Bupe (Suboxone) Question about Mu-opioid Antagonist Neloxone and it's effect's

[Chemist4Hire]

I have a question about Suboxone, specifically the antagonist in it by the name of Naloxone. Now i clearly see the painted picture here on bluelight that it's believed Naloxone has zero effect on the µ receptors. This thread will show what I'm talking about, many users feel Naloxone is inert or inactive and they even go as far to say bupe causes withdrawals and Naloxone does not.
The reasons given for thier belief vary greatly ranging from bupes higher affinity to Naloxone having low BA (bioavailability).

This thread is riddled with misinformation and is viewable to all:
>> Link to thread <<


Obviously iv roa disproves ba being the cause, and quite possibly bupe only being an antagonist to the kappa abd being a partial agonist to the mu.


I'm a former pharmecutical engineer assistant and have a background with organic chemistry, i was under the impression that allthough bupreneorphine has a higher affinity to µ opioid receptors than many full agonists and antagonists like narcan/naloxone still binds to some receptors in the central nervous system and brain. That is showing as a medical certainty, it is yet to be determined what Symptoms are present from the removal of Naloxone caused by the higher affinity of the Partial Agonist. I'm lead to believe this happens to some degree in normal sublingual use, at least Naloxone holds back bupe from attaching when first dosed and later when Naloxone loses grip around 1hour after administration.
All the doctor's and chemistry majors I've asked seem to think 13-30% coverage by Naloxone is present.
Understandably I'm confused with some of the info here.
So if anyone can explain why so many feel symptoms of opiate antagonist present from bupreneorphine alone i would very much like to hear it.
I'm struggling to understand why bupreneorphine/Nor-bupe would pull preexisting bupe/nor-bupreneorphine off the receptors acting like an antagonist which it is not and normally does not behave in such way?

Just to clear up my question:

• why is bupe the only one present on receptors?
  

• how can we account for symptoms of opioid removal from mu receptors?

• And what evidence do we have from medical studies that show Naloxone is 100% inactive?

From what i could identify through my own tests:
(Suboxone Sublingual Films) 8mg Bupreneorphine - 2mg Naloxone, inactive ingredients:

• acesulfame potassium
• citric acid
• maltitol solution
  
• hypromellose
• polyethylene oxide
• sodium citrate
• lime flavor
• Sunset Yellow FCF
• white printing ink

It is my understanding Bupe converts to Nor-Bupreneorphine inside the body before it attaches to µ-receptors. and it has the same affinity to the µ receptors as previous attached bupe as it has a half life of more than 33hours, so dosing multiple times in one day should not account for symptoms of removal?

Many report in double blind studies that users of Suboxone administered subliminally experience the following symptoms believed to be caused by Antagonist removal from receptors by Bupreneorphine:

• Headaches
  
• Persperation
  
• cold sweats (not common)
  
• Agitation of skin
  
• Muscle pain
  
• neurological pain (mild to moderate)

LINK:

NSFW:

https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM191529.pdf

Adverse Events from double blind study:
(?5%)by Body System and Treatment Group in a 4-week study
Symptom>Medication>%experienced

• Headache: Suboxone=36.4% Subutex=29.1%
• Pain: Suboxone=22.4% Subutex=18.4%
• Withdrawal Syndrome: Suboxone=25.2% Subutex=18.4%
• Constipation: Suboxone=12.1% Subutex=7.8%
• Sweating: Suboxone=14.0% Subutex=12.6%

It's entirley possible symptoms are caused by adverse events, but again that's speculative and i have no evidence for that claim, although:


Update: Tuesday, November 14, 2017:

The most common adverse events reported in clinical trials with

Suboxone and Subutex were:

