Tapentadol (Palexia Retard) - Retrospective - Underrated Opioid

[Forever Changes]

Tapentadol is no better for me for analgesia (pain relief) than any other opioids I've tried - my pain doctor is now suggesting Capsaicin (!) - that's the same stuff as in chilli peppers. Apparently you can get Capasaicin patches for nocioplastic pain relief.

However, recreationally I do get something from Tapentadol - moreso than from the (admittedley limited) other opioids I've tried - Codeine, DHC, Tramdol and Kratom. None of which have done anything for me. I only tried Tramadol once as I was too wary to take too much due to seizure risk.

Anyway my experience with Tapentadol:

Been using Tapentadol for a while now. Started off with a 100mg and gradually increased the dose over time by using it daily so of course my tolerance started to increase and now I'm taking somewhere in the region of 800mg-1000mg at a time to feel the same effects. Also sometimes combine it with Soma (Carisoprodol). Not willing to risk combining it with Benzos

When it works, Tapentadol is strange but I quite like it - it gives a sort of buzzy-type high. Sometimes when I stare at something like the carpet or the wall I could swear it looks like it's shifting and moving. However the duration doesn't usually last for long. And sometimes it doesn't have any effect at all which is a bit frustrating. Also - a bit like with Benzos - I've found that it's made me do some strange shit that I have no memory of doing- like discovering that I've moved objects and put them in weird places during the night - so that's slightly alarming and something to be careful of. Another side effect is it makes it difficult to urinate - After a Tapentadol session I find I'm standing over the toilet willing my bladder to empty as it trickles out....

I'm abstaining for a while to bring my tolerance down though. I obviously didn't learn from my Pregabalin expereince - with Preg I really enjoyed the buzz so I started using it daily and saw a rapid tolerance rise which eventually saw me taking very high doses to feel the same effect. Discipline! Discipline! Discipline!

 

[nznity]

Do you have experience with other opioids/have a tolerance?

Massive morphine tolerance but when I tried tapentadol I was on a break, still felt underwhelming meh

 

[MsDiz]

Tapentadol is no better for me for analgesia (pain relief) than any other opioids I've tried - my pain doctor is now suggesting Capsaicin (!) - that's the same stuff as in chilli peppers. Apparently you can get Capasaicin patches for nocioplastic pain relief.

However, recreationally I do get something from Tapentadol - moreso than from the (admittedley limited) other opioids I've tried - Codeine, DHC, Tramdol and Kratom. None of which have done anything for me. I only tried Tramadol once as I was too wary to take too much due to seizure risk.

Anyway my experience with Tapentadol:

Been using Tapentadol for a while now. Started off with a 100mg and gradually increased the dose over time by using it daily so of course my tolerance started to increase and now I'm taking somewhere in the region of 800mg-1000mg at a time to feel the same effects. Also sometimes combine it with Soma (Carisoprodol). Not willing to risk combining it with Benzos

When it works, Tapentadol is strange but I quite like it - it gives a sort of buzzy-type high. Sometimes when I stare at something like the carpet or the wall I could swear it looks like it's shifting and moving. However the duration doesn't usually last for long. And sometimes it doesn't have any effect at all which is a bit frustrating. Also - a bit like with Benzos - I've found that it's made me do some strange shit that I have no memory of doing- like discovering that I've moved objects and put them in weird places during the night - so that's slightly alarming and something to be careful of. Another side effect is it makes it difficult to urinate - After a Tapentadol session I find I'm standing over the toilet willing my bladder to empty as it trickles out....

I'm abstaining for a while to bring my tolerance down though. I obviously didn't learn from my Pregabalin expereince - with Preg I really enjoyed the buzz so I started using it daily and saw a rapid tolerance rise which eventually saw me taking very high doses to feel the same effect. Discipline! Discipline! Discipline!

You need to get that dose down, whilst I said the seizure risk is lower there is still a risk. Tapentadol max dose is 500mg. I would really caution you with taking those big doses.

Take a tolerance break or taper down to a lower dose.

 

[Forever Changes]

You need to get that dose down, whilst I said the seizure risk is lower there is still a risk. Tapentadol max dose is 500mg. I would really caution you with taking those big doses.

Take a tolerance break or taper down to a lower dose.

Will do, thanks for the advice. As Benzodiazepines and Pregabalin are Anticonvulsants, would taking them along with Tapentadol lower risk of seizures, or would that be too dangerous since Opioids + Benzos are a big no-no for HR? (I've never dared do that combo before)

 

[MsDiz]

Will do, thanks for the advice. As Benzodiazepines and Pregabalin are Anticonvulsants, would taking them along with Tapentadol lower risk of seizures, or would that be too dangerous since Opioids + Benzos are a big no-no for HR? (I've never dared do that combo before)

The advice very much is to not mix benzos and opioids. Pregabalin along with tapentadol will also increase side effects and it won’t be a nice feeling. It goes without saying it’s also dangerous.

