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About Tramadol and SERT Values.

supersonic89

supersonic89

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Sep 17, 2019
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First of all, I don't know if I'm asking in the right place. Hope so.

I've been reading the Wiki entry on Tramadol (https://en.wikipedia.org/wiki/Tramadol#Pharmacology) and I read that the Serotonin Transport (SERT) value is 992-1190 (I don't know much about this, but I guess the closer to 0 the higher the action or effect of the drug on the serotonin, right?). While a widely used antidepressant called Sertraline has a value of 0.4-2.8. Pretty freaking low.

So I'll have a few questions about this:

(1) What do these values mean?

(2) This SERT value (of tramadol) shows that, contrary to popular belief, tramadol doen't have much action or effect on serotonin?

(3) Regarding the above, would this show that the antidepressant effects of tramadol are actually product of its opioid metabolite? Which would demostrate that in fact any opioid can be used as an anti-depressant?

Thanks in advance.
 
The affinity values overestimate the effectiveness of sertraline because most of it is bound to proteins in plasma and isn't available for receptor binding.
 
↑Really? I never noticed that. I'm on desvenlafaxine. State insurance usually doesn't pay for that one here but I got an exception when my GeneSight test recommended it for me. I need to check if it has opioid affinity, it's probably just different enough not to, though.
 
Nagelfar said:
↑Really? I never noticed that. I'm on desvenlafaxine. State insurance usually doesn't pay for that one here but I got an exception when my GeneSight test recommended it for me. I need to check if it has opioid affinity, it's probably just different enough not to, though.
Click to expand...
Indeed, it’s in most of the literature in regards to tramadol. Here’s a pic.

 
↑Yes I noticed once it was mentioned. Reminds me of the difference between methylphenidate and phenmetrazine.
 
Thanks guys and girls.

That's why I guess I fail chemistry. :LOL:

But, there was excellent data provided by you.

PrincessDiz said:
Tramadol definitely has SNRI properties, in fact it’s very similar to venlafaxine even structurally, they are closely related.

Heres a good link to read for you...

Click to expand...

That's something I did know. In fact, venlafaxine appears to have some kind of affinity for opioid receptors. (https://en.wikipedia.org/wiki/Venlafaxine#Pharmacology)
In theory, @Nagelfar, desvenlafaxine should behave similarly to venlafaxine, as it's its main metabolite. Something like taking O-DMST instead of tramadol e.g.. Just like I said, I think it should have a little affinity for opioid receptors, at least venlafaxine has them (https://en.wikipedia.org/wiki/Venlafaxine#Pharmacology).

Funny thing is that many people who have switched from tramadol to venlafaxine say they don't "feel" same at all and feel venlafaxine works worse on its depression . But, I suppose it's due to the lack of o-desmethyltramadol in venlafaxine.

I would like to go back to taking venlafaxine, it was the most effective "typical" antidepressant for my depression and anxiety. But my insured does not cover it. I took it almost 10 years ago, so I wouldn't know how to compare it to tramadol. Although I didn't take it alone, but together with sertraline. On the advice of my psychiatrist. Something weird, right? Like some kind of California Rocket Fuel. But I know it was the venlafaxine that made me improve, because before I was taking only sertraline for almost 1 year and I didn't notice much improvement.

ibtisam midlet said:
i have calculate it for you, the lower number the higher affinity find the lowest affinty in all the drug and the metabolism so the metabolism of tramadol DSMT have strong affinity to mu-opiates receptors by 17ki nm
multiple it by x5 you get 85

Metabolism: Tramadol is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.

so multible 85 by (100/(100-30)) you get 121,42ki nm

tramadol have 6h helf life where dsmt have 7 so 121,42/(7/6)=104,07kinm

for Protein binding tramadol bind by 20% but dsmt have no info, so lets say its the same

after of all this calculation it means that any value over 104kinm is not relevant in therapy doses and tramadol have 992 nm for SERT/NET binding
data got from http://www.bindingdb.org/bind/as.jsp

992(SERT/NET binding)/104.07(lowest kinm value found)=9,54

the lowest dose of tramadol is 50mg/day 50x9.54=477
finally mean any doses more then 477mg/day will able to block serotonine and noradrenaline transporters, so yeah you have serotonine and noradrenaline dependence
Click to expand...

Really interesting. But I think I understood half of what you wrote, but you definitely gave me enough material to research this Friday night. :LOL:

I wonder if that value of tramadol (9.54), what antidepressant can be comparable? Someone knows?

Anyway, thank you all for your responses. ♥️
 
ibtisam midlet said:
Metabolism: Tramadol is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.
Click to expand...

