Ultra low dose Naltrexone for tolerance (question)

[Charles Ferdinand]

So, I don't know much about opioids, just the basics (never even tried any other than tramadol) as I'm more a GABAergic guy.
I recently saw this article from Jonathan Ott, which someone here in bluelight posted here (can't remember whom or where), I remember his astonishment as he said he was amazed how not many people knew about this (don't know if that's the case though), it's titled:
"Obviation of Opioid Withdrawal Syndrome by Concomitant Administration of Naltrexone in Microgram Doses:
Two Psychonautic Bioassays"

Here's the link:
http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=7716&DocPartID=6829

And my question would be: how would this could possibly work??? I only get that naltrexone is not an inverse agonist, such as naloxone, so.. how? Could this be done with, let's say, benzos and an equivalent antagonist? Not an inverse agonist as flumazenil (I think).
I personally find this very fascinating.
[Sorry I'm not sure if this belongs to ADD, thought this was pretty simple for a knowledgeable opioid user bluelighter, please relocate if appropiate]
Regards!

 

[Mass08]

Cant answer your question but holy SHIT that is interesting man. I have 50mg pills of naltrexone so what do I have to do shave off 1/1000th of the weight to have a .5mcg dose? Lol..That would literally be nothing

 

[Charles Ferdinand]

I know right? I actually have no interest in it as I never touch opiates, but the implications for the average user are GREAT, plus it's just plain fascinating.
Why not dissolving it in water, kind of like a benzo water titration? Don't those pill's usually have binders and other shit in them?

 

[Mass08]

Definitely. Tons of binders and fillers. 50mg pill probably weighs ~400mg

 

[Swimmingdancer]

I have 50mg pills of naltrexone so what do I have to do shave off 1/1000th of the weight to have a .5mcg dose? Lol..That would literally be nothing

The way many people do it is by making a proper solution in water.

I have seen some case reports of people using, say 1-2mcg twice a day and finding it effective. I think dosing would depend on the person, the opioid they are taking and how much. One could start with a very tiny dose and gradually increase it.

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Moving this to Other Drugs as it's not really a basic question.

BDD -> OD

 

[Mass08]

Would the naltrexone dissolve equally throughout the liter? It has to right?

 

[Charles Ferdinand]

Apparently it does:
http://www.dr-bob.org/babble/20100103/msgs/932467.html

It says it has to "be dissolved in distiled water..."

One precaution to the above. After initially dissolving the tablet in the specified amount of distilled water and shake it thoroughly to insure the Naltrexone is fully dissolved and disperesed in the solution, do NOT shake it anymore (as in prior to using it). The sediment - particles in the solution when you shake it - are binder substance compounds and several manufacturers use a dietary form of iron powder as one of their binding agent components and that can adversely affect Lupus patients and others with similarly related disorders.

 

[Bruce Haze]

This is amazing, yet hard to believe, as I think all of you will agree. I want to believe this is true, but I would like to hear more moderators opinions before I let it be set in stone

 

[Charles Ferdinand]

Well, there's already a drug that is (or was) being developed, which combined oxycodone with naltrexone, precisely to combat tolerance, Oxytrex:
http://en.wikipedia.org/wiki/Oxytrex

 

[Swimmingdancer]

This is amazing, yet hard to believe, as I think all of you will agree. I want to believe this is true, but I would like to hear more moderators opinions before I let it be set in stone

There is actually a ton of info online if you look up "ultra low dose naltrexone". And there are other threads on the topic here on BL.

 

[Charles Ferdinand]

I've searched for ultra low dose naltrexone, but couldn't find anything about how it works to eliminate withdrawal
In wikipedia (my first result on google) I understood from what I read that it was some kind of fringe theory some guys used to promote naltrexone as some magic treatment for autoinmune diseases.
It didn't say much about it's use for opiates, and nothing at all about how it would work.
In that article from erowid, Mr Ott explained something very simple about how it worked, but tbh I didn't understand much about its precise mechanism.

 

[Charles Ferdinand]

The way many people do it is by making a proper solution in water.

I have seen some case reports of people using, say 1-2mcg twice a day and finding it effective. I think dosing would depend on the person, the opioid they are taking and how much. One could start with a very tiny dose and gradually increase it.

---

Moving this to Other Drugs as it's not really a basic question.

BDD -> OD

Well, Mr Ott used .5 mcg for 800mg of codeine, and since every 100 mg of codeine are equivalent to 10 of morphine, then he used .5mcg of naltrexone for 80mg of morphine.
Or .0625mcg of naltrexone per every 10mg of morphine.
But I don't know shit about opioids and just did that in with windows calc and wikipedia's opioid equivalency table.

