tone
Veteran
Reged: 06/29/03
Posts: 531
Loc: Chicago
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Suppose i went off an opioid and waited two weeks for it to be completely out of my system and withdrawl to be over....
then after that i went out an opioid antaganost like naltrexone for 2 weeks
then i go off the naltrexone for a week and go back on opioids for my physical pain and their positive mental side effects....
being on the naltrexone would upregulate my mu receptors much like being on opioids downregulates them, so would this reset my sensitivity to opioids and make it almost like i never took them before? in otherwords, would this treat my tolerance more so than just taking a break from opioids without using naltrexone to upregulate?
thanks for your insights
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karmapolice
Stranger
Reged: 11/11/03
Posts: 18
Loc: Toronto
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I can't say for sure, but I think you may be on to something here. This is a good point and reminded me of a study I read just the other day. The study used a group of people with a fairly moderate tolerence to opioids. They were given a very small amount of an opioid antagonist along with there regular dose. (in this case morphine) The study clearly showed a DECREASE in tolerence and therefore an increase in effectivness. This seems to contradict moast studies but.... hey? thats just what I read. What you are saying seems pretty logical to me.
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tone
Veteran
Reged: 06/29/03
Posts: 531
Loc: Chicago
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yea that study about the tiny tiny amount of naltrexone with opioids is interesting
the hypothetical logic here is that, well, since chronic administration of opioid agonists, even if on and off, causes some degree of long term tolerance, then perhapes a somewhat chronic administration of an opioid antagonist would cause some degree of opioid sensitivity. i thought about trying it myself. i dont think it would reset you back to before you ever took an opioid, but it might help a lot more than just simply taking a few weeks break from the opioids
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Trampy
Pooh-Bah
Reged: 04/02/02
Posts: 1230
Loc: Southwest U.S.
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Quote:
I can't say for sure, but I think you may be on to something here. This is a good point and reminded me of a study I read just the other day. The study used a group of people with a fairly moderate tolerence to opioids. They were given a very small amount of an opioid antagonist along with there regular dose. (in this case morphine) The study clearly showed a DECREASE in tolerence and therefore an increase in effectivness. This seems to contradict moast studies but.... hey? thats just what I read. What you are saying seems pretty logical to me.
Look up a company called Pain Therapeutics (ticker PTIE). They have a patent for a new kind of combination mu agonist/antagonist drug and are developing combination drugs that are in clinical trials now. The theory behind their patent is much more complex than tone's idea. Much more complex. Basically, they say that ultra-low doses of mu antagonists enhance analgesia and lower tolerance to opiates taken in combination.
Trampy
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Your mileage may vary ...
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tone
Veteran
Reged: 06/29/03
Posts: 531
Loc: Chicago
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Yes yes trampy, i am well aware of the studies but its not what im talking about, Plus its bad news because it interferes with the excititory effects of opioids.
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Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability
by
Crain SM, Shen KF.
Department of Neuroscience,
Albert Einstein College of Medicine,
Yeshiva University, Bronx, New York, USA.
Pain 2000 Feb;84(2-3):121-31
ABSTRACT
Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with ultra-low doses of clinically available opioid antagonists, e.g. naloxone and naltrexone, markedly enhances morphine's antinociceptive potency and simultaneously attenuates opioid tolerance and dependence. These preclinical studies in vitro and in vivo provide cellular mechanisms that can readily account for the unexpected enhancement of morphine's analgesic potency in recent clinical studies of post-surgical pain patients cotreated with morphine plus low doses of naloxone or nalmefene. The striking consistency of these multidisciplinary studies on nociceptive neurons in culture, behavioral assays on mice and clinical trials on post-surgical pain patients indicates that clinical treatment of pain can, indeed, be significantly improved by administering morphine or other conventional opioid analgesics together with appropriately low doses of an excitatory opioid receptor antagonist.
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Attenuation of morphine dependence and withdrawal by glycine(B) site antagonists in rats
by
Kotliska J.
