The main problem with opioid analgesics is development of tolerance. Its inherently a problem for a few reasons. One, cost. two, tolerance to analgesic /therapeutic effects develops faster than tolerance to side effects of various kinds. For example, you could develop tolerance to the painkilling effects of oxy, but not the respiratory depression or constipation, thus making the toxic to therapeutic dose ratio way smaller.
There are two main types of medication that I can think of for attenuating the development of opioid tolerance. I believe
@Hip has already covered NMDA antagonists, but the other class of medication is opioid antagonists (at low doses).
(interestingly, kratom has all of these: opioid agonists, low doses of opioid antagonists, and nmda antagonists, all in it. If i wasn't so intolerant to the stimulant effects , I'd say its a perfect med for me)
I had read a little on ultra low dose naltrexone and low dose naltrexone for attenuating opioid tolerance and side effects, and i was prescribed it for pain/inflammation anyway, so I have decided to try and use it to help keep my tolerance reasonable. It seems very promising but I don't have any idea if there's a bunch of solid evidence on the dose range or schedule needed to totally reset tolerance.
[This](
https://www.ncbi.nlm.nih.gov/pubmed/20398374) study shows ultra low dose naltrexone attenuating morphine tolerance in rats. [This one](
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469510/) shows that adding uldn to oxycodone attenuates hyperalgesia that can occur in long term opioid use for chronic pain. There was a drug in development, oxytrex, that was a combination of oxy and ultra low dose naltrexone, to help attenuate side effects/tolerance to oxy, idk why it never came to market.
ULDN is a way lower dose range than LDN. It seems like LDN is not used in these studies bc it is more likely to either block some of the analgesia, or precipitate withdrawals, which could be nightmarish especially in chronic users. But since im not dependent on opioids, im more comfortable getting near that boundary, and it seems like the higher dose range of LDN might be more helpful in actually reversing tolerance, whereas uLDN only slightly attenuates it. I also read a now-deleted post from r/opiates in which someone said LDN, not uLDN, totally keeps them from gaining tolerance, but they had to start the LDN before the opioids and take it daily.
Also kratom users sometimes take stem and vein kratom, which has more of the opioid antagonists and less agonists, to reset their tolerance, and it seems to work well.
I had an experience with too high a dose of LDN (I believe it was 1.5 mg) taken too soon after my opioid dose, seemed to cause dysphoria and negative symptoms. But when taken after the opioid effects totally wear off, it has few side effects, so maybe I should be dosing higher? My dose is usually like .5 mg a day.
The theory is that it upregulates opioid receptor density in response to a partial blockade. this is part of my theory of why LDN works for some chronic pain patients, on its own, that it increases opioid recceptor density so ones sensitivity to ones own endorphins is way higher. From personal experience/anecdote in the past i felt like it took about five days of 1 to 1.5 mg doses of LDN before i was experiencing "getting extremely high off my own endorphins". I did experience some episodes of agitation, insomnia, and hypertension from the LDN, but I don't think thats normal, and the hypertension wasn't too bad.
So all in all, it seems like there are a few studies on uLDN for this purpose, promising but not a ton of evidence, a bunch of anecdotes, and very few studies on LDN for resetting tolerance (although there are studies on its use as an antiinflammatory and for chronic pain, like [this one](
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/) , from which we might infer it could help with tolerance?)
This was a little bit rambling but I guess I'd be interested in any form of evidence on this topic, anecdotal or published, since the existing evidence is so scant. Has anyone here had experience with uldn or LDN for tolerance? Has anyone found good posts on reddit or forums about it? or good studies?