Spoiler: Side Effects of Suboxone and Subutex inside

• headache
  
• withdrawal syndrome,
  
• pain
  
• nausea
  
• insomnia
  
• sweating
  
• abdominal pain
  
• back pain
  
• constipation
  
• infection
  
• asthenia
  
• rhinitis
  
• anxiety
  
• depression

Understanding Adverse Event is the same as Side Effects from medication's or Adverse Reaction's. This is commonly a Blanket term given for explained symptoms and frequently symptoms without identified causes, but notably they where narrowed down to adverse events from both Suboxone and Subutex. So i know these symptoms can occur without Naloxone present. Now I've had over 15 years in pharmaceutical engineering-Bio/Organic chemistry field, but I have not personally worked with anything like Suboxone, I do have quite a bit of familiarity with opiates, opioids and alkaloids/chemicals that mimic opioids attachment to Mu/Kappa, and 3/6 ether's like 9-methoxy-corynantheidine the major alkaloid constituent extracted from Kratom(sometimes called: Ketum) leaves and 7-hydroxymitragynine, a minor constituent of Kratom(Mitragyna speciosa). Most medical professionals i talk with pertaining this matter agree Naloxone is the cause of most of these symptoms listed above excluding: Constipation, nausea, headache and withdrawal syndrome.



My question is if the symptoms are not caused by Naloxone (which my colleges tell me is the case, that is has a lower affinity to the receptors and they get pulled off by the bupe which causes the symptoms of discomfort) what is it caused by if that's not the case, and how and if its not to much to ask what studies and evidence supports this theory?
Note: i know bupreneorphine will cause withdrawals when used when other full agonists are present on receptors but i don't yet understand why opiates of the same affinity to mu opioid receptors would?
I enjoy this forum and don't want to make waves, i simply have questions for presented facts and did not find links of evidence which would have cleared up my understandable confusion.


I am hoping [MENTION]captain heroin[/MENTION] (or one of the many knowledgeable members on here) can answer some of these questions for me.
BTW i thoroughly enjoyed your micron thread, and cudos for educating others on how to use safely, it's a tremendous thing to behold.



Facts:

NSFW:

(FDA.gov): The Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), in collaboration with the National Institutes of Drug Abuse, the Centers for Disease Control and Prevention, the Substance Abuse and Mental Health Services Administration, and the Health Resources and Services Administration, is announcing a scientific workshop to initiate a public discussion about issues surrounding the uptake of naloxone in certain medical settings – such as on ambulances and in association with prescriptions for opioids – as well as outside of conventional medical settings to reduce the incidence of opioid overdose fatalities. Academia, government, industry experts, and patient advocates will discuss which populations are at risk for opioid overdose and how public health groups can work together to use naloxone to reduce the risk of overdose. We will also explore legal, regulatory, logistical and clinical aspects related to making naloxone more widely available. Will show the Web Recording below:

Web Recordings

July 1, 2015

• https://collaboration.fda.gov/p4d177tb0lb/

References and current up to date facts (2017):
https://www.fda.gov/downloads/Drugs/NewsEvents/UCM454748.pdf
https://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm191533.pdf


Medical Studies:
https://www.fda.gov/downloads/Drugs/NewsEvents/UCM454748.pdf

-I will continue to update as i get more information or as new information presents itself. -
​

 

[Hodor]

What do you mean, naloxone is "inactive"? It's certainly active, just as an antagonist/inverse agonist.

Or do you mean why naloxone is added to buprenorphine preparations like suboxone? That is done to deter people from injecting it. When used by mouth/sublingually, very little naloxone will enter your central nervous system due to its extremely poor bioavailability (even when compared to buprenorphine's modest oral bioavailability). When IV'd however, naloxone's bioavailability will be drastically increased, which will counteract some of the euphoria produced by the buprenorphine.

However, due to buprenorphine's very high binding affinity, naloxone isn't nearly as effective as an abuse deterrent as it would be for a low-affinity/full agonist type like pentazocine or tilidine.

Edit: Clarification: bupe's oral BA is "good" compared to naloxone, but still pretty poor when compared to something like oxycodone. However, the increased BA of IV bupe is offset by the even greater proportional increase in the BA of IV naloxone, and the diminishing returns from higher blood concentrations of bupe due to it only being a partial agonist.

