Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated change

[tathra]

this is old news, but it looks like the post i made about it years ago has vanished, and its still interesting.

pubmed abstract

Opiates produce analgesia by activating mu opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. After chronic opiate exposure, an excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia. Ultra-low-dose opioid antagonist co-treatment blocks the excitatory effects of opiates in vitro, as well as opioid analgesic tolerance and dependence, as was demonstrated here with ultra-low-dose naloxone combined with morphine. While the molecular mechanism for the excitatory effects of opiates is unclear, a switch in the G protein coupling profile of the mu opioid receptor and adenylyl cyclase activation by Gbetagamma have both been suggested. Using CNS regions from rats chronically treated with vehicle, morphine, morphine+ultra-low-dose naloxone or ultra-low-dose naloxone alone, we examined whether altered mu opioid receptor coupling to G proteins or adenylyl cyclase activation by Gbetagamma occurs after chronic opioid treatment. In morphine-naïve rats, mu opioid receptors coupled to Go in striatum and to both Gi and Go in periaqueductal gray and spinal cord. Although chronic morphine decreased Gi/o coupling by mu opioid receptors, a pronounced coupling to Gs emerged coincident with a Gbetagamma interaction with adenylyl cyclase types II and IV. Co-treatment with ultra-low-dose naloxone attenuated both the chronic morphine-induced Gs coupling and the Gbetagamma signaling to adenylyl cyclase, while increasing Gi/o coupling toward or beyond vehicle control levels. These findings provide a molecular mechanism underpinning opioid tolerance and dependence and their attenuation by ultra-low-dose opioid antagonists.

 

[negrogesic]

Yes, yes...

 

[tathra]

this abstract suggests that, not only can effects be potentiated and dependency prevented, but also at least some of the "damage" from long-term opioid dependency could be reversed (re-binding G proteins to their receptors). at least one article i stumbled across said that naloxone was an opioid reverse agonist, rather than opioid antagonist. if thats the case, naloxone could have significant long-term effects, although its impossible to speculate, beyond simply reversing opioid-induced damage and preventing dependency.

 

[MeDieViL]

Every few months someones posts this but there are barely ppl that try this... I dont have any acces to opiates so i cant.

 

[negrogesic]

I've tried, but with not enough precision and objectivity. In other words, it didn't work.

 

[sebukab]

http://drgimbarzevsky.com/Naltrexone/Low_Dose_Naltrexone_Observations1.html

The most interesting effects of naltrexone were when it was used alone. Thus far I have one patient in whom naltrexone was effective in this manner and while the results may be secondary to the placebo effect, I've seen enough ULDNTX effects to think otherwise. This 80 year old woman had severe spinal stenosis and eventually developed continuous pain in her low back and legs. She sought me out because of my tolerance for "alternative" treatments and was reluctant to take any opiates or COX-2 anti-inflammatories which I initially suggested to her. When I saw her, my interest in ULDNTX was near its peak and I suggested it to her. Somewhat to my suprise, she was very receptive to the idea and I started her on 1 microgram of Naltrexone 3 times daily with instructions to increase the dose by a factor of two daily until she got relief of pain. I gave her some 1 mg Naltreone capsules which she dissolved in juice and diluted appropriately to get the necessary doses. When I next saw her, she was up to 10 micrograms 3 times daily and her pain was gone. She was ecstatic that she finally had relief from her unremitting spinal stenosis pain.

If the result was due to placebo effect, then one would expect pain relief at the 1 microgram dose. This dose did absolutely nothing for her and once she hit 10 micrograms good analgesia resulted. Now the placebo effect is thought to be mediated by endorphins as placebo analgesia can be blocked with intravenous naloxone and it could be that my action of giving her the naltrexone resulted in increased endorphin release and the ULDNTX potentiated these endorphin effects. She continued to use the naltrexone with good results until she finally had surgery for her spinal stenosis and thereafter needed no further exogenous analgesics.

I'd like to try it alone and then go exercise just out of curiosity.

 

[shibireru]

Questions:

1) Is there reason to believe that naltrexone would be a good substitute? If indeed it's the case that while naltrexone is simply an antagonist naloxone is an inverse agonist, then naltrexone may not produce the same effect and, therefore, they may not be interchangeable. Either of them might also have affinities for another/other receptor(s) as well. Thoughts?

2) Assuming that naltrexone would produce the described effect, is there reason to believe that only ultra-low doses would suffice, or would larger doses give rise to even more pronounced coupling of mu-opioid receptor proteins to Gi-HTGPs and suppression of Gs-HTGP-coupling?

I happen to have a prescription for naltrexone on hand: 60 50mg naltrexone tablets. I was planning to use them to cure my anhedonia. Does anyone have any recommendations as to what I should do with these to achieve the most desirable results? (I also happen to have hydrocodone on hand as well, if that's useful or relevant information.)

