Will all opiates metabolize into M3G or similar? Even if I was using weekly rather daily is it likely I am going to be building up some of these nasty inflamatory metabolites? I'm talking about opium or codeine. I've noticed no sickness but some anxiety and depression on the days following. I usually have 4 days between doses but not always.
Yes most if not all opiates have a xxxx-3-glucuronide metabolite. For example in buprenorphine its called buprenorphine-3-glucuronide.
The build up of the xxxx-3-glucuronide metabolite is a complex issue. Where it builds up, and by how much is something you could read for days on.
This article however is quite interesting. abstract explains that in chronic opiate users
7. Following systemic administration, morphine and HMOR are metabolized primarily to the corresponding 3-glucuronide metabolites, morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G), which are not only devoid of analgesic activity but evoke a range of dose-dependent excitatory behaviours, including allodynia, myoclonus and seizures, following intracerebroventricular (i.c.v.) administration to rats. 8. Several studies have shown that, following chronic oral or subcutaneous morphine administration to patients with cancer pain, the cerebrospinal fluid (CSF) concentrations of M3G exceed those of morphine and morphine-6-glucuronide (analgesically active morphine metabolite) by approximately two- and five-fold, respectively. 9. These findings suggest that when the M3G concentration (or H3G by analogy) in the CSF exceeds the neuroexcitatory threshold, excitatory behaviours will be evoked in patients
Anyway re build up of the Proinflammatory Cytokines (PCs). These are really complex chemicals/factors; IL-1β, IL-6and TNF-α are just some of the cytokines that are produced. Worse, to make it more confusing some of these chemicals are both inflammatory and proinflammatory. This is why there is anecdotal evidence that large doses of vitamins help during dope sickness. Basically they're fighting those cytokine fuckers that are floating around in your blood.
Now there is a drug in trials, ibudilast that apparently combats these cytokines. I don't understand the mechanism in that is it got multiple effects i.e. it suppresses TLR4 activation and or the products of TLR4 activation?
The trials I've read about have the users take the ibudilast after they've stopped using heroin. However from my reading and understanding you'd want to start taking ibudilast whilst you're using, to directly counter the effect of M3G and avoid the build up the PCs. So in that vein I would if I wanted to avoid the build up, apart from simply abstaining, would be to:
1. Up my daily vitamin dose.
2. Really import, eat fresh fruit/vegies. See in a green apple there are thousands of compounds called polyphenols that facilitate the uptake of vitamins into the body. Taking vitamin C without these polyphenols is kinda pointless as only a very small amount of Vit C gets taken up as a result.
3. reduce your last dose. See whenever I used to be naughty I would always take a supermassive last shot. This I have realised is a no no. All that last shot is doing is building up the M3G & PCs. Taking less on your last shot = less M3G & PC to.....
4. Metabolic rate. This is really important. If you're being naughty before a piss test and you're drink lots of water thinking that'll defeat the test and what not, what your actually doing is fucking with your metabolic rate, making it slow down. What you want is a fast metabolic rate. You want energy and b-group vitamins. You want to eat big meals, you want be active, exercising whatever. This will clear the M3G out of your system faster then sitting around moping about will. Now I know that when your in the middle of dope sickness that the last thing you want to do is eat and do shit but trust me the difference between withdrawing for 5 day vs 2-3 days is huge, and the severity is much lower.
5. It appears that different opiates produce different levels of their M3G and that it has different half-lifes. I know that when my heroin has been cut with long life agonists that they're a real fucker to get off. The dope sickness they create is far worse then straight up heroin. So kids don't use Oxy, just use straight up heroin.
I'm going to try and convince my doctor to prescribe ibudilast off-label seeing that it's already used and approved for other conditions. I'm also looking for other drugs that have a similar mechanism.
Fun fact it looks like the people who have MS are basically going through what we go through when you're in the middle of dope sick. It looks like MS is caused by a malfunctioning TLR family which spew out PCs that basically fuck up your body causing immense pain.
