haribo1 said:
It has a higher binding affinity than most, but not all opiates. Fentanyl, for example, has a higher binding profile It's true that only very high doses of methadone 'blockade' because not all of the receptors are filled without such a high dose. Opiates are not competative, if one opiate has bound to a receptor, another opiate will not 'knock it off'. Antagonists don't knock the agonists off, they simply bind to free receptors with an antagonistic action. If you were to take, like 100g of methadone, no antagonist in the world is going to help once the methadone is binding...
Ok, I'm slightly embarrassed to admit that after 3-4 years of hungrily researching opioid activity everywhere I could find information, if this is true, I sure didn't know it, and furthermore, have trouble understanding it.
Of course, I'm a niggling IT manager/executive by day and professional classical vocalist on downtime, so at least I have a working excuse that I have no reason to know much pharmacology other than the pursuit of sheer hobbyist and harm-reductionist goals (if 2-3 years of hard narcotic addiction can be considered a hobby).
That said, what is "antagonistic action?" My understanding is that opioid agonists bind to opioid receptors (mu/delta/kappa/that funny one ORL-1 or whatever), where said binding precipitates the excretion by said receptor of various neurotransmitters like dopamine, norepinephrine, seratonin, etc. In addition, various synaptic responses are triggered, leading, in opioids' cases, to the various analgesia and pleasurable/euphoric "feelings." I realize that (to a pharmacologist, chemist, biologist, or MD) this is an incredibly elementary view.
However, in the above context, what happens when an antagonist binds to the receptor? I mean, to my knowledge, there aren't corresponding neurotransmitters for "anti-dopamine," "anti-seratonin," "anti-noradrenaline," etc. I may accept that there may be synaptic responses that can be triggered that cause the reverse of the agonist responses; do you have a source that could explain this to me in a better fashion?
Finally, I specifically recall reading (especially while considering and undergoing Suboxone treatment) a GREAT DEAL of sources that specifically mentioned that A) opioids with higher affinity were competitive with opioids with lower affinity; B) Buprenorphine had something like a 95% affinity compared to a ~60% affinity for most full agonists/earlier-generation opioids; and C) Buprenorphine would specifically REMOVE opioids with a lower affinity (e.g. full agonists like heroin) from the receptors to which they were attached and take their place.
Indeed, the above phenomenon must happen to some degree, unless the phenomenon of precipitating subjective withdrawal in an opioid-tolerant and -intoxicated user by simply administering buprenorphine can be explained away by some other means. That is (and I've experienced it to some degree), if one administers his normal dose of his opioid of choice (let's say 240mg oxycodone) and is happily euphoric/nodding/pain-free or whatever, and sometime in the next 1-3 half-lives of that opioid (4-12 hours in this case) administers a comparable quantity of buprenorphine (4-12mg), the buprenorphine with its higher affinity has the ability to strip oxycodone (or one of its metabolites like noroxycodone or oxymorphone) from the receptor it has targeted, and replacing it at that receptor. This happens on a fairly large scale, and while some oxycodone/metabolites may remain, and some receptors may be unbound, since buprenorphine is only a partial agonist at mu, the user immediately experiences a debilitating subjective withdrawal, since the level of his mu agonist activity has suddenly dropped far below the threshold to which he has become accustomed. The quantitative mu agonist activity has decreased significantly.
I refuse to accept the phenomenon of "antagonist action" to explain the above phenomenon, because buprenorphine is not in any way antagonistic at mu. It is simply a partial agonist. So there is no antagonization happening (except at kappa which is not, or not very, germane to this discussion), yet the user experiences a subjective withdrawal with swift and horrible consequences. If higher-affinity opioids do not remove lower-affinity opioids from their receptors, how is this phenomenon explained?
I freely admit not having enough knowledge to predict what would occur if a user would take 100g of Methadone (presuming he was not someone of advanced age and perfect kidney function who made it his life's objective since infancy to increase his tolerance such that such a dose was not a big deal) and decided he wanted to live. Assuming he took the Methadone orally, I personally believe that if one could get him on a narcan drip (with an adequate dose administered q15-30minutes since narcan has such a tiny half-life) before a great deal of methadone crossed the blood-brain barrier, I imagine that the Narcan, with the higher affinity for the opioid receptors, presuming that enough Narcan was being given to saturate enough receptors such that any Methadone that successfully attached did not cause fatal respiratory depression, would (with its higher affinity) would prevent a fatal quantity of Methadone to bind to the user's opioid receptors, saving his life (of course the Narcan drip would have to be administered for several days considering Methadone's half-life). But I feel like it could be done. Again, I don't have enough knowledge to be sure, but... whatever.
Anyway -- antagonistic action. Could someone help me understand what that is? I thought an antagonist occupied the receptor but did not agonize/"activate" it. Which one is it?
