Pharmacology - Opioid Tolerance: Reversing Receptor Sensitivity

[fiveleggedrat]

So Swim's been hitting the books lately, and studying lots of medical papers that he'll get to uploading later. He is trying to find a way to reduce the permanent tolerance he has gained, even after taking breaks for months from opioids. He no longer gets ANY euphoria from opioids, and tramadol just completely stopped working.

This all focuses strongly on the Mu receptor. Not interested in playing with K or Delta or any other receptors, since euphoria is tied mostly to the Mu receptor.

So Swim has 3 theories so far:

1) 50mg naltrexone daily regiment (While sober, obviously!) for 1-2 weeks. This in theory would sensitize receptors. Most papers I read say that people often OD when coming off an antagonist, although that could be just from lack of physical tolerance. Swim is very certain of this theory and that blasting the brain the naltrexone for a while would make it sensitive again to endorphins, and therefore, opioids. Cheap to test.

Edit: This idea centers on the use of an antagonist in general. Naltrexone seems like the best choice so far. Also, the 50mg dose is speculation based on what Swim has read.

2) iNOS inducible inhibition. (inducible nitric oxide synthase inhibition). Not even going to attempt to explain this, it's complicated. I'll go in-depth into all 3 of these options later, explaing why I think they would work. More or less, sounds to prevent regulation of the mu receptor. This one sounds good on paper, but would be very expensive to test.

3) Using NMDA antagonists to temporarily or perm. reduce tolerance. Learned about this one studying receptors and neurotransmitters. Cheap to test common ones like DXM and n2o but Swim wants to test this with MK-801. Too bad it's rare and expensive.

Anyone have any opinions/thoughts?

Reputation Comments on this post:

	good thread
	great research
	you really got something goin, hopefully we'll find it.
	Knowledgable, informative post
	Interesting thread.

[W!SE]

swim would like to know WHERE he could get some naltrexone + the other 2 swiy mentioned above .. as well as HOW (what to say, etc.)

gracias

[chillinwill]

well naltrexone is commonly prescribed for both alcohol and opiate dependency so incorporating that fact with a doctor might be a problem if you don't want them to know about you using

[W!SE]

what..the fuck

anything else that's over the counter ? my friend isnt that desperate .he will start exercising daily today

[biggpri]

swim may be wrong here, but isn't nitric oxide potentially toxic to people. it's used for industrial purposes, and is not the same thing as nitrous oxide. swim was under the impression that it should rarely, if ever, be used by humans. again, swim may be wrong here, but thought a warning would be helpful.

[fiveleggedrat]

Nitric oxide is produced in the brain naturally and is involved in signal transmission, or something along those lines.

Yes, I do believe nitric oxide is not safe to put into the body, but what I mention is something to interact with nitric oxide in the brain that's already there.

[RoboCodeine7610]

SWIM likes the natreloxone idea, since hes always wandered the same thing:If one were to take an opioid antagonist for a while and develop a tolerance to it, wouldn't that make an opioid agonist much stronger?
Nice research fiveleggedrat.
Robo

[fiveleggedrat]

Swim ended up looking all this up mad as hell that opioids don't cause euphoria anymore, and his doses have gone 2x-4x what they used to be. No one can really explain Swim's mental tolerance. Swim uses 1-2 times monthly, and usually misses at least one of those times due to lack of opioids, so when Swim gets them and they don't do much besides a mild buzz and mild CNS depression, Swim wants answers.

Besides, many others stand to benefit from this. Can we imagine if those who are actually in pain and suffering and taking opioids for pain, and stuck on insane dose regiments could renew their tolerance like a opioid naive? That would be some amazing information.

Swim is amazed by the idea of taking someone on 240mg oxycodone daily and getting them back on 20mg and having it work, only having to do some type of "tolerance therapy" every now and then to get tolerance down.

I know such a concept is certainly farfetched, but I really am calling for more research on the actual mechanisms of tolerance and interacting with brain chemistry, as opposed to "potentiators", which have been a joke for Swim.

fiveleggedrat added 5 Minutes and 49 Seconds later...

Oh yeah, Swim combined 50mg DXM with a 10mg hydromorphone rectal dose a few days ago. Of course, the DXM was oral. Combined 20 minutes in advance.