 

[Swimmingdancer]

I've searched for ultra low dose naltrexone, but couldn't find anything about how it works to eliminate withdrawal

Sorry, I should have specified more specific search terms to narrow things down. I assumed you were talking about naltrexone being used to reduce tolerance, as in the title of this thread (which there is a lot of easy-to-find info on).

I don't think it generally "eliminates" withdrawal exactly, I think there is some promising research and case reports, but IMO the jury is still out on how well this would actually work as far as reducing withdrawal symptoms to a substantial degree for the average human who is already dependent on opioids. A the right dose it doesn't seem like it has any real adverse effects though. (Aside from perhaps the possibility of making opioids less addictive/enjoyable, if one would consider that an adverse effect - I wouldn't as long as it didn't make me depressed etc). If I'd had some naltrexone on hand I think I would have tried it, or might still consider it trying it now even though I am past the acute withdrawal stage. [EDIT: I think I will!]

Here is some info (*note that "significant" just means statistically significant):

IN HUMANS:

Although current treatments for opioid detoxification are not always effective, medical detoxification remains a required step before long-term interventions. The use of opioid antagonist medications to improve detoxification has produced inconsistent results. Very low dose naltrexone (VLNTX) was recently found to reduce opioid tolerance and dependence in animal and clinical studies. We decided to evaluate safety and efficacy of VLNTX adjunct to methadone in reducing withdrawal during detoxification. In a multi-center, double-blind, randomized study at community treatment programs, where most detoxifications are performed, 174 opioid-dependent subjects received NTX 0.125 mg, 0.250 mg or placebo daily for 6 days, together with methadone in tapering doses. VLNTX-treated individuals reported attenuated withdrawal symptoms [F = 7.24 (2,170); P = 0.001] and reduced craving [F = 3.73 (2,107); P = 0.03]. Treatment effects were more pronounced at discharge and were not accompanied by a significantly higher retention rate. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Further studies should explore the use of VLNTX, combined with full and partial opioid agonist medications, in detoxification and long-term treatment of opioid dependence.
From: Very low dose naltrexone addition in opioid detoxification: a randomized, controlled trial

^This is interesting as they used much higher doses than others, 125-250mcg.

Physical dependence or withdrawal is an expected effect of prolonged opioid therapy. Oxytrex (oxycodone + ultralow-dose naltrexone) is an investigational drug shown here to minimize physical dependence while providing strong analgesia with twice-daily dosing. In this 719-patient, double-blind, placebo- and active-controlled Phase III clinical trial in chronic low back pain, patients were randomized to receive placebo, oxycodone qid, or oxytrex qid or bid. Each oxytrex tablet contains 1 μg naltrexone; oxytrex bid and qid treatments provide 2 and 4 μg naltrexone/day, respectively. Following a washout, patients with pain ≥5 on a 0-10 scale were dose-escalated weekly from 10 up to 80 mg/day until reaching adequate pain relief (≤2) or a tolerable level of side effects. Following titration, the dose was fixed for 12 weeks. Active treatment groups attained comparable analgesia despite significantly lower drug use (P = .03) by oxytrex patients. Patients taking oxytrex bid reported 55% less physical dependence than patients on oxycodone (P = .01) by the Short Opiate Withdrawal Scale 24 h after treatment cessation.
From: Oxytrex Minimizes Physical Dependence While Providing Effective Analgesia: A Randomized Controlled Trial in Low Back Pain

Not sure if they're referring to humans or animals or both here:

In standard doses, opioid antagonists such as naloxone or naltrexone block the effects of morphine and other opiates. Khem Jhamandas, in the Department of Pharmacology and Toxicology, has demonstrated that ultra-low doses of opiate antagonists enhance the analgesic properties of morphine, and reduce the development of analgesic tolerance to these drugs. We demonstrated that these effects were not confined to analgesia: ultra low dose naltrexone also extended the duration of morphine's rewarding effect in the conditioned place preference paradigm. While this initial work on reward used sub-analgesic doses of morphine, subsequent work, conducted in collaboration with Pain Therapeutics Inc. demonstrated that ultra-low-dose naltrexone blocks the acute rewarding effects of analgesic doses of both morphine and oxycodone, as well as the motivationally aversive effects of withdrawal from their chronic administration. In addition, the analgesic effects of ultra-low dose antagonists are not a motor artifact in that the same doses do not alter the cataleptic effects of morphine. Although the mechanisms underlying the paradoxical effects of ultra-low-dose anatatonists are not fully understood, molecular pharmacology work showed that ultra-low-dose opioid antagonist co-treatment attenuates a switch in G protein coupling that occurs following chronic administration of the opiate alone. Taken together, these studies have important implications for long-term pain management. Indeed, these paradoxical effects could help those with chronic pain who require prolonged opiate therapy.
From: Paradoxical Effects of Opioid Antagonists

