagonist(s).

 

[Opana313]

I usually wait a day or two before I do it. And if I know I'll be doing it, I usually start to lower my doses ahead of time a bit.

But I stayed on the hydros for 2 weeks & still noticed up until the very end that I just didn't feel completely satisfied on hydrocodone at all. Which is odd to me, being that it's a full agonist & should be more 'enjoyable' than bupe. Ironically when I jumped back on the bupe, I got more of an "opioid" like effect from the bupe (as in warm body rushes, feeling floaty, chatty & then noddy).

I know the hydrocodone were real because they came from the pharmacy though.

Thanks for the response at least. No one ever answers my questions on here anyway, so I dunno why I bother to ask or try to start any discussion.

What mg of hydrocodone and what was your dose & regimen? Also whats your buprenorphine dose and dosing like?

For me, about 24 or 48hrs after say 1mg bupe sublingual..I would injest 10mg hydrocodone but would need AT LEAST 20mg to feel normal(this would upset me anyway as it is not enough, never is really, but at least any physical pangs/cravings would be much less). So normally I would actually prefer a 40mg dose and then probably another 20-40mg in the afternoon...to me these little gear switches to me were just something to give me a break from subs, ultimately they helped for a long while then it turned into to me wanting to just be free of it.
I think alleybenzine may be onto something. I think the Naloxone or Naltrexone could be mostly the reasoning why a full agonist still does not work well yet? Obviously bupe is powerful so maybe your tolerance is much higher? I am sure anyone would of preferred oxy over the vicodin BUT still you should be able to stack or take a break from subs, but don't expect the oxy or hydrocodone to do it all like they used to, the longer your brain is saturated the harder it will be to feel your pain meds.
Sorta like how one 5mg hydrocodone probably would barely even take the edge off of anything for you or me. I would need at least two to feel anything and even this would be veryvery modest and would possibly get more pain relief with a few more Tylenol or ibuprofen

 

[DeathIndustrial88]

I reckon TLR4 might be involved. It plays a key role in opioid-related issues:








The most well-known TLR4 blockers are naloxone and naltrexone besides the multiple OTC options. Blocking TLR4 helps to reduce opioid-related issues:


I reckon that blocking TLR4 could be worth trying in your situation. I wrote this practical overview on how to address opioid-induced TLR4 issues. It doesnt rely on any experimental or expensive items, it's 100% OTC.

Imo anyone using opioids long-term would benefit from a TLR4 antagonist(s).

Thank you! That was very well thought out! I will have to take a look into all these links & try & get a better grasp at what's being presented here.

From what I'm gathering, are you saying buprenorphine causes inflammation because of it's properties at TLR4? And that antagonists would stop this? Well my buprenorphine is combined with naloxone technically, but we all know buprenorphine over-powers it anyway.

I'm confused why this would cause dysphoria & WD-like symptoms when switching from buprenorphine to hydrocodone though & why it only gets eliminated by taking small doses of buprenorphine with the hydrocodone.

I'll look into your overview though, cause that could come in handy! I use magnesium to help with tolerance. And I use to use DXM until it started giving me problems. I use to love DXM-tripping but then in 2021, after a DXM trip, I had what I can only describe as "sort of like costochondritis". I'd have sharp pains in my neck & shoulders, a pain in my chest when I would take a breath & a mild fever. Usually lasted 1-3 days. This kept on happening up until recently. I didn't think DXM could be causing something like that, but I did an experiment & quit DXM for a year & a half. And during that year and a half, I didn't get these 3 days weird chest pain episodes at all. And so then I decided to start using DXM again last year & what do you know, I got that weird chest pain within a few days of using it every time. So I quit again at the beginning of this year & so far, so good again. So I guess I can scratch DXM off my list of tools, which sucks cause I really liked the versatility of DXM.

What mg of hydrocodone and what was your dose & regimen? Also whats your buprenorphine dose and dosing like?

I was using the 10/325mg pills. And I would use up to 30-60mg a day some days.
As far as bupe goes, it varies. I've always been able to feel full agonists on bupe, as long as I'm at a very low dose before or during taking it.
So when I know I'm gonna be using a full agonist, I always taper down.

I had no trouble feeling it honestly, it was just wasn't enjoyable really at all. Even pinned my pupils on it. But I still felt anxious the entire time, like I was on a norepinephrine releaser or something. The hydrocodone did help pain a little better than bupe, but only some of the days.

I think alleybenzine may be onto something. I think the Naloxone or Naltrexone could be mostly the reasoning why a full agonist still does not work well yet?

Well I did use the hydros for over 2 weeks straight. So I'm not sure the naloxone from my subs would've still been hanging around even after two weeks. I abstained from bupe for those 2 weeks, except for like 2 or 3 days where I took .75mg cause I felt like the hydrocodone wasn't making me feel content enough. I actually felt a more enjoyable buzz from my bupe the day I jumped back on it after stopping the hydros. Of course this feeling disappeared by the 2nd day of using again. I guess I can only chalk that up to the fact that not all opioids are cross tolerant either.

Obviously bupe is powerful so maybe your tolerance is much higher?

This is my only guess Which kinda brings me back to my original question too, that if some one's body has gotten accustom to having higher receptor saturation (rather than lower saturation, but full receptor activation, like you get with a full agonist) or if because bupe's binding is just so strong that it's altered my ability to be fully held by some of the less potent full agonists. I'm guessing the answers gotta be a mix of everything a little bit.

 

[DeathIndustrial88]

I was doing some research on hydros the other day.
And I discovered that common listed side effects included things like : Anxiety, fear, dysphoria, paranoia, etc...

My guess is hydrocodone & oxycodone probably produce strong kappa agonism, which is what causes that "dark cloud hanging over me" type effect, very similar to the way tapentadol feels.

I think this is actually what the issue is. Maybe I just don't really do well with strong kappa agonizing opioids. And maybe this is why I prefer opioids like tramadol, heroin, buprenorphine (with no tolerance), etc...

That's the only thing I could come up with. The fact that "anxiety/fear/etc.." are listed as actual side effects of hydros, then I think I might be on to something. But I would assume tramadol & heroin are also kappa agonists to some degree, maybe they're just not as strong of kappa agonists as the codones? Idk.