Result: No change. Swim got a considerable buzz from that 50mg, actually, and significant pupil dilation for about 10 minutes. Went back to normal quickly. Swim hesitated to add more, and ruin his hydromorphone by being too "spaced out" from the DXM, a substance Swim never has a good experience with.

And lastly, for reference, check this out: Swim used hydromorphone 1 week, and dose was 8mg rectal. Pretty darn good, even with no euphoria. Swim used ONE WEEK LATER, exactly. Result? Swim did 8 and got a buzz. Swim dropped another 8, and still, lame. Swim wasted 16mg rectal with the same exact conditions. Swim even added 25mg promethazine. How can swim do 8 one week and be good, and next week, 16 feels like 4, maybe 6? Why?

This is the insane Mental tolerance Swim bitches about all day.

[medievil]

Ultra low dose naltrexone looks most promosing, regular doses of naltrexone arent neceserry and would probebly make swiy feel bad

[fiveleggedrat]

Swim certainly does not expect a naltrexone regiment to be pleasant. Swim expects at least some unpleasant side effects.

Swim does not, and will not, have the ability to do ULD anything. ULD requires super precise equipment, at least from my understanding. Besides, ULD does not seem to answer the problem. I believe I have read ULD only prolongs the inevitable. I believe ULD is also largely unproven. Any studies here would be great, I'm almost too busy at the moment to find any on my own.

I'd love for anyone else with theories or ideas on inducing receptor sensitivity to share or speculate.

Swim even considered MAOIs, and clearly, nothing in common between Swim's goal and combining an MAOI + opioid.

I know it's laughable, but Swim is trying to find a believable method that would run under $100 for experimentation. Hence, the leaning towards naltrexone. Only brand name and chem supply is expensive. Generic is much cheaper. About 1/10 as cheaper vs. other suppliers.

[Psych0naut]

Using an antagonist certainly helps to reset the receptor sensitivity to certain drugs. The Benzodiazepine antagonist Flumazenil is being used in research regarding protracted withdrawl syndrome. The Benzodiazepine protractred withdrawl syndrome is a syndrome where the Benzodiazepine receptors in the brain have been inverted, making them permanently useless, or for the duration of most of one's life. These inverted receptors can't be activated during normal brain situations either, because of them being inverted. This is where the Benzodiazepine antagonist Flumazenil comes into action. It's being used for just a single administration in it's normal dosage to these patients, and like magic, all the Benzodiazepines receptors return to their natural position, making the inverted situation undone, so they can be activated again. So in this situation, the specific antagonist can help to reduce permanent tolerance to a certain drug by a full hundred procent. I assume it would work the same for opioids, with Naloxone or maybe Naltrexone.

Reputation Comments on this post:

	Thank you very much for the info, much appreciated.
	good info

[Matt The Funk]

Originally Posted by Psych0naut

Using an antagonist certainly helps to reset the receptor sensitivity to certain drugs. The Benzodiazepine antagonist Flumazenil is being used in research regarding protracted withdrawl syndrome. The Benzodiazepine protractred withdrawl syndrome is a syndrome where the Benzodiazepine receptors in the brain have been inverted, making them permanently useless, or for the duration of most of one's life. These inverted receptors can't be activated during normal brain situations either, because of them being inverted. This is where the Benzodiazepine antagonist Flumazenil comes into action. It's being used for just a single administration in it's normal dosage to these patients, and like magic, all the Benzodiazepines receptors return to their natural position, making the inverted situation undone, so they can be activated again. So in this situation, the specific antagonist can help to reduce permanent tolerance to a certain drug by a full hundred procent. I assume it would work the same for opioids, with Naloxone or maybe Naltrexone.

How easy would it be for SWIM to obtain this in a medical setting? He feels as though his GABA receptors (or something of the sort) may be highly "out of whack" from benzo addiction and prescription use and would like to know if he should simply ask his psychiatrist about this?
(sorry if this is too off-topic)

[fiveleggedrat]

Not an issue. In a medical setting, it sounds likely difficult. In a self admin setting, from a chem supply company, possible. Then again, I do not know about the drug SwiPsychonaut mentioned; not much information seems to be out there on it.

Swims suggest getting the chem name and checking some supply houses. It's likely uncontrolled. Also, Swim is NOT encouraging illegal behavior or law breaking. Only consider self work if legal in one's area.

