Pharmacology - MAOIs and Opioids

[killersnowman]

swim posted something similar to this in another thread and got no answers, so he wanted me to post this here.

Swims knowledge of how the whole opioid->euphoria system works is very limited. swim has been going on the assumption that once an opioid receptor is activated the effects on the body must be mediated by an endogenous neurotransmitter. swim is unsure what neurotransmitter is associated with opioid use (GABA, dopamine, serotonin, maybe acetylcholine). now, lets say the euphoria comes from a combination of increased GABA and dopamine in the brain somewhere, would adding an MAOI keep these pleasureable neurotransmitters in the brain for longer than they normaly would?

swim is well aware that stims activate dopamine production and it is well known that combining with an MAOI dramaticaly increases the effects of the stimulant. is this the same with opioids? is swim even close? please correct me if i am wrong... swim has been thinking about this for quite some time now and is confused as to why an MAOI would effect the neurotransmitters of a stimulant and not those associated with opioids? is it the location in the brain these neurotransmitters are released?


found this on wiki http://en.wikipedia.org/wiki/Monoami...dase_inhibitor
"MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, both legal and illegal etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine, tramadol, and dextromethorphan[citation needed]. Agents with actions on epinephrine, norepinephrine or dopamine must be administered at much lower doses due to potentiation and prolonged effect. Purely opiate-acting analgesics, such as morphine, and buprenorphine may be used safely with MAOIs, but may require a dosage adjustment."

does the bold part mean that it potentiates pure opiate substances?

thanks...
-swimmy

[Gradient]

The reinforcing activity of every drug we know of can be either directly or indirectly attributed to dopaminergic activity - mediated by dopamine. You're absolutely correct, however, in asserting that the quality of the euphoria that a given drug will generate will be a function of its activity at all main neurotransmitter sites (eg. GABA, DA, NE, 5-HT, Glutamate). Ethanol, for instance, generates a release of both dopamine and GABA - among other, more motoric effects - while opioids stimulate the 3 or 4 main opioid receptors (µ, κ, δ), the most significant to euphoria being µ receptors in the periaqueductal grey. This has repercussions at the other main neurotransmitter systems - notably a release of DA in the medial-forebrain-bundle.

It's very important to note, however, that the vast majority of opioid-analgesics in pharmacology aren't true opiates, or purely isolated from natural sources (as morphine, codeine, and thebaine). The more potent ones (oxycodone, hydrocodone, heroin) involve substituents to parent compounds, and are considered semi-synthetic - thereby slightly altering the molecule's interaction with amino acids comprising active regions on dendrites. This will inherently modify the way the opioid molecules act at receptors, potentially generating new interactions. The fully synthetic opioids (fentanyl, meperidine, tramadol) can have activities at receptors that wouldn't otherwise be recruited by the other opioids. Tramadol, for instance, has affinities for the µ-opioid and the serotonin & norepinephrine transporters.

Monoamine-oxidase inhibitors act to suppress the molecules that are responsible for terminating the activity of monoamine neurotransmitters (NE, DA, Ep). The part that you bolded is suggesting that MAOIs may be consumed concurrently with the true-opioids, such as morphine, because the activity of these molecules has been identified to be dominant at the µ-opioid receptor and not monoamine neurotransmitter proteins - however, they seem to suggest that an interaction will still exist due to the fact that µ-opioid activation in the PAG will generate dopamine release in the medial-forebrain-bundle; there will be a potentiation, but potentially a dangerous one.

As the warning you highlighted suggested, be extremely careful with this combination!

[Bodyrot]

Shouldn't you refer to the actual drug it is turned into after it passes the liver? Meaning Hydrocodone turns into Hydromorphone as Oxycodone turns to Oxymorphone and Codiene, Morphine and Heroin all just turn into Morphine. Correct me if I'm wrong, this was just a though.

[Gradient]

Originally Posted by Bodyrot

Shouldn't you refer to the actual drug it is turned into after it passes the liver? Meaning Hydrocodone turns into Hydromorphone as Oxycodone turns to Oxymorphone and Codiene, Morphine and Heroin all just turn into Morphine. Correct me if I'm wrong, this was just a though.

I don't think that I understand this question - please clarify what you mean by referring to an actual drug? These are all well-known drugs. I referred to all three classifications of opioid drugs, giving examples of each. While most opioids have active metabolites - when referring to the initial compound, all discussed effects imply the activity of its metabolites. For example, when discussing diazepam, the effects of both temazepam and oxazepam (metabolites of diazepam) are implied in the characterization of a loooong acting benzodiazepine. Hydrocodone has more metabolites than purely hydromorphone;

Unchanged drug (hydrocodone), norhydrocodone, conjugated hydrocodone, 6-hydrocodol, and conjugated 6-hydromorphol: taken from here

Likewise, Tramadol is metabolized into 5 different compounds - all with varying effects at the µ-opioid, serotonin & norepinephrine transporters. It would be cumbersome to discuss the effects of Tramadol by distinguishing the relative contributions to the overall neural activity generated by Tramadol. Rather, it's easier to simply state that Tramadol is characterized by significant activity at the µ-opioid receptor, and NE & 5-HT transporters - while, in reality, some of its 5 metabolites have activity at only one or two of the three discussed proteins.

So you see, it is an oversimplification to simply discuss one predominant metabolite of a given compound to represent all opioids; it's more complex than that. It's more effective to discuss the effects of the mother compound, accommodating the individual activities of the resulting metabolites.

I agree, however, that a meticulous assessment of the individual activities of all of the active metabolites of a given opioid will provide a greater level of comfort when combining MAOIs with mother compounds; this will foster a better understanding of whether or not a given opioid will have activity at monoamine neurotransmitter transporter proteins/receptors. This would be a pretty prudent, self-conserving endeavor - and would likely generate some interesting potential potentiation relationships.

P.S: This would be the beginning of a terrific thread if people decided to distinguish between safe opiates to combine with MAOIs!

[killersnowman]

hey everyone. thanks for all the responses. swim glance through them all and is gonna have to re-read most of it to really obsorb some of this info. but in the mean time swim does have some questions to further discussions:

1. there must be someone out there that has tried this...
2. if someone where to try this, what MAOI would be best... would syrian rue work?

also from what swim understands from reading this thread and related literature that pure opioids that act on nothing other than opioid receptors may be safe and the biggest danger is the danger of serotonin syndrome caused by mixing MAOIs with opioids with mixed functions such as NMDA agonists like methadone.

the level of potentiation of substances like morphine, if any, are yet to be established....

[Bodyrot]

Originally Posted by Gradient

Likewise, Tramadol is metabolized into 5 different compounds metabolites.

I believe you answered you own question in your response to mine. By "actual drug" I meant the drug it turns into after it metabolizes. Pvt. message me if you need further explanation. Sorry if I sound "prickish", it isn't my intent, I just try to use proper English when posting my thoughts on subjects, and I do agree one the PS. you left.

Bodyrot added 3 Minutes and 37 Seconds later...

Originally Posted by Gradient

Likewise, Tramadol is metabolized into 5 different compounds metabolites.

I believe you answered you own question in your response to mine. By "actual drug" I meant the drug it turns into after it metabolizes. Pvt. message me if you need further explanation. Sorry if I sound "prickish", it isn't my intent, I just try to use proper English when posting my thoughts on subjects, and I do agree one the PS. you left. Also, my doctor had said SSRI's are much better for SWIY, correct me if I'm wrong, but I also guess this all depends on your person chemistry.