Pharmacology - Opioid Tolerance: Reversing Receptor Sensitivity

[kimtp29]

SWIM finally gets what you're saying, Richard. But swim swears---Swim had euphoria for 2 years on opiates---straight--same low dosage---everything, then it all went away......(bye, bye, birdie...) Guess swim was lucky. Sounds like lucky than most---sure as hell beat the freaking pain, oh my---the freaking pain!!!
Swim ain't so lucky---anymore!

Reputation Comments on this post:

YES! that's it. you got it! too bad we can't just force others to listen up!

[Jasim]

No clue how to increase opioid receptor sensitivity. As a side note, it may not just be desensitization, but could also include receptor pruning.

I have read of chronic pain causing nociceptor sensitization. Which means pain would be worse. There might be a relationship here between opioid use. Not sure. Does anyone know more about this? If that's the case then you'll also need to consider how to desensitize nociceptors.
Do you experience any pain when not taking opioids?

Honestly, I think the most likely scenario (and I say this from swim's own experiences) is that swiy has induced metabolism of the opiates swiy is using. Meaning the opiates aren't even making it into the brain. You should be able to find out what specific cytochrome isozymes are metabolizing the opiates. Avoid anything that induces them. And try taking the opiate concurrently with a competing substrate for the particular isozyme. Swim has had a lot of success with this.

Swim has used tramadol for several years now. Just getting back on it after a couple months of abstaining. Had to have a friend hold on to swims stash once because swim was taking around 500mg per day with little effect. After being off for a couple of months, effects came back. Swim just made sure that swim wasn't taking anything else that might induce metabolism or affect same receptors.

Swim has chronic pain and is very interested in this topic. Please let us all know how it works out.

Has swiy tried Kratom? Swim has some coming in the mail. Never tried it before. Read that it has similar euphoria to opiates.

[tyrus568]

Somehow SWIM lost his reply after typing it out so he'll try again.

He just wanted to reiterate what Jasim said above. Perhaps SWIY's body is increasing its metabolic rate specifically with opiates, so less is getting to the brain? He guesses this is possible even without abuse, but just prolonged use, although it certainly happened to him with DXM.

Downregulation of receptors is certainly one possibility.

More efficient metabolism has happened in SWIM's experience, albeit with twelve years of DXM abuse. He used to experience the full gamut of effects. Now, even going being clean for months, side effects are minimal; he can down 300-450mg DXM and get euphoria and slurred speech, but few other, mostly unwanted, effects (lots and lots of fatigue in the days afterwards, though). The DXM will affect him for three, four hours at most now. He wonders if he suffers from PAWS (a more-or-less persistant state of withdrawal associated mainly with benzos, alcohol and opiate abuse) or if he's just generally an addict, dealing with cravings day after day. Now he takes opiates twice a week or so, sometimes less, sometimes more, and rides a mood roller-coaster.

SWIM apologizes to those in chronic pain for having to read this - it makes him feel guilty getting into the situation he's in only because of depression/emotional imbalances and wanting to get high all the time, when there are unfortunates out there who genuinely need analgesic treatment.

[kimtp29]

Hell, don't feel guilty---depression can be just as worse! well, not really! Have that too, but gave up the meds, because read they were stopping opiates from working?
Tyrus, how would one degregulate receptors?

Thanks for any info!

[dyingtomorrow]

SWIM hates suboxone, but he was able to go from 8 mgs + shooting 4 mgs on the first day, down to 1 mg within a little over a week with the first day being the only uncomfortable one (partially from shooting the 4 mgs SWIM imagines). He did a nickle bag of dope and got a rush and high after that. One good thing about suboxone is it is easy to lower your tolerance with.

[tyrus568]

Cellular responses to a given substance become minimized over time, that's a fact. It's how people become immune to any given poison - lots of small exposures over the long term. SWIM thinks that after enough usage (different for everybody I imagine) the user crosses an undefined threshold and "you can't go back again". If one were to quit and stay clean for years in this condition then even when they used again it wouldn't be as if it were for the first time... the body will still remember how to efficiently process the substance, for less effect.

Basically what SWIM is trying to say is that the body learns from experience just as the mind does - and both do remember that experience over the long term. SWIY can only be a virgin once.

These increases in processing are so gradually incremental it would be like watching the hour hand on a clock.

SWIM also has no idea what he's talking about; he's not a professional and doesn't have professional knowledge on the subject. As for "fixing" this, SWIM only knows that over time the body will attempt to return to normal, but SWIM's not aware of any other solutions.

Reputation Comments on this post:

Good post

[Jasim]

Good post Tyrus. Swim has spent a LOT of time studying metabolism and tolerance and experimenting trying to find ways of combating tolerance. Swiy is correct in saying that there is no permanent or one single solution. Though there are ways of 'tricking' the body temporarily to reduce tolerance a bit.

[fiveleggedrat]

Makes sense to me.

Still, Swim will always be interested in ways to reverse to having the closest to no tolerance possible.

