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Misc Medications that attenuate opioid tolerance

C

copium7777

Bluelighter
Joined
Apr 26, 2020
Messages
411
Opioids/opiates, specifically mu opioid agonists (occasionally delta) can be an important part of pain treatment and also help other me/cfs symptoms, such as insomnia or PEM. But they cause rapid tachyphylaxis (development of tolerance).

This thread will be a long one in which we discuss all of the medications that can lower tolerance or slow its development.

Anecdotal reports welcome, and i will provide science lirerature soon. But right now in a crash so going to start with a list of relevant chemicals without much citation:

Classes of drugs known or thought to help with this:
NMDA antagonists:
(Ketamine is one example)

Low dose opioid antagonists
(LDN is one example)

Kappa opioid agonists (low evidence)
(Ibogaine is one example)

Tlr4 antagonists/glial cell inhibitors
(Ibudilast is one example)


Heres the full list of specific substances:
Agmatine
Memantine
Ketamine
Dextromethorphan
Nitrous oxide (risk b12 deficiency)
High dose transdermal or iv magnesium

Xenon
Ibudilast
LDN
ULDN
Rhyncophylline (p sure this is opioid and nmda antagonist in cats claw and kratom, maybe spelled wrong)

Ibogaine
Salvia divinorum
Taurine
 
Ibogaine is probably one of the weirdest on this list bc it supposedly resets the opioid receptors somehow, not just dealing with psychological aspects of withdrawal only but also physical aspects of tolerance and dependence, but i cant find any info on which parts of its pharmacology are responsible for this. Is it the Kappa opioid agonism, in which case the safer salvinorin a should work? Is it the nmda antagonism in which case the safer ketamine or memantine should work?
 
Agmatine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923207/
"Agmatine is an endogenous amine derived from arginine that potentiates morphine analgesia and blocks symptoms of naloxone-precipitated morphine withdrawal in rats. In this study, we sought to determine whether treatment with agmatine during the development of morphine dependence inhibits the withdrawal symptoms and that the effect is mediated by cAMP system. Exposure of rats to morphine for 7 days resulted in marked naloxone-induced withdrawal symptoms and agmatine treatment along with morphine significantly decreasing the withdrawal symptoms. The levels of cAMP were markedly increased in morphine-treated rat brain slices when incubated with naloxone and this increase was significantly reduced in rats treated with morphine and agmatine. The induction of tyrosine hydroxylase after morphine exposure was also reduced in locus coeruleus when agmatine was administered along with morphine. We conclude that agmatine reduces the development of dependence to morphine and that this effect is probably mediated by the inhibition of cAMP signaling pathway during chronic morphine exposure."

This makes me wonder what cAMP is and if there are other inhibitors of it that may be useful. The following article: https://www.frontiersin.org/articles/10.3389/fimmu.2016.00123/full
Explains that this pathway has to do with cellualr signalling and inflammation and immunity and is dysregulated in autoimmune disorders.
 
LDN.
https://academic.oup.com/painmedicine/article/16/6/1239/2460766
This isnt about tolerance, but LDN is used in humans alongside morphine to prevent adverse effects, which is interesting, bc maybe it suggests something simialr to the literature on ibudilast, that the subtle antiinflammatory effect helps offset side effects without lowering analgesia.
As for tolerance: here we go, a rat study. https://pubmed.ncbi.nlm.nih.gov/16527399/
That said there are many more studies but i am going to try and stick with one for now, as im getting tired, others are free to fill in gaps. There are studies on LDN attenuating hyperalgesia, which is interesting as maybe attenuation of hyperalgesia is related to attenuation of tolerance
 
Can't believe that this topic doesn't get more attention here, maybe people read the title and think it's just about ibuprofen and antihistamines ... I reset tolerance before, with NMDA antagonists, it's not magic but the best pharmacology can offer to day. Unfortunately I relapsed into maintenance because in the country I lived before they illegalized all the dissos and getting a Rx for memantine was nearly impossible, and very expensive. Some times I faked one, but here now things are readily available and I'll do it again.. still unsure about what exactly to use, best would be O-PCM (long acting ketamine derivate) yet maybe only able to get K, and memantine. These two don't like each other, competing for the receptors and doing weird things with sensory input.

Scared to go the naltrexone route but maybe I'll titrate up, together with memantine. Might get ibogaine, seems it doesn't require flood doses but multiple days of lower doses work too..

