Tramadol is a fully-synthetic opioid pro-drug with SSNRI activity. Upon ingestion, the digestive cytochrome enzymes - the cytochrome P450 family specifically - metabolize Tramadol into five distinct compounds. O-Desmethyltramadol, one of the five, has a markedly high affinity for the µ-opioid receptor, far more so than Tramadol itself. The same enzymes that convert Tramadol to its 5 metabolites, cytochrome P450, ionize these metabolites for water-soluble excretion. Therefore, the metabolism of Tramadol revolves entirely around the metabolic activity of cytochrome P450 in the liver.
Cimetidine (Tagamet) is a potent inhibitor of the cytochrome P450 enzyme, in addition to acting as a pH neutralizer. Therefore, if one were to ingest cimetidine prior to ingestion of Tramadol, one would likely experience a reduction of effects. However, if one were to wait until ingested Tramadol had time to be converted to its metabolites (30-180 mins), the ionization of the metabolites of Tramadol should be inhibited. This would be expected to enhance and prolong the effects of Tramadol at the µ-opioid receptor considerably. In sum, in order to potentiate the effects of Tramadol with cimetidine, timing and sequence is key.
In addition, subsequent to regular administration of recommended doses of cimetidine, the liver will up-regulate the expression of the enzymes responsible for converting Tramadol to its more potent metabolites. In other words, after ingesting cimetidine for a regular interval of time, one will become more sensitive to the effects of Tramadol. It should be noted, however, that this dynamic would render an individual less sensitive to other non-synthetic and semi-synthetic opiates over time.
A friendly chimp has revealed that this has been a highly effective and reliable method of potentiation. He doesnt ingest Tramadol without cimetidine anymore. It should be noted that grapefruit juice has indeed been noted to be a cytochrome P450 inhibitor as well, though not quite as potently as cimetidine. This method should produce no anticipated ill-effects, as the magnitude of effects will never exceed the SSNRI activity inherent to the initial dose ingested. So long as one takes care not to initially ingest too-high a dose, this method of potentiation will not enhance SSNRI activity rather, it should selectively enhance µ-opioid activity because it's the metabolites, not Tramadol, that are being enhanced.
Hope this helps to get the most bang-for-your-milligram in as safe a way as possible ! Since this method of potentiation is so distinct from typical methods for the majority of other opiates, I figured it warranted a thread of its own - I apologize if this was a mistake. I'd be quite interested to know if this works for any other chimps out there.
Added subsequent to Richard_smoker's post: I've confirmed that the CYP2D6 is indeed responsible for both the metabolism of Tramadol to its five metabolites, as well as the ionization of o-desmethyltramadol for excretion. Therefore, the described relationship is likely to exist.
However, this doesn't necessarily mean that I'm correct! There is no study on this specific interaction (including the sequencing of ingestion of the compounds). Please suggest any potential issues with this theory that we might iron out, I'd greatly appreciate it!
Last edited by Gradient; 13-09-2009 at 20:05.
Reason: Checked on cytochrome enzyme upon Richard_smokers suggestion
hmmm... you know there are several different specific subtypes of the CYP (cytochrome 450) enzyme. I can tell you a much more effective way of enhancing the drug than this approach.
Some information about which specific type of P450 enzyme breaks the tramadol down, and which one breaks down the O-Desmethyltramadol.
If there's any data out there for which enzyme breaks down the O-Desmethyl, then if that enzyme is DIFFERENT than the one which breaks down tramadol itself, then someone could presumably take a specific inhibitor of THAT p450 enzyme. this would allow the tramadol to convert into the 'better' drug which would accumulate in a hypothetical person's bloodstream because its break-down enzyme would be unavailable (cuz it's being inhibited).
hmmm... you know there are several different specific subtypes of the CYP (cytochrome 450) enzyme. I can tell you a much more effective way of enhancing the drug than this approach.
Some information about which specific type of P450 enzyme breaks the tramadol down, and which one breaks down the O-Desmethyltramadol.
If there's any data out there for which enzyme breaks down the O-Desmethyl, then if that enzyme is DIFFERENT than the one which breaks down tramadol itself, then someone could presumably take a specific inhibitor of THAT p450 enzyme. this would allow the tramadol to convert into the 'better' drug which would accumulate in a hypothetical person's bloodstream because its break-down enzyme would be unavailable (cuz it's being inhibited).
Richard_smoker,
Quite true. However, to the best of my knowledge, it is indeed the same enzyme: CYP2D6.
Here's a quickie abstract that suggests that cimetidine does indeed inhibit CYP2D6:
Quote:
Originally Posted by Drug interaction between cimetidine and timolol ophthalmic solution: effect on heart rate and intraocular pressure in healthy Japanese volunteers
Systemic adverse effects of timolol ophthalmic solution given at usual therapeutic doses have been well characterized. Timolol is partially metabolized by cytochrome P450 (CYP) 2D6. Cimetidine inhibits the activity of cytochrome P450, including CYP2D6, leading to reduced systemic clearance of concomitant drugs. Coadministration of cimetidine has been speculated to affect the pharmacological effects of timolol ophthalmic solution, resulting in increased blood concentration. To evaluate whether administration of cimetidine with timolol ophthalmic solution increased the degree of beta-blockade, 12 healthy Japanese male volunteers ages 19 to 26 received cimetidine (400 mg), on oral placebo, timolol maleate 0.5% (0.05 mL to each eye), or placebo eye drops in a randomized, double-blind, Latin-square design. The oral drug alone was given for 3 days, and on the 4th day, eye drops were applied after oral drug administration. At baseline and 1, 3, and 6 hours after eye drop administration, blood pressure and heart rate (HR) were measured before and after exercise. Intraocular pressure (IOP) was measured at rest. A visual analog scale (VAS) was used to assess subjective bodily feelings in exercise tolerance after every physical exercise. The exercise HR, exercise systolic blood pressure (SBP), and resting SBP were reduced following timolol with and without cimetidine compared with the placebo (p < 0.01, respectively). Administration of cimetidine with timolol ophthalmic solution resulted in additional reductions of the resting HR and IOP. VAS detected a significant reduction in exercise tolerance from timolol ophthalmic solution (p < .05). In conclusion, administration of cimetidine with timolol ophthalmic solution increased the degree of beta-blockade.