So in theory, if in about 6-8 hours of consumption of tramadol (1200 mg.) you could get through urine, in the best case (30% of the metabolites), something like 100-150 mg. of o-desmethyltramadol, right?
 
ibtisam midlet said:
no consumption of 1200mg tramadol will lead to 720mg of o-desmethyltramadol after that you could get through urine
1200/(100/60)=720
Click to expand...

Okay. Thanks a lot.

A few last doubts. Sorry for bothering you so much. :LOL:

Will my body excrete the metabolites of tramadol from the moment it's metabolized in my liver and my kidneys are ready to eliminate them, right? At what point will my body be mostly excreting the metabolites? After the onset of action of the drug (0-1 hour)* or during its elimination-half life (6.3 ± 1.4 h)**?

We're talking in case some normal metabolizer guy.

* https://www.drugs.com/monograph/tramadol-hydrochloride.html
** http://reference.medscape.com/drug/ultram-er-tramadol-343324#showall
 
i have calculate it for you, the lower number the higher affinity find the lowest affinty in all the drug and the metabolism so the metabolism of tramadol DSMT have strong affinity to mu-opiates receptors by 17ki nm
multiple it by x5 you get 85

Metabolism: Tramadol is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.

so multible 85 by (100/(100-30)) you get 121,42ki nm

tramadol have 6h helf life where dsmt have 7 so 121,42/(7/6)=104,07kinm

for Protein binding tramadol bind by 20% but dsmt have no info, so lets say its the same

after of all this calculation it means that any value over 104kinm is not relevant in therapy doses and tramadol have 992 nm for SERT/NET binding
data got from http://www.bindingdb.org/bind/as.jsp

992(SERT/NET binding)/104.07(lowest kinm value found)=9,54

the lowest dose of tramadol is 50mg/day 50x9.54=477
finally mean any doses more then 477mg/day will able to block serotonine and noradrenaline transporters, so yeah you have serotonine and noradrenaline dependence
Click to expand...

This is so wrong it hurts... you can't just multiply and divide affinities like that, it doesn't make sense.
The binding affinity or Ki is a measure of the concentration of a drug needed to displace 50% of a ligand from a receptor site. It's specific to each individual drug and cannot be used to accurately predict the affinity of other drugs.
The correct way to estimate drug binding at a receptor is to first find the blood concentration of the drug in question, convert it from milligrams/mL to millimoles/mL by dividing by the drug's molecular weight, then compare the concentration to the Ki. If the concentration is greater then the Ki you can assume it will bind the receptor.
This still does not tell you how much the receptor will become activated though, you need a separate measurement called EC50 to determine that.


Will my body excrete the metabolites of tramadol from the moment it's metabolized in my liver and my kidneys are ready to eliminate them, right?
Click to expand...
Your kidneys and liver are always working, they will start metabolizing and excreting any drug that enters your bloodstream.
 
Last edited:
sekio said:
This is so wrong it hurts... you can't just multiply and divide affinities like that, it doesn't make sense.
The binding affinity or Ki is a measure of the concentration of a drug needed to displace 50% of a ligand from a receptor site. It's specific to each individual drug and cannot be used to accurately predict the affinity of other drugs.
The correct way to estimate drug binding at a receptor is to first find the blood concentration of the drug in question, convert it from milligrams/mL to millimoles/mL by dividing by the drug's molecular weight, then compare the concentration to the Ki. If the concentration is greater then the Ki you can assume it will bind the receptor.
This still does not tell you how much the receptor will become activated though, you need a separate measurement called EC50 to determine that.



Your kidneys and liver are always working, they will start metabolizing and excreting any drug that enters your bloodstream.
Click to expand...
At 400mg a day sure inhibits sert at some lvl.
Sekio, i have read and learned your posts over a decade and would love to hear your take on tramadol on pain or opioids in general for pain.

For me tramadol is the only painkiller doing it all and no tolerance for pain. Where as all pure opioids is like trying to put a fire down with gasoline in the long run. Is it just the trams synergy of all it's influencing it is there something I'm not seeing?

I know pharmacology at low lvl but can read quite hard text's if necessary.
 
Real santa from Finland said:
At 400mg a day sure inhibits sert at some lvl.
Sekio, i have read and learned your posts over a decade and would love to hear your take on tramadol on pain or opioids in general for pain.

For me tramadol is the only painkiller doing it all and no tolerance for pain. Where as all pure opioids is like trying to put a fire down with gasoline in the long run. Is it just the trams synergy of all it's influencing it is there something I'm not seeing?

I know pharmacology at low lvl but can read quite hard text's if necessary.
Click to expand...