Kratom fully substitutes for 120mg morphine, is even stronger than it in some sense. No clue about whether the partial agonism leads to partial recovery or if it just pushes full withdrawal 6 hours further. At least people eat kilos of this without problems, so a ton safer than overdosing loperamide (which I never did, but for some it's the only option)..
 
plumbus-nine said:
Can't believe that this topic doesn't get more attention here, maybe people read the title and think it's just about ibuprofen and antihistamines ... I reset tolerance before, with NMDA antagonists, it's not magic but the best pharmacology can offer to day. Unfortunately I relapsed into maintenance because in the country I lived before they illegalized all the dissos and getting a Rx for memantine was nearly impossible, and very expensive. Some times I faked one, but here now things are readily available and I'll do it again.. still unsure about what exactly to use, best would be O-PCM (long acting ketamine derivate) yet maybe only able to get K, and memantine. These two don't like each other, competing for the receptors and doing weird things with sensory input.
Click to expand...
I agree , there should be way more discussion on this... It seems promising. I haven't found any single magic bullet but honestly between tolerance breaks , LDN, and memantine and ketamine , and agmatine , I have been able to limit tolerance if not totally get rid of it. It's not double blinded study, so I don't know how much tolerance would grow without it , but still. And a lot of the stuff is relatively low risk, like ldn or even memantine at sub dissociative doses .. I'm just taking what my neurologist has me in, haven't tried higher doses yet.

Btw glial cell activation is apparently involved in tolerance so I think that ibudilast is worth a try. I'm going to be trying it a decent amount this month

Additionally, I think that both for tolerance but also for pain and depression many of the glycine site specific nmda antagonists, like kynurenine, glyx13, or xenon, merit consideration
 
I’ve found Ketamine can help some. Mainly for the week after, where my dosage can get lowered a bit. But there’s a bit of a rebound.

Zinc and proper Vit D supplements also seem to help me lower my dosage.

-GC
 
G_Chem said:
I’ve found Ketamine can help some. Mainly for the week after, where my dosage can get lowered a bit. But there’s a bit of a rebound.

Zinc and proper Vit D supplements also seem to help me lower my dosage.

-GC
Click to expand...
interesting. what would be the mechanism of zinc and vitamin d helping? I always wonder if its worth taking those for health in general . im always vitamin d deficient, but never seem to notice any big difference
 
www.ncbi.nlm.nih.gov

Vitamin D and Its Potential Interplay With Pain Signaling Pathways

About 50 million of the U.S. adult population suffer from chronic pain. It is a complex disease in its own right for which currently available analgesics have been deemed woefully inadequate since ~20% of the sufferers derive no benefit. Vitamin D, known ...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov

www.sciencedaily.com

Inadequate Vitamin D Levels Linked To High Use Of Narcotic Medication By Patients In Chronic Pain

New research shows a correlation between inadequate vitamin D levels and the amount of narcotic medication taken by patients who have chronic pain.
www.sciencedaily.com


Here’s some research, the jury seems to still be out on zinc but Vit d definitely helps.

I personally don’t take large amounts, supplement about 50-100% DV.

-GC
 
Dopamine agonists (more sources) - let's not forget that memantine is at least as strong at agonizing D2 as at antagonizing 5ht7 & NMDA.
The use of dopamine antagonists aka antipsychotics in withdrawal is imho based on a wrong assumption, that suppressing some jumps and shakes in rats means less intense withdrawal but they test against high doses of usually haloperidol, and what do such do? Cause extrapyramidal rigidness and dysphoric sedation. Better use neutral antihistaminergics like hydroxyzine. Also dopamine agonists (usually something like apomorphine) seem to induce the opposite even without opioids, make the rats try to climb out of their cage (escape, maybe?).

Dopamine agonist withdrawal symptoms:
include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings.
Click to expand...
Sounds familiar? :)

Edit: Dopamine agonists won't attenuate tolerance but withdrawal. When taking a pure dopa agonist together with morphine, most probably you'll get increased PAWS.

A strange one: Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area | Journal of Neuroscience (jneurosci.org)

Also we have an-jun-ning which reverses dopamine and DAT associated changes (anybody possibly knowing the ingredients or active chemicals?).

G_Chem said:
I’ve found Ketamine can help some. Mainly for the week after, where my dosage can get lowered a bit. But there’s a bit of a rebound.
Click to expand...
Do you have experiences with longer acting dissociatives to compare?

IME K is just too short acting, but I also was never able to hole or get anything sustained out of it, like antidepressant activity. More the opposite.
 