Department of Pharmacodynamics,
Medical University School,
Staszica 4, PL-20-081,
Lublin, Poland
Pharmacol Biochem Behav 2001 Jan; 68(1):157-161 1999 Sep;124(1):51-5
ABSTRACT
Numerous data indicate that noncompetitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of physical dependence on opioids when these substances are administered together, and NMDA receptor antagonists are used at lower range of doses. Higher doses of these antagonists can enhance some opioid-induced effects. The present study extends these findings to the effects of NMDA/glycine (glycine(B)) site antagonists. Wistar rats were rendered dependent on morphine by implantation of morphine pellets. Both of the glycine(B) site antagonists used, 7-chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)-quinolone (L-701,324; 2.5 and 5.0 mg/kg) and 5,7-dichlorokynurenic acid (5,7-DCKA; 25, 50, and 100 mg/kg), suppressed the expression of morphine withdrawal syndrome estimated as wet dog shakes. Furthermore, L-701,324 (2.5 and 5 mg/kg), given twice a day during the development of morphine dependence, attenuated the development of morphine dependence, and the results were comparable to those obtained after administration of noncompetitive NMDA receptor antagonist - MK801 (0.1 mg/kg). Our data suggest that glycine(B) site antagonists may attenuate wet dog shakes (withdrawal) and the development of dependence, both being induced by chronic morphine administration in rats.
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night_shade
Threadhead
Reged: 08/26/03
Posts: 907
Loc: The State of Hockey
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Quote:
being on the naltrexone would upregulate my mu receptors much like being on opioids downregulates them, so would this reset my sensitivity to opioids and make it almost like i never took them before? in otherwords, would this treat my tolerance more so than just taking a break from opioids without using naltrexone to upregulate?
I disagree. Tolerance to opiates stems from the additional growth of receptors. For example, an opiate-naive person has (for example's sake only...) 100 mu receptors. The same person gets oxycodone for, say, 6 months worth of treatment...now that person has 200 receptors and it takes twice as much of the drug to be effective. The opposite is also true. If that same person with 200 receptors goes on a taper schedule for 3 months and is off opiates entirely, within that 6 month period, the extra receptors die off and the person's tolerance goes way down.
So, using an antagonist won't actually kill off the extra receptors. It will only displace the opiates for the duration of it's action (which is generally shorter than the action of most opiates.) Only time and abstinence will reduce the number of receptors. And a week or two's "holiday" doesn't really make a huge difference in this reduction of receptors.
This is how my anesthesiologist explained it to me. I will have to look and see if I can provide any references to this.
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Never underestimate the predictability of stupidity.
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tone
Veteran
Reged: 06/29/03
Posts: 531
Loc: Chicago
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oh no i wouldnt use the naltrexone while still on opioids, that would mean instant acute withdrawl. im talking about using then during the break period, while completely off opioids, to further upregulate receptors. also in low dose, in the same low dose people now use naltrexone for autism, and immune system boosting
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Trampy
Pooh-Bah
Reged: 04/02/02
Posts: 1230
Loc: Southwest U.S.
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Quote:
Yes yes trampy, i am well aware of the studies but its not what im talking about, Plus its bad news because it interferes with the excititory effects of opioids.
Exactly! You understand the implications of Crain's finding ... but ... for reasons given below, i have a hard time believing that PTIE will ever get that drug approved.
Just have some fast-acting mu agonists on hand when you try this experiment. Trust me, you might need them very badly if the abstinence period is only two weeks. Reason being that the mu-receptor flourish/atrophy cycle takes months, not weeks.
Of course, a lot depends on how high and how long you've been up on the opiate ladder, and what level of naltrexone or naloxone dose you plan on using. If you plan on using Revia instead of naloxone, just be aware of how long-lasting its effects are, in case the experiment is a failure.
Trampy
P.S. Most scientific experiments end up as failures. But please let us know if this one is different.
P.P.S. I have more experience in trying to duplicate the ALGO/ENDO/Lyle/NMDA effect as well as the PTIE/Crain/ultra-low-dose-mu-antagonist effect than i care to mention. The ultra-low-dose antagonist approach was a total failure. Nobody i know has ever noticed the claimed effect and many combinations of protocol and concentrations were tried.
The NMDA approach was found to have some merit, but since any doctor could mimic the effect by prescribing OTC cough syrup, even if it was approved it won't make ENDO any money. I doubt that the FDA will approve either company's combination drug, but ENDO is ahead of PTIE with the science. It's truly amazing that John Lyle got away with $100 million from selling Algos to Endo ... all because of the patent he got from one study he did with a few rats that he got published in a totally obscure journal ... but hey, it's easy to get a patent if you know the rules.
The *only* approach i've ever found to work in this area is with the CCK-antagonist proglumide, which was first popularized in 1998 with Jonathan Ott's interview in Entheogen Review. Google will find it in a jiffy.
Edited by Trampy (02/18/04 04:57 PM)
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tone
Veteran
Reged: 06/29/03
Posts: 531
Loc: Chicago
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i too like the looks of the NDMA and other routes rather than directly interfereing with the perfection the holy Mu Agonist
I believe there is DXM Cough Syrup Still availible that only has DXM in it and no other drug. Vicks 44 with no letter is one of them i think......
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