Swim definately does feel like less passes the BBB, and that can account for physical effects remaining in greater amounts than mental effects.

Swim does think it's largely hopeless though.

[Jasim]

Thanks for reposting that holku, I must have skimmed over it the first time. I have access to quite a few journal databases and was able to get a pdf copy of Enhanced Analgesia with Opioid Antagonist Administration. It's a very interesting read, and less than 3 pages long. I'm a bit new to the forum and don't know how to post it...sorry.
If someone could give me some directions, I will post it and can probably get quite a few other articles of interest if anyone wants. Freedom of Information!!!

[pixplzthx]

SWIM actually printed the aforementioned study and gave it to the primary care physician. Also there is another report that has twenty-three patients in the sample pool using buperenorphine.

In the first one, all three experienced marked decreases in the required amount of opiates needed for analgesia. In the second one 21 of 23 should decreases in the amounts of medicines.

Wonderfully interesting and SWIMs doctor was surprised as well.

Reputation Comments on this post:

great idea!

[kimtp29]

SWIM saw this quote on another forum and wanted to post it---it talks about the CCK protein, which honestly, SWIM's not sure what it means, but it seems to get rid of the CCK protein that blocks opiates, but here goes....SWIM can't wait to get SWIM's and am praying it will work. Not that expensive

Helping one get through WDs is one thing, but proglumide is more than that. It actually works by removing one of the main factors involved in the buildup of tolerance.... the CCK protein.

Basically CCK works by "getting in the way" of opiates. Let's say you need 200 mg of oxy or whatever to get a good high. Get rid of the excess CCK and you might only need 80 or 100 mg to do the same job. Nice!

Reputation Comments on this post:

Great Info! I never knew that about CCK

[Jasim]

Originally Posted by kimtp29

SWIM saw this quote on another forum and wanted to post it---it talks about the CCK protein, which honestly, SWIM's not sure what it means, but it seems to get rid of the CCK protein that blocks opiates, but here goes....SWIM can't wait to get SWIM's and am praying it will work. Not that expensive

Helping one get through WDs is one thing, but proglumide is more than that. It actually works by removing one of the main factors involved in the buildup of tolerance.... the CCK protein.

Basically CCK works by "getting in the way" of opiates. Let's say you need 200 mg of oxy or whatever to get a good high. Get rid of the excess CCK and you might only need 80 or 100 mg to do the same job. Nice!

Wow! Thanks for the great post! I always thought of CCK as being involved in digestion. Never knew there was any relationship to neurochem or pharmacology beyond that. I need to do some studying.

[kimtp29]

This IDIOT DRUG-ADDICT "friend" I had (sorry, I didn't like it when she stole swim's pain meds and put me through w/d's) has been a drug addict since she was 19. It doesn't matter how long she stops or starts---she gets euphoria EVERY time! What does she have that some of us don't?

[imyourlittlebare]

cck is a hormone involved in opiate tolerance along with hunger and stuff. But there are other factors that play a role. Theres no evidence to support this but perhaps exercise could enhance opiates effects? There was a poster at the society for neuroscience meeting this year where regular exercise increased the expression of mu receptors. But I am deviating. CCK, oxytocin, transporters of certain neurotransmitters such as SERT, DAT and others may play a role along with NMDA receptors, AMPA receptors, and GABA-B. It could be changes in brain areas associated with addiction and pain relief. If there was a simple answer to reversing tolerance they would have an answer. Its a number of different chemical processes that occur which cause changes in protein expression. At this SFN conference, I mean some of the things they were talking about, jesus christ. Way over my head.

Another point is for anyone just tuning in. Euphoria and Analgesia are different things. If you get analgesia back that is not the same as being able to get high. Read my earlier post. A chemical in kratom is 25 times more potent than morphine. So is buprenorphine the active ingredient in suboxone. Doesnt get you as high.

[Jasim]

Originally Posted by imyourlittlebare

A chemical in kratom is 25 times more potent than morphine.

Not trying to be a stickler, just want to have swim's info correct. In kratom 7-hydroxymitragynine is the most potent at 17 times the potency of morphine. If swiy has a source stating otherwise, would swiy please share. Thanks.

[imyourlittlebare]

Originally Posted by Jasim

Not trying to be a stickler, just want to have swim's info correct. In kratom 7-hydroxymitragynine is the most potent at 17 times the potency of morphine. If swiy has a source stating otherwise, would swiy please share. Thanks.

i meant just buprenorphine. Sorry bud. Theres alot of variance in what has been said in strength of kratom alkaloids. Swims about to use rats here and find out for his fricken self, swim has a hot plate here and sum rats. anyway, I found 13, ive seen much higher estimates. so its disputed but you did catch me.

Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa

[Jasim]

Buprenorphine is a semi-synthetic thebaine derivative, it is not in kratom. But you are correct on the potency.\]

Thanks for the link. Lots of useful information there.

[fiveleggedrat]

Potency is only an estimate generally, and once you put that drug in a person, all the numbers are out the window.

