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High efficacy partial agonists vs lower efficacy full agonists

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Limpet_Chicken

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A quick question popped into my head while reading the replies to my mirfentanil thread.

Would a partial mu opioid agonist cause precipitated withdrawal in a person dependent upon a full agonist, if the partial agonist had a greater efficacy at mu receptors than did the full agonist the subject would be dependent on?

I'm possibly considering trying mirfentanil at some point in the future, but I've been on dihydrocodeine for a good few years, although at the moment I'm stable at 30mg BD, (and am slowly tapering down a tiny chip off each tablet, getting to a slightly larger chip every few days) I imagine that no it wouldn' cause a precipitated withdrawal, (as if I do try it, I will probably have access to multiple grams, probably more than enough to completely saturate the receptors and stop them howling for their daily DHC.

What I really don't fancy is sudden precipitated withdrawal, especially from something with an affinity high enough to require something bloody potent I don't have to hand to boot it out and make way for a full agonist that binds tightly enough to take its place.

Unusual situation I would have thought, there is bupe, I know, but its quite efficacious, a lower efficacy, high affinity partial agonist, hmm, not so common in practise, so anybody care to venture a theory?
 
Assuming I remembered my pharmacology lectures correctly...

I thought that efficacy = how strongly a ligand produces a response. So full agonists would have high efficacy, and the higher efficacy ligand would produce a stronger response.

Agonist/partial agonist, etc all relate to efficacy. Antagonist being 0 efficacy, (full) agonist being the most, and partial agonist is somewhere inbetween.
 
Yeah, I think this is a bit of a misnomer?
Partial agonist = medium efficacy.
Full agonist = high efficacy.

Unless the ligand in question has particular functional pathway activation characteristics that allow it to simultaneously be high efficacy yet low activation for the clinically relevant pathway (say, lisuride, which is a strong 5-HT2A agonist yet doesn't produce hallucinations like others like LSD), the above relationships will hold.
 
If you look at the compounds he's comparing, he's talking about using a low binding affinity full agonist and a high binding affinity partial agonist.

Lets look to another high binding affinity partial agonist, buprenorphine. Does it cause precipitated withdrawal? Yes.
 
Isn't it just that partial agonist affinity x partial agonis efficiency > full agonist affinity x full agonist efficiency for withdrawals not to occur? Of course corrected for bbb penetration differences.

Or is that too simplistic?
 
Couldn't there be low binding affinity with high receptor binding conformation efficacy?, or low binding (as per conformation) efficacy and high binding receptor affinity (how easily it binds not in what manner it binds)?
 
You could simply do what full agonist opioid addicts have been doing since the introduction of partial agonists: wait until you are in mild withdrawal before taking the partial agonist, then waiting until mild withdrawal before taking the full agonist again?

Pentazocine, Nalbuphine, Buprenorphine have all been documented to be abused this way by Heroin/other full mu agonist opioid addicts.

Mirfentanil sounds awful. Worse than Meperidine and all of its quasi-opioid bastard kin. Benzomorphans sound good compared to it.
 
Never had pethidine (as we brits call it) but it sounds pretty good to me, save for antimuscarinic effects, my memory is awful and I'm taking a cholinesterase inhibitor for that end, surely you meant pentazocine when you said meperidine, which isn't a benzomorphan, its a phenylpiperidine class opiate.
 
Limpet_Chicken said:
Never had pethidine (as we brits call it) but it sounds pretty good to me, save for antimuscarinic effects, my memory is awful and I'm taking a cholinesterase inhibitor for that end, surely you meant pentazocine when you said meperidine, which isn't a benzomorphan, its a phenylpiperidine class opiate.
Click to expand...

I meant the Benzomorphans sound good compared to the Pethidine's. Just my opinion.

What is it about Mirfentanil that makes you interested in trying it?
 
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