Novel drugs for countering opioid tolerance

[CrimpJiggler]

Looking into novel anti-anxiety drugs, I've been running into a lot of novel ways to counteract opioid tolerance. Just thought I'd start compiling it in a thread for future reference.

CRF-antagonists - Antalarmine is the most well known drug of this class, I can't find an OTC source though and its insanely expensive to buy from a chemical supplier.

CCK antagonists - Proglumide is the most well known one. Its been a while since I was reading about it, I found a product that contains it which can be ordered over the internet. I'll dig up the info now. I read a report from someone who obtained it and used when they were tapering off hydrocodone. They claimed that it instantly cut their tolerance in half. A product containing proglumide is Milid.

Glutamate antagonists - NMDA antagonists are well known for blocking tolerance to opioids and other classes of drugs but it seems AMPA and kainate antagonists also block tolerance to opioids:
https://en.wikipedia.org/wiki/Tezampanel

Sigma Antagonists:
https://www.sciencedirect.com/science/article/pii/030439409511504P
Supposedly they potentiate opioid analgesia, don't know if that applies to recreational effects or whether they counteract the onset of tolerance.

 

[rob1895]

Is there a way to reduce tolerance while still being on 350mgs a day of Methadone. I have severe chronic pain, @ of course am hooked on opiates. I 've been clean for 7 years but my tolerance to everything remains insane. I need a non-antagonist type way, I realize this is a result from being on methadone or others opiates since 1987.

 

[CrimpJiggler]

Iboga greatly lowers tolerance to opioids. To fully interrupt hardcore withdrawals, you need a full on flood dose but you can use lower doses to reduce opioid tolerance. Iboga is expensive though, the cheapest way I know of is NMDA antagonists. Look into finding proglumide online, its not too expensive either.

 

[Professer]

Jonathan Ott was onto something using microdoses of naltrexone to completely reduce opiate tolerance or go cold turkey with zero WDs.

http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=7716&DocPartID=6829

It's all there. It seems pretty great, surprised this isn't that 'out there.'

 

[rakketakke]

Is there a way to reduce tolerance while still being on 350mgs a day of Methadone. I have severe chronic pain, @ of course am hooked on opiates. I 've been clean for 7 years but my tolerance to everything remains insane. I need a non-antagonist type way, I realize this is a result from being on methadone or others opiates since 1987.

I doubt you will ever regain the joys of former opiate use. The methadone more as likely has saturated you enough. Permatolerance.

 

[Tussmann]

If Proglumide is an opioid receptor agonist, I don't really see how it would be beneficial. Just seems like an additive affect, i.e caffeine + dmaa

 

[sekio]

It's not, it's supposedly a CCK antagonist...?

 

[Tussmann]

It's not, it's supposedly a CCK antagonist...?

Proglumide exhibits delta opioid agonist properties.
Rezvani A, Stokes KB, Rhoads DL, Way EL.
Abstract

Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors.

 

[sekio]

Okay, but do remember delta-opioid is not the same as mu-opioid.

 

[Tussmann]

Okay, but do remember delta-opioid is not the same as mu-opioid.

Indeed, but activity of both tends to exhibit analgesia and mood altering side effects.

 

[polymath]

At least in animals, mu-agonist tolerance can be partially prevented by administering a delta-antagonist simultaneously. Here's someone's doctoral thesis on the subject: http://deepblue.lib.umich.edu/bitstream/handle/2027.42/89854/lpuring_1.pdf?sequence=1

In this thesis, I examined the ability of the δ antagonist naltrindole to prevent acute antinociceptive tolerance after a single dose of the μ agonist morphine. I demonstrate reduced μ agonist-induced antinociceptive tolerance with δ antagonist administration in vivo. Ex vivo, morphine exposure produced a decrease in high-affinity μ receptors and decreased ability of subsequent μ agonist to stimulate G protein. These effects were reversed with δ antagonist administration

 

[CrimpJiggler]

Proglumide exhibits delta opioid agonist properties.
Rezvani A, Stokes KB, Rhoads DL, Way EL.
Abstract

The recreational (not sure about analgesic) effects of opioids are due mainly to mu receptors. Drugs like deltorphin I believe have no abuse potential and are not commonly used as analgesics, but rather they're used as adjuncts to opioid treatment to reduce respiratory depression and other things. And proglumide having some delta opioid activity doesn't change the fact that its CCK activity reverses opioid tolerance. It even mentioned that in the article you quoted:

and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat.

