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ULDN - The magic weapon to reduce and keep tolerance to Opioids low

Thanks to all of those who answered to my questions. I'm glad that some things becoming more clear for me. So I'll try to use naloxone intranasally while trying to get some naltrexone tablets, it shouldn't be hard with a help of some fake recipes..

I'll report back if I'll get any noticeable results
 
4DQSAR said:
@nosti - naloxone is rapidly metabolized by the liver (gluconation). Being so lipophilic, it will tend to redistribute from the brain into ALL fatty tissue. I don't know much about 6β-naltrexol other than it's a metabolite of naltrexone, not naloxone. Do you mean 6β-naloxol?
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I was actually just trying to help 'Dastromar' understand why naloxone isn't a great candidate for getting the same results as naltrexone at low doses. The potency and half-life of their different metabolites is the main reason, from what I've gathered. But I'm no expert at all, so I might be getting things mixed up.
 
Enzymatic leverage strategies

• Re glucuronidation of naloxone:
4DQSAR said:
naloxone is rapidly metabolized by the liver (glucuronidation).
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Hepatic metabolism primarily occurs via glucuronidation to form naloxone-3-glucuronide, a pharmacologically inactive metabolite.​
...​
Glucuronosyltransferase (UGT) is a glycosyltransferase that catalyzes the addition of a glycosyl group from a UTP-sugar to a small hydrophobic molecule. Although the majority of UGT enzymes are expressed in the liver...​
​
Some UGT enzyme inhibitors:

• Re sulfation of opioid drugs:
Buprenorphine, pentazocine, and naloxone are opioid drugs used for the treatment of pain and opioid dependence or overdose. Sulfation [...] is involved in the metabolism of a variety of xenobiotics including drug compounds. Sulfation of opioid drugs has not been well investigated. Collectively, these results imply that sulfation may play a role in the metabolism of buprenorphine, pentazocine, and naloxone in vivo.​
​
Sulfotransferase (SULT) are transferase enzymes that catalyze the transfer of a sulfate group from a donor molecule to an acceptor alcohol (C-OH) or amine.​

Some SULT enzyme inhibitors:

• Re glutathione conjugation of opioid drugs:
Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin.​
​
Glutathione S-transferase (GST) enzymes catalyze the conjugation of reduced glutathione (GSH) (using a sulfhydryl group) to electrophilic centers on a wide variety of substrates.​

Some GST enzyme inhibitors:
​
• P450 metabolism of morphine:
More than 90% of morphine N-demethylation could be accounted for via the action of both CYP3A4 and CYP2C8. The in vitro findings suggest that hepatic CYP3A4, and to a lesser extent CYP2C8, play an important role in the metabolism of morphine into normorphine.​

CYP3A4 inhibitors

CYP3A4 - HerbPedia

herbpedia.wikidot.com herbpedia.wikidot.com
CYP2C8 inhibitors

CYP2C8 - HerbPedia

herbpedia.wikidot.com herbpedia.wikidot.com
 
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nosti said:
UPDATE. I am currently increasing my naltrexone dose to 3 mg (1 mg every 8 hours, at 5 AM, 1 PM, and 9 PM). I’ve had some mild withdrawal symptoms, mainly at night, the 9 PM naltrexone dose was messing with my sleep a little, so I fixed it by switching my methadone to two 15 mg doses a day, one at 9 AM and one at 10 PM. It worked. Now I'm sleeping well again.
The 15 mg of methadone before bed helps me sleep well. And the 15 mg in the morning keeps me pretty stable for the rest of the day. Some days I take a 150 mg dose of pregabalin at 3 PM. That helps a lot, too.

3 mg of naltrexone a day is already a considerable amount. I'm totally in shock that this amount isn't messing dramatically with my methadone dose, and that everything is going so smoothly and calmly. The super slow, gradual increase I've been doing must have been the key.

Tomorrow I’ll probably increase the naltrexone by 0.2 mg per dose (bringing the total to 3.6 mg of naltrexone per day). I’ll keep taking the same methadone dose. Not planning to lower it for now. Maybe I will in the future, maybe I won’t, honestly, I have no idea. The naltrexone is already doing its thing, resensitizing my opioid system on its own, and I’m focused on increasing the naltrexone dose really, really slowly.
[EDIT: I ended up not going through with the dose increase after all. I'm going to stick with my current naltrexone dose for another week to let my body adjust. I'm in absolutely no rush.]

I have diazepam 10mg (limited supply) and pregabalin (almost unlimited), so I’ll use them if I need to.

So yeah, experiment continues.

PS. As a sort of confirmation bias for my current strategy (absolutely irrelevant for objective scientific purposes but very important to keep me going with the experiment), I have to say that during winter I had some really serious issues with back pain and inflammation in my sacroiliac joint, plus pain radiating down my leg. In fact, I’m currently on medical leave. By no means am I linking these issues to methadone, but the anti-inflammatory effect of VLDN is well known. Well, for the first time in months, I’ve noticed the pain has gone down in intensity, and on some days it’s almost unnoticeable. Of course, and like I said in my previous post, the constipation has totally disappeared, along with other negative side effects associated with methadone.
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UPDATE 2

I decided to stop the experiment. My willpower broke.

I failed again.

At least I confirmed that things like constipation and other methadone side effects can be fixed with VLDN, starting with ULDN and going up really slowly, though. I'll update if anything changes or if I decide to give it another try. It's terribly disappointing. None of my attempts to quit methadone ever work out.

Thanks to everyone who's been reading, and I hope you're all doing well
 
E-52862
S1RA.png

S1RA is being developed by Esteve for the treatment of neuropathic pain and the potentiation of opioid analgesia and has successfully completed Phase I clinical trials showing good safety and tolerability, and a pharmacokinetic profile compatible with once a day oral administration.<a href="https://en.wikipedia.org/wiki/E-52862#cite_note-Abadias_2013-6"><span>[</span>6<span>]</span></a> Phase II clinical trials are currently underway, making S1RA the first selective sigma-1 receptor antagonist evaluated in humans for these conditions.
 
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