Anywho, an update guys.

Since Swim obtained a large amount of morphine and oxy, about 2/3 of the oxy was eaten (out of 1/2g total) and about 1.5g of morphine in about 2 weeks, on and off to avoid addiction.

Swim used for a few 50 hour marathons, redosing every few hours to stay nice and high.

Now, the high Swim gets from 80mg oxycodone is like that of 5-10mg on the opioid naive, except that they get a much enjoyable euphoric high.



So, anyways, officially, Swim has given up on opioids. Swim has dosed about once or twice in the past 2 weeks (for Swim to have so much morphine and not eat it all, that numbers are significant. In the past, Swim would have done it ALL in about a week's time)

Swim no longer wishes to torture himself with this cruel quest. It is seriously stressful sitting around thinking of the high he used to get. Opioids were the best experience of his ENTIRE LIFE, and now they mock him. That's ok. Swim's over them. It's a shame.

I will continue to study them and these problems, but I have shifted my focus to cannabinoids and marijuana. I want to explore the receptor systems in the brain. I also have some really fascinating ideas on how to potentiate marijuana and other cannabinoids.

[avidigital1]

swims been on and off naltrexone for 5 years...he says that staying off opiodes completely for 2 weeks and taking naltrexone for 2 weeks would have the same effect...the naltrexone only acts as an antogonist, it does not make your body more sensative to opiates, rather just blocks its transmision...DO NOT take naltrexone if your currently using or if youve used within 3 days...after 3 days your pretty much safe, maybe mild withdrawls...but if your like swim, youve had a hard time staying off opiates for more than a week so the naltrexone can help you do that...the longer your clean the stronger the high will be when you get back to it but there is a point of dimishing returns, i would say after 3 weeks you could get that same ol feeling again or close to it....remember, your brain has already developed the pathways for this pleasure and for the rest of your life those pathways will exist and part of the initial highs you experience is your brain developing those pathways so there will always be an element missing no matter how long youve been clean once you hit again

[Jasim]

Originally Posted by avidigital1

swims been on and off naltrexone for 5 years...he says that staying off opiodes completely for 2 weeks and taking naltrexone for 2 weeks would have the same effect...the naltrexone only acts as an antogonist, it does not make your body more sensative to opiates, rather just blocks its transmision...DO NOT take naltrexone if your currently using or if youve used within 3 days...after 3 days your pretty much safe, maybe mild withdrawls...but if your like swim, youve had a hard time staying off opiates for more than a week so the naltrexone can help you do that...the longer your clean the stronger the high will be when you get back to it but there is a point of dimishing returns, i would say after 3 weeks you could get that same ol feeling again or close to it....remember, your brain has already developed the pathways for this pleasure and for the rest of your life those pathways will exist and part of the initial highs you experience is your brain developing those pathways so there will always be an element missing no matter how long youve been clean once you hit again

There are studies suggesting that use of naloxone can reduce opiate tolerance. I can provide some more information and sources when I have some more free time.

[fiveleggedrat]

So Swim has not had an opioid experience for at least a month or two, if not more, this week. Swim recently came into 3gm morphine and 500mg oxycodone so he has good ability to test various admin methods to produce the closest possible to euphoria.

For Swim, the first 50mg rectal did the most. The 50mg rectal redose 40min later was mild at best. Two other 50mg rectal redoses, with a 40mg oxycodone oral dose did produce some powerful nodding at it's peak, but no true euphoria was noted. However, a good, clean social feeling and exceptionally good mood were both noted. All doses were divided evenly between 11:00am and 2:00Pm of the same day.

800mg "mids" quality marijuana smoked (usually smokes daily;took a 90 hour break, smoked14 hours ago) at around 12:00am midnight, 10 hours since any opioids, a strong nodding and mild combination of marijuana euphoria and what was almost opioid euphoria. Social feeling was also present. A warm glow also was felt, which is rare, and itching was brought back from not present. These results are remarkable because it is the first time out of around 20 experiences previously where marijuana and opioids were combined but the experience was poor or a complete waste.

Swim also did consume Tums (Calcium Carbonate, 1000mg) and Rabeprazole Sodium (a PPI) taken about an hour before the oral oxycodone dosage.

Swim would not reccommend dosages anywhere near Swim's, he believes they would definately be unsafe for most with anything but a high tolerance.

Swim also has done Subcutanous morphine sulfate of 50mg with 100mg dosed rectal 1.5 hours earlier, and the SC had only mild effects, oddly to Swim.

All dosages present caused pupil pinning, moderate to mildly strong physical sedation, a good sense of analgesia, and ringing in the ears was present as well/hearing difficulty, a temporary condition Swim usually gets during opioids.

All in all, pretty decent experiences, even though dosages ended up going MUCH higher than Swim predicted they would.

Oxycodone produces a more euphoric, social, energetic, clean high.

Morphines produces a more warm, soft, nodding, relaxed, body heavy high.