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Pharmacology questions - point in case: opioids

Solipsis

Solipsis

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Hi,

can you help explain how the pharmacological profiles of buprenorphin and methadone make them appropriate to put addicts on them? I tried reading some websites that cover these basics such as wiki but I am not sure if I really get it.
They are probably both a bit different stories, like bupe being mixed agonist while I hear from methadone that it mostly lacks the "flash" that drugs like heroin produce.

Is it basically that drugs like these are a midway solution between being "gone" in nodland and completely kicking opiate habits? Is it a matter of being functional? What is the point in either of these for people who are not necessarily substituting a heavier habit for these ones? I am not asking from a perspective of having any desire to try things like these but I find the significant difference between (A) things like oxycodone, hydrocodone, heroin and other what sound like "standard" opiates, (B) things like buprenorphine or methadone - if they are even remotely to be put together in a category! - and (C) something like fentanyl which seems like another completely different animal entirely...

I guess it also has to do with the fact that I struggle to see what the practical consequences can be for affinity as opposed to efficacy, intrinsic activity, receptor dissociation and other factors of binding.

(Perhaps the choice of thread title was not ideal to cover my actual questions....)
 
Hi Solipsis,
Solipsis said:
Is it basically that drugs like these are a midway solution between being "gone" in nodland and completely kicking opiate habits? Is it a matter of being functional? What is the point in either of these for people who are not necessarily substituting a heavier habit for these ones? I am not asking from a perspective of having any desire to try things like these but I find the significant difference between (A) things like oxycodone, hydrocodone, heroin and other what sound like "standard" opiates, (B) things like buprenorphine or methadone - if they are even remotely to be put together in a category! - and (C) something like fentanyl which seems like another completely different animal entirely...
Click to expand...

Interesting questions, and I have no answers. However, I might perhaps suggest that probably your classification is a bit off and the discrepancy might provide a clue to your question. The issue is that actually methadone and fentanyl are close analogues and strikingly different from the other opiates. On the other hand, oxycodone, morphine and even buprenorphine and very similar among themselves and share clear structural aspects. Thus in fact 2 opiate classes exist (A) classic opiates which include the latter ones and (B) "the weird derivatives", that include the family of fentanyl and methadone.
 
Methadone is an NMDA antagonist, I would assume this has some utility in its otherwise opioid effects.
 
I was under the impression the reason methadone was used for maintenance was due to its once-a-day dosing, as opposed to e.g. IV heroin, which would be something like q4-6h. The basic idea for MMT was that methadone would substitute fully for the opioid-of-abuse and you would be able to titrate dosage down on a scale of weeks to months. (Of course some people just stay on it indefinitely). The totally synthetic nature probably helps too. (easy manufacturing)
 
Honestly, I think that these compounds have been selected in particular because addicts have difficulty getting high on them, which isn't a particularly appropriate criterion. While it's advantageous that both are long-acting, those on methadone maintenance can easily time dosing to allow themselves to get high on their opiate of choice when they desire. And then methadone withdrawal is so protracted that it's often tougher to kick than heroin. Bupe' seems a much more appropriate medication, as the withdrawal syndrome from partial agonists appears far less brutal, making them easier to kick. Additionally, partial agonists like bupe tend to have a 'ceiling effect', limiting escalating dosing for those who do enjoy it with limited self-control. Also, bupe's high receptor affinity makes it difficult to push through and get high on other agonists.

I'm skeptical as to whether methadone's antagonism at NMDA is strong enough to be particularly relevant.

But in short, bupe seems like the best maintenance med' we have.

ebola
 
I disagree ebola, the difficulty in getting high on buprenorphine or methadone is an especially appropriate criterion. I would say that it's more important than the super long half-life, though this is somewhat a function of the half life.

For an addict to have a drug that he or she can take one or twice a day that will completely block withdrawal is critical, one that tickles the same receptors and maybe gives a slight touch of that opioid-y feel, is important to preventing relapse- just getting rid of withdrawal is important, but getting rid of psychological craving is essential, too.

Not being able to get high on the drug itself is critical, though. If you're just going to be getting high on it, you might as well be using heroin. An opioid replacement that produces as little as the "liking" effects as possible while still blocking withdrawal and psychological cravings is the goal. It just happens that opiates with very long half-lives work best for this.