 

[Tussmann]

The recreational (not sure about analgesic) effects of opioids are due mainly to mu receptors. Drugs like deltorphin I believe have no abuse potential and are not commonly used as analgesics, but rather they're used as adjuncts to opioid treatment to reduce respiratory depression and other things. And proglumide having some delta opioid activity doesn't change the fact that its CCK activity reverses opioid tolerance. It even mentioned that in the article you quoted:

I Like. Is proglumide a scheduled drug?

 

[sekio]

It's not scheduled, but it's prescription-only.

Decreasing gastric motility combined with opioids doing the same is not a good idea IMO, you would never shit again...

 

[CrimpJiggler]

I Like. Is proglumide a scheduled drug?

No. It used to be sold OTC as an anti diarrhea drug (I think thats it, I may be mixing it up) I think it was, but it was replaced by newer antidiarrheals like loperamide. The product can still be ordered over the internet if you look hard enough.

It's not scheduled, but it's prescription-only.

Decreasing gastric motility combined with opioids doing the same is not a good idea IMO, you would never shit again...

There must be viable ways to counteract that. I'm not an opioid user (although I have gone on a few two week binges so I know how bad the constipation gets, I actually went to the ER the first time because I didn't know opioids caused constipation, I though I had some kinda disease) but why not take amphetamines or another strong stimulant every few days?

 

[polarbearsarecool]

my secret has been modafinil(among other pka activators, forskolin) /quercetin/ AND uridine monophosphate , there are some superiornutraceutical supplements websites that will help you, i can no longer abuse opiates now because the effects are quite strong.. but for you guys?

quercetin and forskolin will be your god, add uridine if you believe me, but these are amazing, even better than proglumide

 

[sekio]

why not take amphetamines or another strong stimulant every few days?

If you don't see the problem with that, perhaps you should not be using addictive drugs in the first place... it's a good way to get a polydrug addiction, using amphetamines to counetract the opioid side effects.

Traditionally ingestion of lots of black coffee, nicotine, and Metamucil is the "gold standard" for restoring gastric motility to opioid users.

 

[CrimpJiggler]

my secret has been modafinil(among other pka activators, forskolin) /quercetin/ AND uridine monophosphate , there are some superiornutraceutical supplements websites that will help you, i can no longer abuse opiates now because the effects are quite strong.. but for you guys?

quercetin and forskolin will be your god, add uridine if you believe me, but these are amazing, even better than proglumide

Interesting, I'll look into all that. First time I hear of quercetin, forskolin and uridine, can these be found in health food shops?

BTW that product containing proglumide I was talking about is Milid.

 

[MeDieViL]

nefiracetam with quercetin
or forskolin with quercetin
Minocycline

I think can be added, ill elaborate more later, (srry to never elaborate too lazy at times and often think others can do some research with me prompting them in a direction).

Nitric oxide inhibitors

Curcumin

 

[CrimpJiggler]

Just came across an interesting one. Nigella sative. According to this article:
http://eprints.hec.gov.pk/1813/1/1742.htm
it counteracts opioid tolerance by blocking calcium channels. Heres what they concluded from that experiment:

It was observed that Nigella Sativa showed a rapid improvement in signs and symptoms of acute opioid abstinence. It was also observed that Nigella Sativa prevented the development of significant craving and relapse. It is concluded that Nigella Sativa is effective in long term management of opioid dependence and it is suggested that further long term follow up studies may be designed with greater number of patients.