Ultra-low-dose opioid antagonist cotreatment was first shown paradoxically to enhance opioid analgesia and to reduce analgesic tolerance and physical dependence. In this chapter, we review data demonstrating that ultra-low-dose naloxone or naltrexone reduces several components of opioid dependence and addiction. While the reduction in opioid dependence, first demonstrated as a reduction in somatic withdrawal signs, might seem merely a correlate of the attenuation in tolerance, the data reviewed here show that ultra-low-dose naltrexone also reduces the “psychological” or negative affective aspect of acute opioid withdrawal. In addition, the acute rewarding properties of opioids are reduced by ultra-low-dose naltrexone. The attenuation of rewarding effects occurs in the same ultra-low dose ranges shown to enhance analgesia, thus dissociating the rewarding or addictive effects of opioids from their analgesic properties. Furthermore, in intravenous self-administration procedures in rats, ultra-low-dose opioid antagonists coadmin-istered with opioids reduced their rewarding potency, reduced motivation to obtain the drug, and reduced “drug-seeking” in the absence of drug availability. Finally, in a Phase III clinical trial, the ultra-low-dose naltrexone component of Oxytrex™ significantly reduced physical signs of opioid dependence after abrupt cessation of treatment, compared to withdrawal from oxycodone alone. Together, the data reviewed in this chapter suggest a reduced potential for opioid dependence and addiction by certain ultra-low-dose opioid antagonists combined with opioids, concurrent with the enhanced analgesia from these opioid agonist/antagonist cotreatments.
From: Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids

IN RODENTS:

Ultra-low-dose NTX coadministration blocks the acute rewarding effects of analgesic doses of oxycodone or morphine as well as the anhedonia of withdrawal from chronic administration.
From: Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance.
From: Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats

Reduction of withdrawal upon chronic very low naltrexone administration may be due in part to decreased activation of brainstem noradrenergic neurons in morphine dependent rats.
From: Chronic very low dose naltrexone administration attenuates opioid withdrawal expression

Elevated μ-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent rats

A lot of the studies I've seen on ULDN and tolerance/dependence/withdrawal are on mice and rats. I will try to find some more on humans.

I can post more stuff if you're interested

 

[jollypecker]

i was led to believe naltrexone was not water soluble , it may need to be dissolved in a solvent of some type 1st u do not want precipitated wd from it i took 50mg while addicted to heroin and ended up in hospital, be safe people

 

[Swimmingdancer]

i was led to believe naltrexone was not water soluble , it may need to be dissolved in a solvent of some type 1st u do not want precipitated wd from it i took 50mg while addicted to heroin and ended up in hospital, be safe people

Naltrexone hydrochloride (the kind found in naltrexone pills) is plenty water soluble, 100 mg can be dissolved in 1 mL of water.

 

[Charles Ferdinand]

Elevated μ-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent rats

After reading this the first thing I thought was about naltrexone antagonizing some sort of autoreceptors or maybe agonizing central receptors of some sort much like clonidine does with the adrenergic receptors in the brain, but I'm just guessing.

I can post more stuff if you're interested

Please do. Any information related to the mechanism of this phenomenon will be GREATLY appreciated.
This kind of things always amaze me and fascinate me.
Thanks for posting the information.

 

[mrflowers00]

how big of a difference could this really make though

 

[Charles Ferdinand]

Reducing tolerance to opiates? None for me as I never even tried them, but I love pharmacology. I already said that.

 

[manman]

I dont know why anbody would ever fuck around with naltrexone, regardless of the reason. Pure poison.
What happened to a good old fashioned 'tolerance break'.

 

[Swimmingdancer]

Any information related to the mechanism of this phenomenon will be GREATLY appreciated.

Here's something interesting:

Opiates produce analgesia by activating μ 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 μ opioid receptor and adenylyl cyclase activation by Gβγ 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 μ opioid receptor coupling to G proteins or adenylyl cyclase activation by Gβγ occurs after chronic opioid treatment. In morphine-naïve rats, μ 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 μ opioid receptors, a pronounced coupling to Gs emerged coincident with a Gβγ 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 Gβγ 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.

From: Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gβγ signaling

I dont know why anbody would ever fuck around with naltrexone, regardless of the reason. Pure poison.
What happened to a good old fashioned 'tolerance break'.

We are talking about extremely low doses of naltrexone, not blocking doses. Many people can't take a "tolerance break", people are seriously physically dependent, perhaps they take opioids for chronic pain, perhaps they are trying to get off opioids - many people would want reduced tolerance and reduced dependence/withdrawal symptoms for reasons other than just to get high.

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EDIT: I decided I'm going to try using low doses of naltrexone for my post acute withdrawal syndrome - I started a thread here: Low dose or ultra low dose naltrexone for post acute withdrawal syndrome?