 

[Chemist4Hire]

Forgive my phones poor vocabulary and grammatical errors

I'm fully aware of all of that. what i mean by Inactive, it is not my assumption that its inactive but almost every drug forum including this one. many have made the statement that "Naloxone does nothing" and they even say it doesn't even attach to receptors.

I currently believe Naloxone has a large effect on the body even with bupreneorphine present on the mu-opioid receptors (at least until i'm provided with sufficient evidence to believe otherwise, or find the evidence myself).

I do however believe that many symptoms from Suboxone are precipitated by Adverse Events, I have personal experience with this as i have many symptoms including withdrawal symptoms while on my current regiment dose that has been onging for a year+.

I'm just trying to find someone with knowledge and evidence to support as to why Naloxone does not cause any WD or PWD?
Or at least provide evidence as to how and why bupreneorphine causes the symptoms despite Naloxone being present?

 

[Jabberwocky]

Naloxone has a very low BA when using sublingually. Buprenorphine's is much higher. Buprenorphine also has a stronger affinity for opioid receptors than naloxone does. It also has a much longer half life. All these factors should answer your question regarding PWD and WD.

 

[~QuirKyNai~]

Naloxone has a very low BA when using sublingually. Buprenorphine's is much higher. Buprenorphine also has a stronger affinity for opioid receptors than naloxone does. It also has a much longer half life. All these factors should answer your question regarding PWD and WD.

also norbuprenorphine does act as a full agonist when suboxone is used in small doses.(.25mg)aprox...
As with those experiencing some "discomfort",or even slight withdrawal, then its because they have been on their dose for a while and there's a buildup of more buprenorphine in that person than what their dose is.So maybe the naloxone may try and pull off the bup from the receptors and like u said clinically it does,then then only discomfort I would think of and which I think is a plus,since I've gone down this road,is intestinal movement....BUT,it will only last for so long...less than 20min max I believe.(this helps with the slight constipation).

 

[Kittycat5]

Like TPD said its all about BA (dose amount too. If you took enough naloxone it would overcome bupe at some point). Intravenous or even intranasal naloxone on its own will indeed cause WD or PWD if weaker full agonists are present because the BA is higher via those ROAs.

 

[LucidSDreamr]

I believe the binding affinity of bupe is higher than norbupe or naloxone...to answer your first question. If the receptors are saturated with bupe you have little room for naloxone to bind. even if a small percentage of naloxone can still bind, the effects are barely noticable.

When people on this board are saying that "it is one hundred percent ineffective" they are saying that it has no noticable effect when suboxone is IVed vs bupe only. They aren't saying that not a single molecule of naloxone binds to a single receptor.

I have IVed suboxone and subutex. I do feel that the subutex is slightly better and hits a bit faster. In it does seem that the nalxone is delaying the onset of the IV hit when suboxone is IVed. It does NOT throw someone into WD and does not really make the drug non-iVable.

The main purpose of the suboxone formulation is to trick doctors into thinking its worthwhile, overcharging patients and monopolizing sales of bupe with this patented formulation.

 

[Chemist4Hire]

Like TPD said its all about BA (dose amount too. If you took enough naloxone it would overcome bupe at some point). Intravenous or even intranasal naloxone on its own will indeed cause WD or PWD if weaker full agonists are present because the BA is higher via those ROAs.

Agreed, but for bupe pulling bupe i still haven't found evidence to support it.
Bupreneorphine is a partial agonist to the mu receptors but only an antagonist to the kappa receptors and 3 and 6 ether's. Since bupe does not attach to kappa and its primary bind is to mu.
How is it that bupe pulls bupe off, and this is aimed at suboxone interactions with suboxone only im referring to. Everyone should know both bupreneorphine and naloxone are antagonist to (Kappa).
Full agonists like: Oxymorphone, hydromorphone and diacetalmorphine alike and quite possibly 7-hydroxy mytraginine, but I'm not sure about that one, but 7hm does bind to kappa and mu like most mu full agonists.

 

[Chemist4Hire]

I believe the binding affinity of bupe is higher than norbupe or naloxone...to answer your first question. If the receptors are saturated with bupe you have little room for naloxone to bind. even if a small percentage of naloxone can still bind, the effects are barely noticable.