Swim is very gracious to SwiPsychonaut for that information; it has come in handy for Swim several times already. Swim has more ideas now and more info to back them up.

[fiveleggedrat]

Excellent information. Perhaps that is Swim's problem, inversion is taking place. Very fascinating, and I have had much difficulty finding information about all this in medical literature. It seems like this phenomenon is not common. Swim's friends certainly cannot understand.

Swim is also noticing marijuana having less effects on him as time passes. Could the same be taking place? This is, once again, not a tolerance thing. Also, could the same concept be used? CB antagonists? Or whatever the proper inverse of THC and similar is.

Swim is afraid to use ANY drugs anymore, worried his receptors will become tolerant and he will lose effects to everything.

I chose naltrexone primarily for the long halflife. Naloxone is active for, what, 2 hours? And I don't believe it works orally. Swim does not needle too. Naltrexone works orally, Swim knows. Swim figures the long activity would be better, comparing it to methadone for building a tolerance quicker than a short acting opioid.

fiveleggedrat added 1309 Minutes and 8 Seconds later...

Little question if anyone sees this thread anytime soon: Naltrexone or naloxone? Opinions, please Due to a poor researcher (that's Swim), might not be able to do naltrexone for a bit longer, and Swim is anxious to test this. Considering Naloxone, for cheapness and for the higher Mu affinity. Guess Swim would have to use a needle for the first time ever

[lorzapmail]

Swim says there is a lot of study in DXM stopping opioid tolerance. You might check into that. Just a thought.

[fiveleggedrat]

Swim has done lower dose DXM tests (under 100mg), but still has yet to go higher up with it. Honestly though, Swim doubts it would work. Why? Because Swim 1) Never noticed any difference combining DXM with opioids except feeling spacey and out there, and 2) Swim eats lots of Nitrous Oxide, and since that is also a NMDA antagonist like DXM, why try DXM?

I've studied the chemistry and how all NMDA antagonists work, and honestly, the most potential goes to MK801, with a little chance on ketamine. But honestly, I believe NMDA antagonists are not the answer.

I believe the answer is opioid antagonist dosing, or CCK hormone reducing substances.

[lorzapmail]

Swim respects your opinions greatly and you are a plus plus to these forums. Thanks. Tapering off is the best receipe. Swim is sorry so many cannot find the courage to do it.

[pote]

Hello, this is my first post.

It seems that Ultra-low-dose naltrexone potentiate and prevent from developing opioid tolerance. However, Ultra-low-dose means around some pico gram.This is difficult for a man without certain equipment to weigh out such a small amount. So, I'm considering to dilute with gross liquid.
Normal naltrexone tablet contains 50mg of itselt so it will be that the liquid made of the tablet should be stored long time.
Unfortunetly I do have little knowledge about chemistry.
I want to ask you how long the liquid keeps its potency and resolving by whether ethanol or water affects the longevity .
And also, any idea making it easy to make Ultra-low-dose naltrexone is welcome.

Sorry if my English in too broken.

[Matt The Funk]

Originally Posted by lorzapmail

Swim respects your opinions greatly and you are a plus plus to these forums. Thanks. Tapering off is the best receipe. Swim is sorry so many cannot find the courage to do it.

This thread is about re-gaining that opiate euphoria, that one cannot grasp, even after tapering off and not using for weeks. And that post above me ^^^ is a question I have, as SWIM has acquired a source for naltraxalone, and can most likely get as much as needed (depending on budget constrainsts, yay economy crash!).

[Cakes]

The Benzodiazepine protractred withdrawl syndrome is a syndrome where the Benzodiazepine receptors in the brain have been inverted...

this is saying that using an exact antagonist eliminates all withdrawl symptoms?

He feels as though his GABA receptors (or something of the sort) may be highly "out of whack" from benzo addiction and prescription use and would like to know if he should simply ask his psychiatrist about this?

In light of Psychonaut's post, it sounds like it might be a very good idea.

Little question if anyone sees this thread anytime soon: Naltrexone or naloxone? Opinions, please Due to a poor researcher (that's Swim), might not be able to do naltrexone for a bit longer, and Swim is anxious to test this.

if this part is true then it rather sounds as if SWIM may have answered his own question.