 

[silver_lining]

I definitely enjoy Tapentadol much better mixed 1:1 with Soma. Last nights nods were amazing, like i was sitting there with my eyes open aware of my surroundings, while fully dreaming. I'd actually respond outloud to things happening in the dream. I'd bloop in and out of several dreams till i finally zonked out in my chair for a few hours before finding the actual bed.

I also took 10mg Valium that morning, and 2mg Klonopin in the eve. 300g of both Tapentadol & Soma consumed in increments.

 

[Forever Changes]

The advice very much is to not mix benzos and opioids. Pregabalin along with tapentadol will also increase side effects and it won’t be a nice feeling. It goes without saying it’s also dangerous.

Yeah I've never mixed that combo before.

Do you know any painkillers effective for nocioplastic pain? From what I understand it's a relatively poorly understood field - a bit like phantom limb syndrome. After 25 years I finally saw a consultant who suggested that might be what I have

 

[Forever Changes]

I definitely enjoy Tapentadol much better mixed 1:1 with Soma. Last nights nods were amazing, like i was sitting there with my eyes open aware of my surroundings, while fully dreaming. I'd actually respond outloud to things happening in the dream. I'd bloop in and out of several dreams till i finally zonked out in my chair for a few hours before finding the actual bed.

I also took 10mg Valium that morning, and 2mg Klonopin in the eve. 300g of both Tapentadol & Soma consumed in increments.

Be a little careful about zonking out in chairs with arms. I did that once and got a radial nerve palsy - when the nerve under your arm is compressed and it paralyses your wrist - fortunately it was only temporary.

 

[MsDiz]

Yeah I've never mixed that combo before.

Do you know any painkillers effective for nocioplastic pain? From what I understand it's a relatively poorly understood field - a bit like phantom limb syndrome. After 25 years I finally saw a consultant who suggested that might be what I have

Honestly, I have seen SNRIs and gabapentinoids to tread that type of pain but also CBT, exercise and breathing exercises as well.

 

[Azed]

Yeah I've never mixed that combo before.

Do you know any painkillers effective for nocioplastic pain? From what I understand it's a relatively poorly understood field - a bit like phantom limb syndrome. After 25 years I finally saw a consultant who suggested that might be what I have

Have you tried Celecoxib?

 

[Forever Changes]

Have you tried Celecoxib?

They prescribed me Etoricoxib which is I think is a similar NSAID medication. Did nothing for the pain though. Unlike neuropathic or nococeptic pain, nociplastic pain seems to be something to do with a distortion or sensitisation of pain signals in the CNS even long after the original cause of the pain disappeared. They're now suggesting I try Caspsaicin patches

 

[Azed]

They prescribed me Etoricoxib which is I think is a similar NSAID medication. Did nothing for the pain though. Unlike neuropathic or nococeptic pain, nociplastic pain seems to be something to do with a distortion or sensitisation of pain signals in the CNS even long after the original cause of the pain disappeared. They're now suggesting I try Caspsaicin patches

Is Seglentis available for you? It's Celecoxib and Tramadol. Sounds like a tough experience, have you tried/had any success with any other pain management medications?

 

[Fertile]

I don't know why, but when tapentadol was introduced in the UK, it was added to the list of category A drugs with the result that NO doctor ever prescribes it.

Since it's a mixed agonist, I don't understand it from it's potential abuse potential. After all, if you mixed it with morphine, it would reduce the subjective effect of the mixture (if the studies are correct).

Chemically, tapentadol is an open-ring analog of picanadol.

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Image 1 hosted in ImgBB

ibb.co

Close examination of tapentadol will show that it is a ring-open analog of picenadol.

 

[Forever Changes]

Is Seglentis available for you? It's Celecoxib and Tramadol. Sounds like a tough experience, have you tried/had any success with any other pain management medications?

Depends what the doctors are prepared to prescribe in the UK National Health Service (which is in a state of total dysfunction at the moment) - usually it's nothing more than Ibuprofen or paracetemol .I have different kinds of pain - general nociopathic pain due to hypermobile joints/connective tissue disorder and pronated feet which means walking or standing is painful. On top of that one of my big toes has been acutely and permanently painful for about 30 years - which is probably the nocioplastic pain.

As if that wasn't enough, inflamed bowel disease means I often get excruciating painful intestinal cramps - honestly they're the worst pain I've ever experienced - I've actually passed out several times during a bout... now I know what it's like for women to give birth! LOL

I've tried self-medicating with slightly stronger analgesics I've acquired online but never found them much use

 

[Forever Changes]

I don't know why, but when tapentadol was introduced in the UK, it was added to the list of category A drugs with the result that NO doctor ever prescribes it.

