4 ms·

It’s the the binding strength which has direct impact on addiction and withdrawal which is a bit scary since Fentanyl is 100 times stronger than morphine alread

It’s the the binding strength which has direct impact on addiction and withdrawal which is a bit scary since Fentanyl is 100 times stronger than morphine already, heroine is only 5 times as strong for comparison.

jessriedel 8y ago
Are you talking about binding affinity? Do you have a cite for the relationship between this and the relative addictiveness of opioids given at their normal effective doses? Everything I'm turning up suggests that, in the clinical setting, the "strength of opioids" is a statement about the relative size of the effective dose (in mg). Presumably that's correlated with molecular properties like the affinity, but I don't think that's what the article is talking about.
- dogma1138 8y ago
  Googling comes up with a WaPo article which seems to cover it pretty well: https://www.washingtonpost.com/graphics/2017/health/opioids-scale/?utm_term=.27b1c87dc55b https://www.washingtonpost.com/graphics/2017/health/opioids-... Edit: Since you edited your question I think you might want to look at opioid agonism across the range of receptors you should probably be able to find quite few NIH studies.
  - jessriedel 8y ago
    I don't think that article answers my question. This seems to be the entire contents that might directly address the issue: > The new, deadlier drugs are altered opioids that bind in more powerful ways to the brain’s receptors and get to the brain more quickly. The combination of factors can make them thousands of times more deadly. > All opioids connect to particular brain and nervous system receptors that exist for the body’s natural painkiller, endorphins... That is the only mention of the word "bind" and the article doesn't contain the word "affinity". It doesn't discuss the relationship between effective-dose-size and potential for addiction, except in cases where it seems to go in the opposite direction of what you suggested: > Methadone is about three times stronger than morphine, but it does not produce a strong euphoric effect. It also lasts much longer and can address physical dependence on other opioids, making it the most common choice for treating opioid addiction.
    - dogma1138 8y ago
      It did when you only had “do you have a cite for this” check my edit look at opioid agonism studies especially around addiction treatments where weak/partial agonists opioids are used to ease widthrawal symptoms without prolonging addiction. Which of receptors the opioids can bind to and at what level also has impact on their addiction as many of these receptors regulate different functions iirc the ones that cause the most physical dependence are the strong Mu receptor agonists.
      - jessriedel 8y ago
        > It did when you only had “do you have a cite for this” check my edit Oh gotcha, sorry about that. I edited my top-level comment fast, so I just assumed you hadn't had time to read the initial version. > opioid agonism studies especially around addiction treatments where weak/partial agonists opioids are used to ease widthrawal symptoms without prolonging addiction. OK, I spend 10 minutes Googling. I found a few authoritative lists of addictiveness that didn't seem to correlate with effective dose (which I am pretty confident is the measure of "power" being discussed in the article). And I couldn't find anything that asserted a reasonably robust correlation between effective dose size and addictiveness, whether mediated by agonism strength or otherwise. But I understand if you don't want to spend a bunch of time on this. Thanks.
        dogma1138 8y ago
        Now I understand what are you looking for no at the “effective” dose it likely won’t matter the problem is that effective dose is irrelevant in this case because we are talking about substance abuse. All full Mu receptors agonists can cause severe physical dependency, the stronger the affinity the more they also can push out other opioids and natural occurring ones and as over time the opioids can actually affect the “shape” of the receptor this is essentially what causes the addiction since what your body produces like endorphine is no longer good enough for you. So if this will be prescribed like fentanyl and other opioids this will be a problem the opioid epidemic didn’t happen because opioids were tightly prescribed and administered in controlled conditions it happened because you sprained your back and instead of some physiotherapy and a sauna you’ve been given a bottle of pills to chew on like candy.
- sndean 8y ago