Can we imagine if those who are actually in pain and suffering and taking opioids for pain, and stuck on insane dose regiments could renew their tolerance like a opioid naive? That would be some amazing information.

amazing. absolutely.

[fiveleggedrat]

Swim has thought intently lately, and decided on naloxone, due to higher Mu receptor affinity and reduced price, and it should be easier to obtain.

[Psych0naut]

Originally Posted by fiveleggedrat

Excellent information. Perhaps that is Swim's problem, inversion is taking place. Very fascinating, and I have had much difficulty finding information about all this in medical literature. It seems like this phenomenon is not common. Swim's friends certainly cannot understand.

Swim is also noticing marijuana having less effects on him as time passes. Could the same be taking place? This is, once again, not a tolerance thing. Also, could the same concept be used? CB antagonists? Or whatever the proper inverse of THC and similar is.

Swim is afraid to use ANY drugs anymore, worried his receptors will become tolerant and he will lose effects to everything.

I chose naltrexone primarily for the long halflife. Naloxone is active for, what, 2 hours? And I don't believe it works orally. Swim does not needle too. Naltrexone works orally, Swim knows. Swim figures the long activity would be better, comparing it to methadone for building a tolerance quicker than a short acting opioid.

fiveleggedrat added 1309 Minutes and 8 Seconds later...

Little question if anyone sees this thread anytime soon: Naltrexone or naloxone? Opinions, please Due to a poor researcher (that's Swim), might not be able to do naltrexone for a bit longer, and Swim is anxious to test this. Considering Naloxone, for cheapness and for the higher Mu affinity. Guess Swim would have to use a needle for the first time ever

Protracted withdrawl syndrome isn't very common among former Benzodiazepine users, but it certainly isn't unique either, it happens with 10-15% who are withdrawing from Benzodiazepines. For more info about Flumazenil's use in treating the Benzodiazepine protracted withdrawal syndrome, have a look at this article. There are several CBD agonists which are used pharmaceutically, and available for retail. It might be possible obtaining those, although I doubt about it's use in resetting tolerance to cannabis. Tolerance to cannabis is created through a different mechanism.

By the way, for some reason, I was certainly able to find plenty of info on these subjects, just take a peek in the medical archives of sites like pubmed and medline, and you'll come up with dozens of documents. Having a pharmaceutical background does help though, as acces to most of these archives can only be bought. However, I found an abstract which was free to view. This is exactly what you're looking for, an abstract with a detailed experiment where Naloxone was used to reset opioid tolerance in opioid tolerance patients.

Originally Posted by Matt The Funk

How easy would it be for SWIM to obtain this in a medical setting? He feels as though his GABA receptors (or something of the sort) may be highly "out of whack" from benzo addiction and prescription use and would like to know if he should simply ask his psychiatrist about this?
(sorry if this is too off-topic)

Flumazenil is only available in ampoule form, for injection, and in ambulant settings. As far as I know, only hospitals have it in stock, doctors certainly don't, and I don't even know if ambulances have. Also, it's only been used experimentally for undoing invertion of the GABA-bz receptors, so asking your psychiatrist about this probaply won't have any use. It might be possible that talking to a sleep specialist in the hospital would yield something though.

Originally Posted by fiveleggedrat

Not an issue. In a medical setting, it sounds likely difficult. In a self admin setting, from a chem supply company, possible. Then again, I do not know about the drug SwiPsychonaut mentioned; not much information seems to be out there on it.

Swims suggest getting the chem name and checking some supply houses. It's likely uncontrolled. Also, Swim is NOT encouraging illegal behavior or law breaking. Only consider self work if legal in one's area.

Swim is very gracious to SwiPsychonaut for that information; it has come in handy for Swim several times already. Swim has more ideas now and more info to back them up.

You're welcome, it was my pleasure helping out!

Originally Posted by Cakes

this is saying that using an exact antagonist eliminates all withdrawl symptoms?

Yes, it eliminates all protracted withdrawl symptoms, as well as normal withdrawl symptoms after having stopped taking them. However, it should only be taken after having quit taking benzodiazepines, after having slowly tapered one's dose to nearly zero befores stopping completely. If Flumazenil is used to reduce tolerance to benzodiazepines when still using Benzodiazepines without having tapered, as well as being physically addicted to them, it will cause instant withdrawl.