Since it's a mixed agonist, I don't understand it from it's potential abuse potential. After all, if you mixed it with morphine, it would reduce the subjective effect of the mixture (if the studies are correct).

Chemically, tapentadol is an open-ring analog of picanadol.

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Close examination of tapentadol will show that it is a ring-open analog of picenadol.

Don't try to understand the reasoning behind UK govt drug policy or classification... it's never made any sense.

Is Tapentadol unusual because it's an NRI as well as an opioid?

 

[silver_lining]

Is Tapentadol unusual..

Super unusual. First few hours are a very much so an upper, and then it takes a 180 and you start to nod 3+ hrs after dosing.
Alot of noise & visual hallucinations, like being in a dream but you respond to the dream while sitting in a room by yourself. First time it happened it scared the shit out of me. Now i'm quite a fan. I also dose it with valium & soma in small doses, while the opioid i keep at around 200-300mg per session.

I don't know if it is common to get the "upper" effect, but honestly i just pop another valium and it calms down. I'm much more interestd in the NOD not the busy mind bullshit

 

[Fertile]

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Image 1 hosted in ImgBB

ibb.co

Sorry - didn't make it abundantly clear.

Tapentanol's minimum energy-state overlays that of the agonist isomer if picenalol. BUT the key difference is that picenalol has a N-propyl moiety at the bebzylic carbon making it an agonist. An antagonist gives a mixed agonist and other elements make it more or less agonistic (see 2 images) and of course, picenalol is chiral and unless you resolve those 2 isomers, you will end up with an agonist isomer and an antagonist isomer.

BUT this does reignite a question that Eisleb and the team at I.G. Farben and while finished items were simply given to allied nations who patented them, unfinished projects went to nothing.

Now it was Eisleb who discovered prodine and many other phenylpiperidine classes of opioid but ketobemidone is unique:

1- The only example of a phenolic phenylpiperidine
2- High potency in spite of lacking any of the modifications associated with strong analgesia (25mg is supposed to equate to 60mg of morphine
3- None of the groups generally added to increase potency resulted in antagonists.

But here is the question - prodine and the other chiral opioids discovered by Eusleb were ALL agonists - it's just that some were much more potent than opioids. But given that adding many of these groups adds a chiral centre and Eiselb never tried to resolve the isomers, how do we know that 1 isomer is an agonist, the other an antagonist and so in animal models, they will appear to be inactive.

https://ibb.co/yBfRJwF

As you can see, adding a 3-methyl to the structure results in 4 stereoisomers. It's also well worth noting that ANY other N-substitution than a methyl also results in an antagonists or a weak partial agonist.

Careful comparison with picenalol suggests that the 3S,4R & 3S,4S are the most interesting (numbering means the 3S,4R overlays the 3R,4R of picenalol. Ciramadol & tapentadol (1R,2R - again, numbering) seems to be an agonist when the phenol and 3-methyl have the same optical position (i.e. aromatic is above methyl).

As to why only the N-methyl is active... well that seems to be the case will all synthetic phenolic opioids Please correct me if I am wrong). But it seems phenolic opioids are SO difficult to design and seem to have so few advantages, researchers just don't go for them..

Meptazinol is another interesting example given lack of ester/ether/ketone/sulfonate or bioisostere and the benzylic carbon having an ethyl chaine - another example of a partial agonist.

So while opioids in general provide a big puzzle, even the experts only know a few scant rules CC phenolic opioids.

I will conclude with a statement seemingly cut and pasted into every book on opioids written between 1950 and 2022 - 'It is believed and phenolic and non-phenolic opioids bind to a different position within the opiate receptor'. Nothing added, nothing taken away, it's officially 'unknown'.

MAYBE only a 3-methyl can be added to ketobemidone but if the product is some x9 more potent.... that places it firmly in the class of 'potent opioids'. Of course, rather than throwing away 75% of the product, it may turn out that 2 are agonists and one is simply more potent... so I would leave that.

But if a decent way to make use of the wasted 50% would make it attractive - after all, if it's 3.5 hours rather than 20 minutes... I PRESUME people would seek it out.

 

[Forever Changes]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Sorry - didn't make it abundantly clear.

Tapentanol's minimum energy-state overlays that of the agonist isomer if picenalol. BUT the key difference is that picenalol has a N-propyl moiety at the bebzylic carbon making it an agonist. An antagonist gives a mixed agonist and other elements make it more or less agonistic (see 2 images) and of course, picenalol is chiral and unless you resolve those 2 isomers, you will end up with an agonist isomer and an antagonist isomer.

BUT this does reignite a question that Eisleb and the team at I.G. Farben and while finished items were simply given to allied nations who patented them, unfinished projects went to nothing.

Now it was Eisleb who discovered prodine and many other phenylpiperidine classes of opioid but ketobemidone is unique:

1- The only example of a phenolic phenylpiperidine
2- High potency in spite of lacking any of the modifications associated with strong analgesia (25mg is supposed to equate to 60mg of morphine
3- None of the groups generally added to increase potency resulted in antagonists.