  Not a primary source, but see slide 11 [0]. In this case, for the "10X" I think they're looking at the binding affinity to the u-receptor. Edit: realized that doesn't answer your question about the relationship between binding affinity, relative effective dose in mg/kg, etc. At least when medicinal chemists I work with say "10X stronger" they're referring to the binding affinity. Not sure about what it means in a person. https://www.ctsi.ucla.edu/education/files/view/training/docs/FERRANTE_M263_Opioid_Pharmacology.pdf https://www.ctsi.ucla.edu/education/files/view/training/docs...
  - jessriedel 8y ago
    Thanks! Though I'm willing to bet this technical parameter isn't what WaPo means by "powerful" :)
    - dogma1138 8y ago
      I’m pretty sure it does the “potency” is derived by the Ki value of the opioid to the Mu receptor which is the affinity while they aren’t identical (the lower the Ki the higher the potency) they are interchangeable at these levels unless you are looking for much more complex pharmacology where agonism and multiple receptors come into play. Since pain relief opioids are full Mu receptor agonists the rest doesn’t really matter in the context of these articles this is accurate enough to be technically correct while not being generalized to all opioids such as low Ki opioids which are mixed agonists or antagonists which can be used to treat addiction and even overdose since they bind to they receptors but don't activate them fully or not at all which means that they block other opioids.
      - jessriedel 8y ago
        Sorry, I don't understand. Elsewhere you said > no at the “effective” dose it likely won’t matter the problem is that effective dose is irrelevant in this case because we are talking about substance abuse. Do you disagree with either of these? 1. In popular news coverage, or doctors talking with lay patients, the term "power" or "strength" of an opioid is shorthand for it's potency on normal (non-addicted) patients. That is, it is inversely related to the number of milligrams that must be administered to get effective pain relief for some fixed reference injury. 2. The potency of a drug is only weakly correlated with its potential for addiction. There are several opioids that are less potent than average but have a higher propensity for addiction than average, and vice versa.
deleted 8y ago
[deleted]
bsder 8y ago
Isn't one of the big issues with the opioid addiction the fact that oxycontin was marketed as being able to control pain for 12 hours when in reality it didn't last that long? So, with oxycontin, you got a big effect at beginning, wearing off too soon, and craving another--all actions which are really good at reinforcing addiction. If your binding strength is much better, wouldn't you get lower doses (less big effect at start), which are more effective (less craving), further apart in time (actually controlling the pain like it was supposed to). This seems like a huge win.
- dogma1138 8y ago
  I’m not an expert on opioids but there are other factors when it comes to how long it lasts the binding strength is just one of them, the delivery method is also important so are other factors such as how quickly it can pass the brain blood barrier, which other receptors it can bind too and what is the half life of the drug in vivo. Fentanyl for example can administrated with a topical patch due to its relative strength to enable longer duration of pain relief, morphine would require an injection to be as effective.
skellera 8y ago
No way that’s true. Buprenorphine has a much higher binding affinity than all the worst opiates yet you don’t see people trying to do that over heroin and all the others. The strengths you’re speaking of are potency. And even then, most addicts I know would rather have an unlimited supply of oxymorphone than fentanyl or any of the others. At a certain point, cost outweighs all of that. There’s so much misinformation out there about these drugs.
- pimeys 8y ago
  You should watch a movie called Reindeerspotting about junkies in Lapland doing buprenorphine. It is quite addictive.
- dogma1138 8y ago
  Buprenorphine is a partial agonist of the Mu receptor (the one which causes the most physical dependency) and is antagonist for the rest, it’s also has a very high affinity which displaces other opioids which is why it’s used in addiction treatment. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581407/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581407/ Yes is more to this than just affinity the type and level of the binding to each receptor is also important but on the grand scheme of things in this context it’s not because all the opioids which are primarily used for pain relief are full Mu receptor agonists which is when the simple affinity strength estimate is pretty much sufficient to estimate potency and potential harm. Also last time I checked the potency is derived directly from the Ki value of the Mu receptor which represents the affinity (regardless of agonism) of the opioid, so these are essentially interchangeable.