Buprenorphine has the added advantage of truly blocking other opiates, as a partial agonist, which also means it produces less of the liking effects. Honestly, as a user of Suboxone, if I were designing an ORT drug, Buprenorphine is more or less the ideal. Long lasting, completely blocks withdrawal and eliminates cravings, if I were to slip up and try using I'd get absolutely no effect out of it, making me less likely to attempt again in the future. With long term use it will produce little or no noticeable effect when dosed (even snorted it produces only limited positive effects, smoked it's enjoyable, but duration is greatly reduced. injection is something i've not done), although using other drugs (benzos, sedating antihistamines, alcohol) will make it somewhat more abusable.

Methadone was a decent starting place when ORT was first being explored. It has more of the liking effects than buprenorphine, but far less than heroin or hydrocodone. With long term use it will build a store in the liver and blood concentrations will even out, less peaks and troughs = less liking effects, generally speaking. It obviously eliminates withdrawal, and for most people, all cravings, and at some doses it will block some doses of heroin. Unfortunately this effect isn't altogether that strong and when tapering (a time when relapse is especially likely) it will probably not be present at all. Also, it's quite easy to abuse methadone, which really necessitates on-site dosing, especially for new patients. Ambulatory dosing of methadone is inadvisable. I remember reading a paper documenting the FDA's case against a Florida methadone clinic, from the late sixties or early seventies, which dispensed methadone prescriptions in week or month increments. When they were closed down many of their patients had daily doses of two hundred milligrams or more, and some were reportedly as high as 400mg. Can you imagine that? They had patients taking very nearly 100 "starter-level" doses of methadone a day!

An ideal ORT drug is difficult to overdose on- because addicts will take crazy doses in attempts to get high. Methadone fails in that department- hard. Dosing it is especially difficult compared to other drugs. Buprenorphine, on the other hand, has a well defined ceiling effect where, once that dose is reached, consuming more of the drug is more or less pointless, and higher doses will not depress the CNS further. Technically, this is around 32mg for most humans, but in practical terms, for someone using the drug recreationally (which can be done if one does not have a tolerance to opiates), once you've reached the point where you're taking 8mg to get high, if you're using it on a mostly daily basis, if 8mg didn't get you high today, trying 10mg tomorrow probably won't do the trick. Going up to 16mg may not add anything, either.

Methadone is a great ORT drug for those who need it, but it's flaws make it inappropriate for the majority of the opioid dependent population.

Man, I was just doing the math, and now I'm bummed. I'm so disappointed in myself- back when I was at 8mg per day, didn't get much out of it so the doc gave me 16mg / day. Holy crap, I though, I'll be high as shit. Nope, unfortunately. I do sincerely wish, though, that my younger stupider self would have said, well 16mg didn't get me buzzed, so I'm gonna but back down to 2mg a day and save 1.75 tabs a day, and in three years I'd have about 21 years worth saved up. Or no, I guess I'd have 18 years worth saved up, I would have eaten three years worth during that time period. er wait, no I did the math right, I'd have 21 years worth saved up. If I had continued at that level for just 6 years (a long time, no doubt, but I've been on Suboxone for almost that long now, though with breaks and intermissions- including one extended attempt at sobriety) I'd have enough to take me into my seventies.

Man, if I would have kept my prescription for 16mg / day, I could have saved up 14mg per day.
 
Good, exhaustive explanation. I find it interesting that having just a taste of opioidergic effects quells psychological craving rather than inciting greater craving. This seems counter-intuitive in light of how operant conditioning tends to function. I too concur that bupe' is a very well suited maintenance drug (I likely misstated my case in my prior post). The brutality of methadone withdrawal still seems problematic to me.

Oddly, as non-dependent, I've found bupe FAR more recreational than methadone.

ebola
 
you are also off of the street and in a more legal setting. Its $6 a day here and covered by employer health insurance if you have it. You can focus on getting a job/school and such, rather then your next score. The long half-life and relative lack of a "Rush" are bonuses too.

Although I must say it is really damn hard to get off of.

I'm referring to Methadone in this post.
 
As a methadone patient who's slowly coming off it and will switch to bupe when i am at around 25-30mg of methadone to help with tapering faster, here's my theory for methadone at least : The NDMA antagonism of d-methadone helps to reset pathways related to pleasure seeking through artificial ways, i've discussed with one of the doctors there and he was telling me about the same thing.

Also the main advantage for me : Stop putting all that money on illicitly procured dilaudid and hydromorph contin. The methadone is free.
 
Great insights, so far this actually helps me get better perspective on the matter and the elaborate explanations are helpful too.
 
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