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Pharmacology The History of Fentanyl

This thread contains discussion about a Pharmacology-related topic
AlsoTapered

AlsoTapered

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Apr 1, 2023
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Note that before fentanyl, phenoperidine was used in surgery. Unfortunately phenoperidine demonstrates how the ACTUAL potency of 'high potency' opioids can vary HUGELY. Phenoperidine is listed as being 20-60x morphine in potency which is a HUGE range.

That is why although their are actually tens of thousands of high potency opioids know, the vast majority suffer the 'potency problem' Etonitazene suffers that problem. Between individuals, activity will vary HUGELY,
 
AlsoTapered said:

Note that before fentanyl, phenoperidine was used in surgery. Unfortunately phenoperidine demonstrates how the ACTUAL potency of 'high potency' opioids can vary HUGELY. Phenoperidine is listed as being 20-60x morphine in potency which is a HUGE range.

That is why although their are actually tens of thousands of high potency opioids know, the vast majority suffer the 'potency problem' Etonitazene suffers that problem. Between individuals, activity will vary HUGELY,
Click to expand...
wow, am shocked for some reason to read that - how the fuck did they manage to safely use an opiod with such potential potency range? Or am I misreading (v stoned...)
 
ageingpartyfiend said:
wow, am shocked for some reason to read that - how the fuck did they manage to safely use an opiod with such potential potency range? Or am I misreading (v stoned...)
Click to expand...
By assuming the lowest potency within that range and gradually going up on the dose if it turns out to be not enough. At least that's what I would do. Don't know how they actually did it since I didn't live back in those days...

@AlsoTapered
How come the vast majority have this potency issue? I mean what's the cause?
 
Hexenstahl said:
By assuming the lowest potency within that range and gradually going up on the dose if it turns out to be not enough. At least that's what I would do. Don't know how they actually did it since I didn't live back in those days...

@AlsoTapered
How come the vast majority have this potency issue? I mean what's the cause?
Click to expand...
You mean highest potency maybe? 🤔

Or lowest possible effective dose based on the range
 
ageingpartyfiend said:
wow, am shocked for some reason to read that - how the fuck did they manage to safely use an opiod with such potential potency range? Or am I misreading (v stoned...)
Click to expand...

It was and is ONLY used during surgery involving general anesthesia where mechanical ventilation AND access to an appropriate opioid antagonists are available (to paraphrase the Operidine packaging). In addition the anesthetist may choose to use a slow intravenous infusion - this technique is referred to as 'balanced anesthesia'.

High potency, short duration of action and sedative properties are highly valued properties in opioids used in anesthesia. Then, as the drug is metabolised, the amount in the body may be balanced.

As I said, fentanyl (Sublimaze) appeared to vary much less between individuals which made it safer than the other agents that were developed at around the same time.

Now sufentanil (Sulfenta) has largely supplanted fentanyl in surgery. It shares the positive trait of a dose calculated by body weight being accurate and has a much, much larger TI (6700) than fentanyl (280). It happens to be around x10 more potent as well, but that wasn't the KEY improvement,

Things like carfentanil are now showing up because someone found the 2010 paper that telescopes down it's synthesis to comparable complexity to plain fentanyl BUT carfentanil has never been licenced for use in humans because the dose-response isn't reliable and it now appears that in man it displays a two-phase metabolism - always a significant problem for medicines.
 
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Hexenstahl said:
@AlsoTapered
How come the vast majority have this potency issue? I mean what's the cause?
Click to expand...

It appears to be genetic variation, most likely the OPRM1 gene.

www.ncbi.nlm.nih.gov

Pain polymorphisms and opioids: An evidence based review

Despite the various different candidate genetic polymorphisms of potential clinical relevance, there is not enough understanding of the inter-individual variability in analgesic administration. The cytochrome P450 2D6 (CYP2D6) genotype is thought to be ...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov

I also suggest other genetic variations will result in major differences in metabolism. The most high profile example of this I can think of is that those of African descent tend to be 'super metabolizers' and those of S.E. Asian descent being 'poor metabolizers' of codeine.

The former is demonstrated by the North American phenomenon of 'purple drank'. I mean - fatal codeine, hydrocodone and tramadol overdoses are much more common among African Americans because O-demethylation occurs rapidly in that populatin.

The latter is demonstrated by the fact that in South East Asian nations, the three opioids I mentioned above aren't used much because the majority of their action is due to their metabolism into morphine, hydromorphone and O-desmethyl tramadol. Yes, hydrocodone is actually active in it's own right, but it's Ki is about 20.
 
The prototype, etonitazene is some x1500 morphine in potency.

But then carfentanil is now turning up in the US and Canada and that's some x10000 morphine in potency.

Tolerance DOES appear to be a requirement - like cafentanil.

Leading people down a one way street.

But I can name many opioids that are MORE toxic. Potency doesn't directly parlay into 'deadly'.

The thing is, their are known opioids some x100,000 morphine in potency. They WILL turn up if only because someone with a dinky glassware set and some unusual but not suspicious precursors can make them in a small space.
 
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