jessriedel 8y ago

Are you talking about binding affinity? Do you have a cite for the relationship between this and the relative addictiveness of opioids given at their normal effective doses? Everything I'm turning up suggests that, in the clinical setting, the "strength of opioids" is a statement about the relative size of the effective dose (in mg). Presumably that's correlated with molecular properties like the affinity, but I don't think that's what the article is talking about.

dogma1138 8y ago
Googling comes up with a WaPo article which seems to cover it pretty well: https://www.washingtonpost.com/graphics/2017/health/opioids-scale/?utm_term=.27b1c87dc55b https://www.washingtonpost.com/graphics/2017/health/opioids-... Edit: Since you edited your question I think you might want to look at opioid agonism across the range of receptors you should probably be able to find quite few NIH studies.
- jessriedel 8y ago
  I don't think that article answers my question. This seems to be the entire contents that might directly address the issue: > The new, deadlier drugs are altered opioids that bind in more powerful ways to the brain’s receptors and get to the brain more quickly. The combination of factors can make them thousands of times more deadly. > All opioids connect to particular brain and nervous system receptors that exist for the body’s natural painkiller, endorphins... That is the only mention of the word "bind" and the article doesn't contain the word "affinity". It doesn't discuss the relationship between effective-dose-size and potential for addiction, except in cases where it seems to go in the opposite direction of what you suggested: > Methadone is about three times stronger than morphine, but it does not produce a strong euphoric effect. It also lasts much longer and can address physical dependence on other opioids, making it the most common choice for treating opioid addiction.
  - dogma1138 8y ago
    It did when you only had “do you have a cite for this” check my edit look at opioid agonism studies especially around addiction treatments where weak/partial agonists opioids are used to ease widthrawal symptoms without prolonging addiction. Which of receptors the opioids can bind to and at what level also has impact on their addiction as many of these receptors regulate different functions iirc the ones that cause the most physical dependence are the strong Mu receptor agonists.
    - jessriedel 8y ago
      > It did when you only had “do you have a cite for this” check my edit Oh gotcha, sorry about that. I edited my top-level comment fast, so I just assumed you hadn't had time to read the initial version. > opioid agonism studies especially around addiction treatments where weak/partial agonists opioids are used to ease widthrawal symptoms without prolonging addiction. OK, I spend 10 minutes Googling. I found a few authoritative lists of addictiveness that didn't seem to correlate with effective dose (which I am pretty confident is the measure of "power" being discussed in the article). And I couldn't find anything that asserted a reasonably robust correlation between effective dose size and addictiveness, whether mediated by agonism strength or otherwise. But I understand if you don't want to spend a bunch of time on this. Thanks.
      - dogma1138 8y ago
        Now I understand what are you looking for no at the “effective” dose it likely won’t matter the problem is that effective dose is irrelevant in this case because we are talking about substance abuse. All full Mu receptors agonists can cause severe physical dependency, the stronger the affinity the more they also can push out other opioids and natural occurring ones and as over time the opioids can actually affect the “shape” of the receptor this is essentially what causes the addiction since what your body produces like endorphine is no longer good enough for you. So if this will be prescribed like fentanyl and other opioids this will be a problem the opioid epidemic didn’t happen because opioids were tightly prescribed and administered in controlled conditions it happened because you sprained your back and instead of some physiotherapy and a sauna you’ve been given a bottle of pills to chew on like candy.
sndean 8y ago
Not a primary source, but see slide 11 [0]. In this case, for the "10X" I think they're looking at the binding affinity to the u-receptor. Edit: realized that doesn't answer your question about the relationship between binding affinity, relative effective dose in mg/kg, etc. At least when medicinal chemists I work with say "10X stronger" they're referring to the binding affinity. Not sure about what it means in a person. https://www.ctsi.ucla.edu/education/files/view/training/docs/FERRANTE_M263_Opioid_Pharmacology.pdf https://www.ctsi.ucla.edu/education/files/view/training/docs...
- jessriedel 8y ago
  Thanks! Though I'm willing to bet this technical parameter isn't what WaPo means by "powerful" :)
  - dogma1138 8y ago
    I’m pretty sure it does the “potency” is derived by the Ki value of the opioid to the Mu receptor which is the affinity while they aren’t identical (the lower the Ki the higher the potency) they are interchangeable at these levels unless you are looking for much more complex pharmacology where agonism and multiple receptors come into play. Since pain relief opioids are full Mu receptor agonists the rest doesn’t really matter in the context of these articles this is accurate enough to be technically correct while not being generalized to all opioids such as low Ki opioids which are mixed agonists or antagonists which can be used to treat addiction and even overdose since they bind to they receptors but don't activate them fully or not at all which means that they block other opioids.
    - jessriedel 8y ago
      Sorry, I don't understand. Elsewhere you said > no at the “effective” dose it likely won’t matter the problem is that effective dose is irrelevant in this case because we are talking about substance abuse. Do you disagree with either of these? 1. In popular news coverage, or doctors talking with lay patients, the term "power" or "strength" of an opioid is shorthand for it's potency on normal (non-addicted) patients. That is, it is inversely related to the number of milligrams that must be administered to get effective pain relief for some fixed reference injury. 2. The potency of a drug is only weakly correlated with its potential for addiction. There are several opioids that are less potent than average but have a higher propensity for addiction than average, and vice versa.

deleted 8y ago

[deleted]

bsder 8y ago

Isn't one of the big issues with the opioid addiction the fact that oxycontin was marketed as being able to control pain for 12 hours when in reality it didn't last that long? So, with oxycontin, you got a big effect at beginning, wearing off too soon, and craving another--all actions which are really good at reinforcing addiction. If your binding strength is much better, wouldn't you get lower doses (less big effect at start), which are more effective (less craving), further apart in time (actually controlling the pain like it was supposed to). This seems like a huge win.

dogma1138 8y ago
I’m not an expert on opioids but there are other factors when it comes to how long it lasts the binding strength is just one of them, the delivery method is also important so are other factors such as how quickly it can pass the brain blood barrier, which other receptors it can bind too and what is the half life of the drug in vivo. Fentanyl for example can administrated with a topical patch due to its relative strength to enable longer duration of pain relief, morphine would require an injection to be as effective.

skellera 8y ago

No way that’s true. Buprenorphine has a much higher binding affinity than all the worst opiates yet you don’t see people trying to do that over heroin and all the others. The strengths you’re speaking of are potency. And even then, most addicts I know would rather have an unlimited supply of oxymorphone than fentanyl or any of the others. At a certain point, cost outweighs all of that. There’s so much misinformation out there about these drugs.

pimeys 8y ago
You should watch a movie called Reindeerspotting about junkies in Lapland doing buprenorphine. It is quite addictive.
dogma1138 8y ago
Buprenorphine is a partial agonist of the Mu receptor (the one which causes the most physical dependency) and is antagonist for the rest, it’s also has a very high affinity which displaces other opioids which is why it’s used in addiction treatment. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581407/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581407/ Yes is more to this than just affinity the type and level of the binding to each receptor is also important but on the grand scheme of things in this context it’s not because all the opioids which are primarily used for pain relief are full Mu receptor agonists which is when the simple affinity strength estimate is pretty much sufficient to estimate potency and potential harm. Also last time I checked the potency is derived directly from the Ki value of the Mu receptor which represents the affinity (regardless of agonism) of the opioid, so these are essentially interchangeable.