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plumbus-nine said:
Dopamine agonists (more sources) - let's not forget that memantine is at least as strong at agonizing D2 as at antagonizing 5ht7 & NMDA.
The use of dopamine antagonists aka antipsychotics in withdrawal is imho based on a wrong assumption, that suppressing some jumps and shakes in rats means less intense withdrawal but they test against high doses of usually haloperidol, and what do such do? Cause extrapyramidal rigidness and dysphoric sedation. Better use neutral antihistaminergics like hydroxyzine. Also dopamine agonists (usually something like apomorphine) seem to induce the opposite even without opioids, make the rats try to climb out of their cage (escape, maybe?).

A strange one: Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area | Journal of Neuroscience (jneurosci.org)

Also we have an-jun-ning which reverses dopamine and DAT associated changes (anybody possibly knowing the ingredients or active chemicals?).


Do you have experiences with longer acting dissociatives to compare?

IME K is just too short acting, but I also was never able to hole or get anything sustained out of it, like antidepressant activity. More the opposite.
Click to expand...

Unfortunately not, although I hope one day to change that... Maybe this summer I stumble into some pcp analogs if I’m lucky.

The only other longer lasting dissociative I’ve tried was DXM, but that ones really strange it’s in its own class, hard to compare to the others.

I feel the longer lasting ones may work better, but no frame of reference to say for sure.

-GC
 
I'm prescribed ketamine. There are at least human studies showing that it attenuated hyperalgesia, etc , which isn't the same as lowering tolerance but most things that lower tolerance attenuate hyperalgesia in rat studies , so maybe it does both. I'm more interested in glycine site nmda antagonists , both for this purpose and in general , however. they seem more promising. If xenon was cheaper it would be perfect
 
Just these days experiencing memantine again. I've been dealing with lingering addiction and PAWS from morphine (including runny nose, sweating), pregabalin (more sweating) and venlafaxine (replaced with fluoxetine, only partial cross tolerance, brain zaps) for weeks now without any real change. Introduced memantine four days ago, yesterday a dissociative dose (60mg), actually I expected high tolerance and thus nothing but it began to get pretty intense. Indeed like a cross between K and DXM. Yet what's really remarkable is that now it's all faded and relembered that now's been much too long without re-dosing or symptoms. Together with the dissociation went all the lingering stuff, the cravings, all. It's just gone. Had some morphine with me today for emergencies and no real thoughts in it.

Dissociatives work. Chemical magic.
 
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"The strong anti-inflammatory effect of melatonin is suggested to be involved in the attenuation of the pain associated with inflammation. Melatonin also increases the anti-nociceptive actions of opioids, such as morphine, and reverses their tolerance through regulating several cellular signaling pathways"

I haven't had much success with melatonin and reversing tolerance. I think I read it takes really big doses.
I do think melatonin can potentiate opioids, possibly to dangerous levels.

One time I even thought I might overdose after taking melatonin while on roughly 2mg of buprenorphine. My breathing became incredibly slow and shallow.


Anyways, the only thing I've really had success with was high dose DXM. And it only really resets tolerance for a day or two and then you're right back where you were.

So I'm definitely curious to hear what else might work, especially easily accessible things.
 
DeathIndustrial88 said:
"The strong anti-inflammatory effect of melatonin is suggested to be involved in the attenuation of the pain associated with inflammation. Melatonin also increases the anti-nociceptive actions of opioids, such as morphine, and reverses their tolerance through regulating several cellular signaling pathways"

I haven't had much success with melatonin and reversing tolerance. I think I read it takes really big doses.
I do think melatonin can potentiate opioids, possibly to dangerous levels.

One time I even thought I might overdose after taking melatonin while on roughly 2mg of buprenorphine. My breathing became incredibly slow and shallow.


Anyways, the only thing I've really had success with was high dose DXM. And it only really resets tolerance for a day or two and then you're right back where you were.

So I'm definitely curious to hear what else might work, especially easily accessible things.
Click to expand...
Very interesting. Gonna try some liposomal melatonin soon
 
So how high van u go with memantine. I dont trust Indian memantine but I've finally been prescribed it and gone up to 25 mg. Seems to help with tolerance a bit
 
G_Chem said:
I’ve found Ketamine can help some. Mainly for the week after, where my dosage can get lowered a bit. But there’s a bit of a rebound.

Zinc and proper Vit D supplements also seem to help me lower my dosage.

-GC
Click to expand...

Can't comment on ketamine, but MXE was awesome for negating withdrawal...
 
probably not, I don;t expect agmatine to do very much drug wise
 
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