Fentanyl Crisis - Next up, Nitazenes

[4DQSAR]

Experts believe breakthrough in US fentanyl crisis may have started in China

US overdose deaths have plunged, but experts warn the ‘supply shock’ from Chinese precursors may only be a temporary fix

www.theguardian.com

Long ago China banned the immediate fentanyl precursors and the result was simply semi-legitimate chemical companies in Mexico were buying pre-precursors from China and converting them INTO the original precursors. In fact, I can imagine a similar ecosystem to the Gong Kai digital arena with middle-men who are comfortable with 10-15% profit to undertake legitimate work.

So it is no surprise to me that in light of the Don's visit to China, the Chinese have indicated to suppliers that leading up to the visit, selling to Mexico (and India - a trans-shipment point) were out. But the market remains and to the best of my knowledge, precursors to nitazenes and possibly even some finished product is not controlled in China or Mexico.

Then add to this the fact that Carfentanil is now appearing.

In short, every time a chemical is legally controlled, people either find the most potent analogue to make precursor purchaces hard to spot and/or simply swap to the next class on the list.

I still cannot explain why 4-phenyl phenapromide or even more potent derivatives have yet to turn up. Not as well explored BUT we know of several modifications to the phenapromide scaffold that comfortably puts them into the same potency bracket as fentanyl. After all, those derivatives OVERLAY fentanyl and the final step, the formation of that amide - that is likely IDENTICAL to the last step of fentanyl synthesis.

None of the above is secret. It would be nice to think that someone put some thought into POTENTIAL fentanyl alternatives and had those phenapromide precursors controlled, but so far, law enforcement has always been reactive, not proactive.

 

[Didgital]

Hasn't there also been somewhat of an emergence of orphine opioids like Brorphine and recently Cyclorphine.
Also SR 17018

 

[4DQSAR]

There has but from the little I know, that class MAY not be quite the goldmine Chinese manufacturers hoped. Brorphine has killed a few, cyclorphine seems to be used more as a cut than a product, likely because while it may well be equipotent with carfentanil in animal models of pain, every other example of an N-2-cyanoethyl moiety has demonstrated far more analgesia than a simple N-methyl BUT every single paper noted two things.

1-It did not SUBSTITUTE for morphine which should at least makes people wonder just what type of analgesic is is.
2-In every study, where the N-2-cyanoethyl moiety was tested, it was shown to be unselective i.e. it mediates that increased analgesia via KOR (dysphoric/hallucinogenic) and DOR (pro-convulsant) opiate receptors.

Now there MAY be a window but it's gone from multiple websites banging on about how amazeballz it is to quietly being traded as a cut.

It is just a hypothesis but having looked at around 100 different medically used opioids that were redirected to the street, one may have potency OR euphoria - not both. Certainly fentanyl derivatives and the more potent nitazenes only seem to produce a 'plastic euphoria' at doses perilously near to toxic doses. I suggest it's mean receptor-occupancy time. High affinity means long receptor-occupancy times and the euphoria is mediated by the binding-unbinding cycle so only in the 'death zone' do they produce any psychoactive effect.

Long, long ago I was prescribed fentanyl patches and if used as stated, it was in fact very good. It controlled the pain without any other notable effects. But if euphoria is the goal, it's a terrible choice.

In the 1980s the UK had all manner of dubious opioids if only because Janssen had somewhat 'flooded the zone' and even stated that he had an opioid appropriate to all legitimate usages. But even his own PR team were less than honest. I saw an ad for dextromoramide (Palfium) which claimed 'high oral bioavailability'. Well, that's a subjective term but in the very same year an academic paper BY Janssen noted oral bioavailability was around 20%.

So peach Palfium is something even dependent opioid users either treated with respect or died. I did ask BLers and one chap recalled a friend nicknamed 'Skaggie Maggie' who was found dead in the toilet of an insalubrious pub. 10mg may not sound much, but 150mg of morphine DOES. She had whacked up several. Diconal was another uniquely British disaster but I noted that US clinicians used to have the option of prescribing oxymorphone (Opana) and Levo-Dromoran (levorphanol). Both fed the needle.

In essence, the best option is an opioid that is MORE active when consumed orally. You may be surprised to learn that oxycodone is an example. But even them, if it can go in a pin, it WILL go in a pin.

It's entirely practical to design a prodrug that essentially means that any and all parentheral routes will yield no effect. Again, this is known. Bentley and Janssen both developed such things 60+ years ago. Heck, even oxycodone from a century ago turns out to mediate around 50% of it's activity due to O-demethylation. But I suspect a parentheral route will be subjectively different as it's action is akin to simple dihydrocodeine. It's active as it is but O-demethylation plays an important role.