Reputation Comments on this post:

	great info. thanks alot.
	Thanks for the article

[fiveleggedrat]

Yeah, Swim's biggest problem is that he often searches with the wrong terms and words. I love pubmed, and sites like that. I use the type of papers there as my main research; most people don't even peruse those types of things for info, so I often find things in them that aren't on here or erowid and such.

I came up with another theory regarding tolerance; I'll share the raw info on the substance/method here:

Proglumide acts as a cholecystokinin antagonist, which blocks both the CCK-A and CCK-B subtypes. It was used mainly in the treatment of stomach ulcers, although it has now been largely replaced by newer drugs for this application.

An interesting side effect of proglumide is that it enhances the analgesia produced by opioid drugs, and can prevent or even reverse the development of tolerance to opioid drugs This can make it a useful adjuvant treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs.

Proglumide has also been shown to act as a δ-opioid agonist, which may contribute to its analgesic effects.

Other CCK inhibitors show similar properties

The chronic administration of opiates, or spinal cord and other CNS injuries, elevates the level of Cholecystokinin (CCK) that is present. Such elevated levels exert an antagonistic effect on opioid activity resulting in significantly diminished analgesic effects. (Watkins et al. 1984; Xu et al. 1993 & 1994)
It is this rise in CCK levels that directly leads to the condition known as drug tolerance and the corresponding increase in its anti-opioid activity that requires the opiate user to use increasingly larger amounts to achieve the same effects.
This anti-opiate effect can be prevented or even reversed through the administration of CCK inhibitors such as proglumide. (Watkins et al. 1984)
Besides just interfering with the adverse action of CCK on opiate activity, proglumide is also known to augment the analgesic effect of opiates. Often this can provide a higher quality of analgesia for those patients who suffer from an incomplete response to pain medications.
Watkins & coworkers reported that proglumide reversed morphine tolerance and also 1) hastened the onset of analgesia, 2) increased the peak levels, and 3) prolonged the duration.
They suggested that not simply did this indicate that effective narcotic doses could be decreased but it also indicated that proglumide might be able to enhance the effects of other procedures, such as acupuncture, which involve endogenous opiates. (Watkins et al. 1984)

Check that shit out! Haha. Yeah, I probably won't explore this method, at least not first.

Thanks for that paper SwiyPsych0naut. You rock! It's a darn shame no one else even bothers helping me out with this. You'd think this would be of importance to someone other than Swim with his goofy broken receptors.

[holku]

Originally Posted by Psych0naut

By the way, for some reason, I was certainly able to find plenty of info on these subjects, just take a peek in the medical archives of sites like pubmed and medline, and you'll come up with dozens of documents. Having a pharmaceutical background does help though, as acces to most of these archives can only be bought. However, I found an abstract which was free to view. This is exactly what you're looking for, an abstract with a detailed experiment where Naloxone was used to reset opioid tolerance in opioid tolerance patients.

Wow I cant beleive there hasnt been more discussion of the above linked paper in this topic. It sounds like real differences in reversing opioid analgesia tolerance were made from the use of naloxone. The author mentions NMDA antagonists as being disappointing in their effeects in this area. I have also read the lit on ulktra low dose naltrexone and while it seemed to hold some promise if you look at the results they got it by no means eliminated tolerance or withdrawal (The authors of those studies tried hard to make it look like ULDN reversed tolerance to analgesia without bringing back any of the euphoric effects but the bulk of the evidence seemed to point in the opposite direction.)
Anyway i think this paper provides at least some evidence that this idea may work. The whole idea of ultra low dose naltrexone is about reversing changes in mu receptors and it could be that a brief high dose version has better effects. In the authors words:

The animal studies on tolerance and dependence and the failure to improve analgesia with NMDA antagonists led to my first naloxone experience in the 1990s. The results were profound. I have used this technique on a series of patients for refractory pain after serial trials of
opioids, adjuvants, procedures, and complementary techniques. These patients have tolerated the acute discomfort of withdrawal to obtain improved analgesia in less than 1 hour on approximately one third of the original opioid dose. Their sensitivity to titration was renewed. The opioid
receptors appear to have “reset.”

[Cakes]

If he does, then keep us appraised by all means.