opioid use disorder medications and craving?

[doubledeuce80]

What is the pharmacologic explanation for how methadone (full mu agonist), buprenorphine (partial mu agonist), and vivitrol (mu antagonist) all reduce craving in an RCT? i.e. how can medications with seemingly opposite effects on mu opioid receptor both reduce craving?

I can understand the psychological effects for craving with vivitrol- i.e. I'm on a blocker and if I use it will likely be a waste of money so I can think about something else. However, in the blinded trials individuals on vivitrol had reduced cravings scores compared to placebo which is suggestive of a different mechanism.

 

[aced126]

I'm not sure how naltrexone reduces craving, and whether it even does. However buprenorphine and methadone essentially reduce craving because they are real opioids (like heroin eg) itself.

The thing with all three of these meds is that they have high affinity for the mu receptor, meaning if one were to say administer morphine, the morphine wouldn't be able to bind to and activate the mu receptor.

Likewise, if an opioid dependant user still has say heroin bound to his mu receptors and takes buprenorphine, that can precipitate withdrawal because the buprenorphine is only a partial agonist (but with high affinity so it displaces all the heroin easily).

 

[serotonin2A]

The effect of depot naltrexone may be psychological, ie the people using it stop focusing on taking opioids. Or it could be that low levels of mu activation precipitate craving in detoxified addicits and antagonists prevent that from happening.

 

[dopamimetic]

It's an inverse agonist and as a such one it could have more effects than plain antagonism (I got heavy mental withdrawal-alike symptoms from an accident with intranasal naloxone, when I didn't have any opioid tolerance) but it comes with a price.

The NMDA antagonists, especially memantine, are more promising for that but they're no magical cure too and it requires strength of mind (they come a bit closer though as actual prevention or even reversal of tolerance appears to be possible, something really unique to NMDARs and mu opioid/maybe involving D2 too) then it's possible to circumvent the biggest part of withdrawal together with PAWS and cravings, as long as they are not purely mentally / learnt in the sense of addiction memory. The actual pharmacological thing gets solved by NMDA antagonism, can't really explain why but it does work ... the mental side is another thing.

 

[anubis23]

http://perspectivesinmedicine.cshlp.org/content/2/9/a012088.full

Indeed it seems naltrexone may interact with glutamate as well. I forget which isomer of methadone is more of an nmda antagonist atm.

http://www.ncbi.nlm.nih.gov/pubmed/15694688

http://www.labome.org/grant/r01/aa/naltrexone/blockade/naltrexone-blockade-of-nmda-6532368.html

The nitric oxide relation in the second link reminds me of agmatine. This last link is probably the most important to answer your question.

http://link.springer.com/chapter/10.1007/978-1-59259-306-4_28

 

[lenses]

I love love love low dose naltrexone - I am an advocate for immune system problems too .

Regular dose naltrexone (50 mg) is dysphoric and terrible - blocks natural endorphins .

Low dose is a different story - I take 2-5 mgs at night , and wake up in the morning feeling *amazing* . After a few weeks it feels like being on 30 mgs oxycodone all the time . The endorphin system gets unregulated noticeably - studies cite 300% endorphin level increase . That dose will block other opiates for 2-3 days .

I think it's the best long term opiate maintenance choice around - LDN overnight cures post acute withdrawal symptoms too - after I take it after being addicted for a while (and then stable) I get my sense of smell back . PAWS symptoms seem to be due to endorphin system weakness and not very sensitive opiate receptors. More people should know about it .

LDN can make one super sensitive to opiates and can lower tolerance in a few days dramatically . I've OD'd after taking LDN for a while and then using a small amount again .

Perhaps I'll make a post about it and my experiences .

-lenses

 

[negrogesic]

The argument for methadone relates to the NMDA antagonism (primarily via the S-(+)-enantiomer for the racemate), and the receptor saturation which makes penetration by other agents, difficult. A sufficient dose will also produce a satiety that will supplant the desire for other opioids (generally).

Antagonists work by the mechanisms discussed, as well as by (ostensibly) addressing drug-induced neuroplasticty and the resulting maladaptions and so forth. Or, as someone else mentioned, they can simply make it difficult to get high, thus reducing cravings through the sheer force of pharmacological logic.

The extent to which these truly reduce cravings is arguable.