Maybe it's the double action of tramadol (opioid and serotonin reuptake). ?
What kind of pain do you take it for? I think some types of pain where duloxetine (an SSRI or SNRI Idk remember right now) is used eg. Have you tried Tapentadol? Like tramadol, it also has a dual action but is not a pro drug.
 
I would stay clear off tramadol long term use. I have had some nightmares dealing with this one. First of all it helped A LOT with heroin WDs, so i thought its pretty good shit. I mean, I wasnt like really getting high on it so i thought its ok. Thats another problem with it though, you do not realize you are addicted to it because it lacks straight forward HIGH moment and appreciation therefore addiction moment. Its more like, subtle, and you keep doing it and it gets to you REAL DEEP to the core. It had some of the worst WDs i have had in a while after i stopped it. i was shocked that it did this. My biggest problem though is, the seizures! I am a regular drinker so i should have been smarter investigating this one better before over using because it caused me some mild seziures when off the alcohol. DAMN!

Conclusion: Highly Underrated opiate, which should be carefully monitored and not be used long term EVER!. Especially people using alcohol or having siezure issues, to avoid completely!!!
 
allone said:
I would stay clear off tramadol long term use. I have had some nightmares dealing with this one. First of all it helped A LOT with heroin WDs, so i thought its pretty good shit. I mean, I wasnt like really getting high on it so i thought its ok. Thats another problem with it though, you do not realize you are addicted to it because it lacks straight forward HIGH moment and appreciation therefore addiction moment. Its more like, subtle, and you keep doing it and it gets to you REAL DEEP to the core. It had some of the worst WDs i have had in a while after i stopped it. i was shocked that it did this. My biggest problem though is, the seizures! I am a regular drinker so i should have been smarter investigating this one better before over using because it caused me some mild seziures when off the alcohol. DAMN!

Conclusion: Highly Underrated opiate, which should be carefully monitored and not be used long term EVER!. Especially people using alcohol or having siezure issues, to avoid completely!!!
Click to expand...

I agree on almost everything. And I would add that people prone to depression shouldn't take it either.
I didn't know about the seizures either until months after taking it daily but luckily nothing ever happened to me. And I thought alcohol, being similar to benzodiazepines, maybe have some anticonvulsant action but I see that I am wrong.
 
allone said:
I would stay clear off tramadol long term use. I have had some nightmares dealing with this one. First of all it helped A LOT with heroin WDs, so i thought its pretty good shit. I mean, I wasnt like really getting high on it so i thought its ok. Thats another problem with it though, you do not realize you are addicted to it because it lacks straight forward HIGH moment and appreciation therefore addiction moment. Its more like, subtle, and you keep doing it and it gets to you REAL DEEP to the core. It had some of the worst WDs i have had in a while after i stopped it. i was shocked that it did this. My biggest problem though is, the seizures! I am a regular drinker so i should have been smarter investigating this one better before over using because it caused me some mild seziures when off the alcohol. DAMN!

Conclusion: Highly Underrated opiate, which should be carefully monitored and not be used long term EVER!. Especially people using alcohol or having siezure issues, to avoid completely!!!
Click to expand...
I agree on many points, mostly that alcoholics shouldn't take it. Users having self control and ability to taper it's a whole another world.

I have used it on off over decade, no seizures even when stupidly stopping benzos wo tapering.

Just saying imo the worst drug to abuse but for some types of chronic pain problems if opioid is needed I would go for it.

I have had quite horrible withdrawal stopping tramadol, lyrica and benzos after getting serious side effects on fluoroqinolone antibiotics.

I have also tapered tramadol too fast causing some withdrawals but nowadays I can taper it easily quite fast. Don't abuse it or prepare for hell!
 
MsDiz said:
Just curious why you think it’s unfortunate? Do you work in a lab?
Click to expand...


Nah I was just curious. I took tramadol for nearly 10 years and it had a great affect on my depression that was unmatched my many other drugs. After I was no longer able to get it, I tried Effexor thinking it would feel similar to tramadol, but it didn't. It actually made me feel sick and dysphoric and even manic at times. So there must be something special about tramadol that Effexor is lacking. I would say the opioid part, but I also take buprenorphine and have used tramadol ontop of it with still some effect.

Of course, I am too ignorant to pull off any chemistry conversion if there were one. lol But I know many other drugs can be turned into something else just by mixing it with certain things. I enjoy learning about pharmacodynamics & pharmacology though and bits of chemistry when I can understand it. So I was just generally curious.
I wish I worked in a lab. :p :p :p
Cheers MsDiz! :)
 
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