When people on this board are saying that "it is one hundred percent ineffective" they are saying that it has no noticable effect when suboxone is IVed vs bupe only. They aren't saying that not a single molecule of naloxone binds to a single receptor.

I have IVed suboxone and subutex. I do feel that the subutex is slightly better and hits a bit faster. In it does seem that the nalxone is delaying the onset of the IV hit when suboxone is IVed. It does NOT throw someone into WD and does not really make the drug non-IV-able.

The main purpose of the suboxone formulation is to trick doctors into thinking its worthwhile, overcharging patients and monopolizing sales of bupe with this patented formulation.

Interesting, you believe norbupreneorphine has a higher mu-opioid agonist affinity than that of bupreneorphine does on receptors?
I gotta say i think you have something here and this is worth exploring. Now do you have any studies, double blind/double dummies, or any medical matierial to prove this? I would very much enjoy the read.

I was not attacking any credible member on this forum by no means, when i said some where making the claim Naloxone was inert, I mean they said it never bonded to the receptors because they believe bupreneorphine has a higher affinity. Which in my opinion is not a factual explanation, and when I implored that's not how the body, brain and central nervous system works, that although bupreneorphine does have greater affinity for mu opioid receptors than naloxone does, naloxone has shown in studies to bind faster than bupreneorphine does, eventually and indefinitely they will lose hold before bupreneorphine does simply because bupreneorphine has a greater affinity and a longer mean time for hold on the receptors.
Naloxone holds receptors around 1.7hours and bupreneorphine holds around 33-37hours. After explaining facts with links provided I was attacked, on a different forum!
This forum despite small misunderstandings have very knowledgeable members with a great deal of understanding, and i hope i have the pleasure of being apart of this data mound of vast information.

If it ever sounds like I'm attacking anyone here, let it be known that is not the case!
I only talk correct things I know of(or think i know of, until I'm provided with adequate evidence otherwise), and have extensive research, use and experience with.
I am also very understanding and realize that it's always possible I can be wrong in my current view of things and for me to grow wise I must to be willing to accept evidence from everyone around me so that my understanding can grow in an intellectual constructive way.

I'm not unwilling to learn, I just accept research, facts over speculation and personal beliefs that can quite possibly be incorrect misinforming hearsay on the part of otherwise intelligent people.

 

[Hodor]

I believe the binding affinity of bupe is higher than norbupe or naloxone...to answer your first question. If the receptors are saturated with bupe you have little room for naloxone to bind. even if a small percentage of naloxone can still bind, the effects are barely noticable.

When people on this board are saying that "it is one hundred percent ineffective" they are saying that it has no noticable effect when suboxone is IVed vs bupe only. They aren't saying that not a single molecule of naloxone binds to a single receptor.

I have IVed suboxone and subutex. I do feel that the subutex is slightly better and hits a bit faster. In it does seem that the nalxone is delaying the onset of the IV hit when suboxone is IVed. It does NOT throw someone into WD and does not really make the drug non-iVable.

The main purpose of the suboxone formulation is to trick doctors into thinking its worthwhile, overcharging patients and monopolizing sales of bupe with this patented formulation.

Yeah, that makes sense - IV suboxone only having a slower onset since the bupe has to compete with the naloxone for the receptors at first, but the naloxone is metabolized far more quickly.

I've read a lot of criticism from doctors complaining that the amount of naloxone in buprenorphine is way too low to completely deter people from IV'ing it.
Then again... sure, it's mostly a cash grab, but if the naloxone decreases its recreational value juuuust enough so that at least some users will abstain from injecting it, it's probably a good idea to have it in there.

Re: Norbuprenorphine, while it is indeed a full agonist, it is also a substrate for p-glycoprotein (similar to loperamide), meaning that it is rapidly eliminated from the CNS, so I wouldn't expect it to contribute too much to buprenorphine's analgesic activity.

http://jpet.aspetjournals.org/content/343/1/53.long

 

[LucidSDreamr]

I don't have any papers ...this is just remember from researching the topic a long time ago...not sure where I got that info from but it's worth double checking.

