Better safer opiods

[vecktor]

Better safer opioids

opiates are not really my field but...
In fentanyl overdose respiratory depression is the primary concern,I suspect that it is the same with heroin and other opiates.

I have been wondering whether a bipartite or tripartite prodrug concept of an opioid linked to a 5ht4a agonist would lead to a class of intrinsically safer opioids. the linker would have to be readily bioreversible. It has been shown that the 5HT4a agonist BIMU8 is effective in preventing the respiratory depression associated with fentanyl (in rats at least.) several 5HT4a agonists have been trialed in humans, but not with opiates as far as I could determine.
It would also appear that the 5ht4a agonist would also reduce constipation and loss of gut motility associated with opiates.


Does anyone know of any other toxicity mechanisms of opiates, other than the obvious ones of respiratory depression and of causing vomiting and inhalation of the vomit?

It seems that provided the patient is kept breathing and the airway is kept clear that opiates are not very toxic and the patient will completely recover from massive doses.

I would appreciate any input from people with expertise in this area,

V

 

[jasoncrest]

I think we already have a family of much safer Opioids; it's the partial agonists.

Partial agonists like Buprenorphine have a ceiling dose. (a maximium effective dose; and taking more provides no more effects)

They cause much less respiratory depression than full agonists Opioids.

Overdoses are very very rare with these Opioids (I think there are only a few cases of Buprenorphine alone overdoses; all the overdoses of Bupe are caused by the association with another CNS depressant, like benzos...)

 

[Helios.]

Heroin ODs can cause massive brain hemorrhages.
Hydrocodone is active per os (by mouth) and is among the safest of the opioids but still causes constipation, in some cases severe.
VVV

 

[Dr.Heckyll]

There's a derivative of Etonitazene which has an analgesic does of 1µg/kg in the mouse s. c., and the LD50 in the mouse i.v. is 25mg/kg. I think that is pretty safe. The corresponding values for Etonitazene are 5µg/kg and 1mg/kg.

Btw, Etonitazene is always claimed to be 1000 times as potent as morphine, but that's not correct:

In morphine abstinent addicts in withdrawal, 1 mg etonitazene orally replaces 60 mg morphine subcutaneously.
Fraser F.H. et al.
Addictiveness of new synthetic analgesics. Add 2, Min. 21st Meet., Comm. Drug Addiction and Narcotics, Natl. Res. Council, Natl. Acad. Sci., Washington, D.C:, 10-11 Jan 1959

 

[Helios.]

a lot of pure, desirable opioid agonists are safe at the recommended dosage but what to do about the chronic, severe constipation that comes from extended use?

"all things in moderation, including moderation" i guess.

 

[Helios.]

etonitazene.

Ar-NO2 --> Ar-Cl

 

[fastandbulbous]

Does anyone know of any other toxicity mechanisms of opiates, other than the obvious ones of respiratory depression and of causing vomiting and inhalation of the vomit?

Severe, potentially fatal drop in blood pressure (both systolic and diastolic) upon parenteral administration. The worst offender is dextromoramide (Palfium), but there are others that can cause severe hypotension, especially in combination with certain other drugs. I've seen the effect on a FOAF of IVing dextromoramide (think it was about 15mg) - a larger dose would have produced a corpse...

 

[methylenedioxy]

vecktor wrote:
There's a derivative of Etonitazene which has an analgesic does of 1µg/kg in the mouse s. c., and the LD50 in the mouse i.v. is 25mg/kg. I think that is pretty safe. The corresponding values for Etonitazene are 5µg/kg and 1mg/kg.
I am surprised, since I thought that all etonitazene analogs are quite risky. Can you give a reference for this analog. Is it the Ar-NO2 --> Ar-Cl analog suggested by Helios?