But here is the question - prodine and the other chiral opioids discovered by Eusleb were ALL agonists - it's just that some were much more potent than opioids. But given that adding many of these groups adds a chiral centre and Eiselb never tried to resolve the isomers, how do we know that 1 isomer is an agonist, the other an antagonist and so in animal models, they will appear to be inactive.

https://ibb.co/yBfRJwF

As you can see, adding a 3-methyl to the structure results in 4 stereoisomers. It's also well worth noting that ANY other N-substitution than a methyl also results in an antagonists or a weak partial agonist.

Careful comparison with picenalol suggests that the 3S,4R & 3S,4S are the most interesting (numbering means the 3S,4R overlays the 3R,4R of picenalol. Ciramadol & tapentadol (1R,2R - again, numbering) seems to be an agonist when the phenol and 3-methyl have the same optical position (i.e. aromatic is above methyl).

As to why only the N-methyl is active... well that seems to be the case will all synthetic phenolic opioids Please correct me if I am wrong). But it seems phenolic opioids are SO difficult to design and seem to have so few advantages, researchers just don't go for them..

Meptazinol is another interesting example given lack of ester/ether/ketone/sulfonate or bioisostere and the benzylic carbon having an ethyl chaine - another example of a partial agonist.

So while opioids in general provide a big puzzle, even the experts only know a few scant rules CC phenolic opioids.

I will conclude with a statement seemingly cut and pasted into every book on opioids written between 1950 and 2022 - 'It is believed and phenolic and non-phenolic opioids bind to a different position within the opiate receptor'. Nothing added, nothing taken away, it's officially 'unknown'.

MAYBE only a 3-methyl can be added to ketobemidone but if the product is some x9 more potent.... that places it firmly in the class of 'potent opioids'. Of course, rather than throwing away 75% of the product, it may turn out that 2 are agonists and one is simply more potent... so I would leave that.

But if a decent way to make use of the wasted 50% would make it attractive - after all, if it's 3.5 hours rather than 20 minutes... I PRESUME people would seek it out.

a lot of that went over my head - you obviously know your chemistry. But as to your last statement, I think the short duration of Tapentadol's effects are what lead me to redose and redose again hoping the effect will be longer and/or stronger, and therefore inevitably upped my tolerance

 

[Fertile]

As I understand it, tapentadol has a LogP of 0.16 μM at the MOR (mu opioid receptor). 'For comparison, that is about 10- to 20-fold lower affinity than morphine or oxycodone.' (the last sentence was a quote.

Now this sounds wrong to me (0.16 sounds about the same as morphine) BUT their are so many methods used for such tests, it's not possible to use the result of 2 different tests to compare.

Tapentadol, as well as it's opioid activity, shows dose-dependent inhibition of norepinephrine reuptake, but only moderate increase in serotonin activity (unlike tramadol. So like tapentadol, it's analgesic action is mediated by multiple actions with 100mg comparing to 15mg of oxycodone as an analgesic.

I can see WHY it's popular with people sensitive or opioid naive or who like the mixed activity of the drug.

It seems safe and well tolerated and I'm sure few people will become dependant but that inhibition of norepinephrine reuptake will lower seizure threshold.

I also appreciate the chemistry. I designed the analogue that is a full agonist with more affinity. Heck - if you like it, I do not see it causing you serious harm.

 

[Forever Changes]

As I understand it, tapentadol has a LogP of 0.16 μM at the MOR (mu opioid receptor). 'For comparison, that is about 10- to 20-fold lower affinity than morphine or oxycodone.' (the last sentence was a quote.

Now this sounds wrong to me (0.16 sounds about the same as morphine) BUT their are so many methods used for such tests, it's not possible to use the result of 2 different tests to compare.

Tapentadol, as well as it's opioid activity, shows dose-dependent inhibition of norepinephrine reuptake, but only moderate increase in serotonin activity (unlike tramadol. So like tapentadol, it's analgesic action is mediated by multiple actions with 100mg comparing to 15mg of oxycodone as an analgesic.

I can see WHY it's popular with people sensitive or opioid naive or who like the mixed activity of the drug.

It seems safe and well tolerated and I'm sure few people will become dependant but that inhibition of norepinephrine reuptake will lower seizure threshold.

I also appreciate the chemistry. I designed the analogue that is a full agonist with more affinity. Heck - if you like it, I do not see it causing you serious harm.

I guess because I never got anything from codeine/DHC/Tramadol/Oxycodone/Poppy tea or Kratom, I was pleasantly surprised that Tapentadol had some effect, albeit not analgesically. Do you think there's anything you can combine Tapentadol with that might make it last longer? It does come in combinations with Carisoprodol/soma