I believe the bupe binding stronger than nor bupe is the reason you see a sort of bell response to dosage which peaks at 2 mg

 

[Chemist4Hire]

I don't have any papers ...this is just remember from researching the topic a long time ago...not sure where I got that info from but it's worth double checking.

I believe the bupe binding stronger than nor bupe is the reason you see a sort of bell response to dosage which peaks at 2 mg

What you said seems to make sense, for the sake of clearing up misinformation, that thread on this forum which i posted in OP should have all this clarified and all misinformation on that is still view-able posts and replys with many members including a few mods stating the following as fact: it clearly says its inert, Naloxone does not attach or cause withdrawals when high affinity opiates are present. none of which are true. Thank you for your insight and i'm glad i made this thread, i will still be researching this topic and updating accordingly until i have sufficient evidence to back up this theory.

My concern is that someone will see that thread from a google search and follow presented facts as truth, as it may be closed to futher replies it is also still view-able to entire internet and since it's closed no one can post on it to clear up misinformation which it's riddled with.

here is the link:
>(The thread in question)<

 

[Jabberwocky]

I don't mean to be nit picky, but OP please don't use such small font. It's hard as hell to read. Normal size=2 in the future please. Thank you.

Good discussion btw. I'm enjoying this thread.

 

[Chemist4Hire]

I don't mean to be nit picky, but OP please don't use such small font. It's hard as hell to read. Normal size=2 in the future please. Thank you.

Good discussion btw. I'm enjoying this thread.

NP i actually wrote it in font size =1 for me to read easy on my phone, but i can do that for ya, if it's bad for you guys on PC
NOTE: i updated the OP and changed size, everything that was size FontSize=1 is now FontSize=2 and everything that was FontSize=2 is now FontSize=3.
let me know if it helps, sorry i thought smaller was better, it looked huge on my phone8(8)8)

I'm currently using Times New Roman Font, Font Size 2, as per your request, because i have partial color blindness. What color do you recommend:

I can't use Black it's to hard for me to differenciate between posts, it makes things much easier, but i want to use something very close to black but enough to tell, and dark enough not to cause distraction on forum posts. I'm thinking this color I'm using "Dark Slate Grey" is pretty good.

Dark enough not to cause distraction IMO:
Comparison test number1, Version 7-hydroxy mytraginine. c6h12o6 = C-6-H12-O-6 = Glucose = Navy "i like this one" top 3
Comparison test number1, Version 7-hydroxy mytraginine. c6h12o6 = C-6-H12-O-6 = Glucose = Indigo = top 2 choices
Comparison test number1, Version 7-hydroxy mytraginine. c6h12o6 = C-6-H12-O-6 = Glucose = Dark Slate Grey - in my top 3
Comparison test number1, Version 7-hydroxy mytraginine. c6h12o6 = C-6-H12-O-6 = Glucose = Dark Grey = i like it but I'm afraid it might cause issues with light background

Out of those which would you prefer?


It seems everyone likes the Dark Slate Grey, Still curious to hear from you on this matter, i hope i do not have any problems with mods or users because of this issue ive always had.

 

[cdin]

what I really don't understand, is why we don't add mcg amounts of naltrexone to oral pharm opioids. 5mcg naltrexone -> 5 mg oxycodone pills would double their effectiveness, stave off addiction and make it to where taking more than 50mg would cross the 50mcg threshhold for naltrexone acting as a real antagonist and stop the opioid effects. *I know why($$) - i just can't believe how little information about actual pharmacokinetics is known by pain docs etc.

 

[Jabberwocky]

I'll never understand how some doctors can remain so ignorant despite all their training, but I think that just speaks to the human condition. Humans are nothing if not fallible creatures.

And thanks for the edits Chemist

 

[Chemist4Hire]

I'll never understand how some doctors can remain so ignorant despite all their training, but I think that just speaks to the human condition. Humans are nothing if not fallible creatures.

And thanks for the edits Chemist

Np, happy to help8) aww shucks