/This study may have elucidated the real reason why hydrocodone causes dysphoria for me now rather than euphoria. I had come to the conclusion that this was due to mu-opioid receptor and d2 receptor downregulation, and kappa-opioid receptor upregulation, and while that may be a component of the issue, it seems that it's perhaps more likely that my MORs have changed in such a way as to strongly facilitate Gs coupling. I have been taking higher doses of Memantine before bed lately and have noticed positive changes in affect. Is this fact consistent with the above theory? (Memantine decreases the neuronal excitation, of course.)

 

[tathra]

^ 1. its only recently that i found out that naloxone is a reverse agonist, rather than antagonist. a reverse agonist works the exact opposite of an agonist, so physiological adaptations to consistent use should hypothetically also be opposite of full agonists. an antagonist would have no such effects, as it merely blocks the receptors from being activated. this idea has facinated the hell out of me lately, because its quite possible that all of the changes brought about my opioid dependency could be completely reversed, possibly to the point where you could be back to your pre-dependency state, or hell, it might be interesting to see what might occur once a person has developed a "dependency" from using naloxone for years...

2. hypothetically, yes. if reverse agonists lead to the exact opposite results as full agonists, then more should lead to larger, faster changes. if it turns out to work this way, it would have broad implications in drug treatment and such, because its possible that it could work like this for other receptors and drug-related damage.

more research is needed before anything definitive can be said though.

 

[tacodude]

What does would one start at for this. What's best ROA? Nasal, oral, sublingual, iv, or im? I have easy access to naloxone. I know someone vending low dose naltrexone for opiate potentiation with 30 mcg to call a ceiling before w/d could set in.

Would naloxone be similar in dosing?
Can sometime list Mcg/kg recommendations for different ROA?
How frequent should I dose each ROA?

I really appreciate answers ASAP. Thank you

 

[adder]

I don't understand why we should treat naloxone as an inverse agonist and naltrexone as a silent antagonist. Has there been any research done that would confirm that naloxone's and naltrexone's intrinsic activity differ so much that one activates MOP receptors in reverse and the other one simply binds and does nothing but blocking receptors from binding opioids with lower affinity? As I imagine it, N-allyl is more inhibitive than N-cyclopropyl or N-cyclobutyl because electrons are more densely packed together and thus perhaps this partial negative charge disrupts some binding between residues in the receptor. N-CPM does this to a lesser extent and N-CBM does this to an even lesser extent because the partial negative charge is weaker due to electrons being more dispersed but the nature of this interaction seems to be the same in all three cases. So how could N-allyl cause the receptors to work in reverse in a manner that N-CPM couldn't? Is the difference in intrinsic activity between naloxone and naltrexone really so big? I would even risk saying that nalrexone with its N-CPM group might be an ultra weak partial agonist/near silent antagonist with an efficacy like 5% or less which is so little that it de facto decreases opioidergic activity if you compare it with a full agonist like morphine.

http://www.ncbi.nlm.nih.gov/pubmed/11413242

 

[serotonin2A]

^I think there is reason to believe that both naloxone and naltrexone are inverse agonists, as shown by the link you posted.

I think that neutral antagonists are much less common than most people believe. Because of how the process of receptor binding works, it is much more likely that a ligand will either be an agonist or an inverse agonist. Neutral antagonists have to be able to bind to the entire range of conformational states of the receptor. Plus, the possibility of agonist trafficking makes it even less likely that an antagonist will be completely neutral.

 

[cdin]

I would also appreciate any information from someone with experience. I've got a load of naloxone around, if i could have been using it to help me, instead of just revive me, it would be nice to know how to go about it.

 

[tathra]

so i've FINALLY gotten around to trying this experiment, and i must say, i am blown away by the results. (i'm shocked this thread is still open too)

so a little background. lately i've been easily shooting a half g of rather good heroin a day, shooting a point every couple hours because if i have it in my possession, i crave it bad, like every 3-4 hrs i need another point shot.

i finally get around to adding ~8-10 micrograms of naloxone to ~70mg of my stuff (i already know to expect increased potency) and it gets me so high that i can't even function because i'm too nauseous. so easily 2x or more increase in potency. not only that, but my usual cravings went away; i could easily make it 6+ hours before i wanted another shot, and in fact didn't even want to do another shot. after each shot i could reduce the dose further and had even less cravings each time (and still got high as fuck). i was able to make a half g last 2-3 days rather than blowing through it in less than a day.

this trial only ran for a few days, so i can't really say how it might help with easing withdrawals or preventing dependency, but increased potency, reduced tolerance, and reduced cravings are confirmed. some help gathering data would be appreciated the magic dose seems to be ~10 micrograms of naloxone (somewhere between 5-15 ug).

 

[Weltmeister]

If this really works it will probably lead to naloxone/naltrexone being more tightly regulated. I have no doubt that authorities will label this as "abuse"