The metabolism of O-Desmethyltramadol is indeed carried out by CYP2D6.
Therefore, cimetidine would be expected act to inhibit the metabolism of Tramadol to its metabolites if ingested first - but would act to inhibit the metabolism of its metabolites if ingested subsequently.
Last edited by Gradient; 18-12-2012 at 20:04.
Reason: wikipedia link
I'm not sure that one would need the metabolite to be ionized by the same enzyme as the pro-drug. One might consider the enzyme-substrate interactions as more of a temporal spectrum of activity - therefore, most of the Tramadol will be metabolized before the o-desmethyltramadol is able to reach phase II metabolism. This is why is think that the sequencing is key.
It takes a given amount of time for all of the Tramadol to be metabolized, sure. However, given the fact that about an hour subsequent to ingestion, these enzymes have had plenty of time to perform phase I hepatic metabolism - the majority of psychoactivity derived from any given dose will be determined by the amount of Tramadol converted within that first hour of metabolism. Therefore, the rate at which o-desmethyltramadol will be ionized by CYP6D4 will hinder the effects more than the metabolism of any remaining (few molecules left) Tramadol might contribute.
I agree with your assertion that there will inevitably be some Tramadol left to be potentially converted after an hour has passed. However, the amount of o-desmethyltramadol in circulation after that first hour will likely outweigh the potential for additional o-desmethyltramadol to be generated from the remaining Tramadol after an hour has passed. In other words - I agree that there will be some remaining Tramadol that will fail to be converted to its 5 metabolites, but I believe that the enhancement of o-desmethyltramadol by inhibition of phase II hepatic CYP6D4 metabolism will serve to outweigh any potential additional metabolites from Tramadol.
I suppose one might consider it to be a question of 'do the benefits outweigh the positives?' - in this case I believe it will. Of course, if one wished to re-dose with more Tramadol, ingesting cimetidine would be quite counter-productive. However, this was a guide to potentiate Tramadol - not to get the best experience out of Tramadol (saving money, low on supply, etc...) I do, however, feel that the interaction you've brought up is indeed central to the fact that this method will not generate serotonin syndrome from a reasonable dose - there is indeed a limit as to how much o-desmethyltramadol can be generated from any given dose.
My chimp has consistently observed that mild muscle-relaxants markedly enhance the general effects of Tramadol. When taken about 30 mins subsequent to ingestion of Tramadol, both carisoprodol and methocarbomol have noticeably generated a much higher level of analgesia and mood-lift than either of the substances alone. With only 100mg Tramadol and 800mg methocarbamol, the chimp observes effects he associates with 300mg+ Tramadol. The chimp hasn't tried NSAIDs in combination with Tramadol, but would be interested to see if there is a similar dynamic.
Has anyone else observed this relationship between mild muscle relaxants and Tramadol?
He started dosage just before the peak of the response curve of the M1 metabolite with cimetidine. It canceled out all effects. even when he was feeling the mu action. his dosages were 300mg tramadol and 400 mg cimetidine. Since then he tried various dosages and timings based an scientific charts then by pure speculation. All in all it was a waste of tramadol and cimetidine for that matter.
^Including cimetidine in all cases reduced the effects of the tramadol? Did your friend give sufficient time between experiments to account for tolerance (mild though it may be)? Possibly he has a slower isoform of the CYPXXX enzyme (forgot which)? Just offering pure speculation here, this is a very interesting topic.
Great post with lots of information but SWIM has some further question around the chemical O-Desmethyltramadol found in Tramadol.
SWIM has recently found himself being able to get hold of O-Desmethyltramadol own its own and pure. SWIM had 5g of this chemical in his possesion his is has not used any yet as he is very unsure of the effects, dosage due to the lack of information on this chemical outside of its effect in tramadol. Do any SWIY who are more literate in science maybe give SWIM a rough idea on effects, potency, dosage and best route of administration (most efficient). SWIM is thinking of IV'ing but is also considering insufflating.
SWIM hopes his post isnt seen as going too off-topic as at the moment reading up on Tramadol is the closest he can get to finding information on said chemical.
swim has taken over 800mg Tram in one sitting and felt nothing. perhaps swim will try this next time there is a chance.
My cat in a hat has taken 400mg of Tramadol on its own and felt only an uncomfortable speediness (he does not do well with many speedy substances) with only slight opiate effects. He read that taking a small amount of benzodiazepine along with tramadol is relatively safe and even prescribed in some cases.
So, he decided to try it out. He took .5mg phenazepam (in PG solution) and three 50mg Tramadol pills (crushed up and parachuted.) It should be noted that he has natural (and also a self inflicted tolerance on top of that haha) tolerance to, for lack of a better blanket term, downers.
Okay, anyway, he was trashed! He felt like he just ate 100mg of morphine for about six hours! He did not feel any of the benzo except that the nod was crazy and it may have contributed to that. No comedown either. That was probably because of the super-duper long half life of Phenazepam, it likely kept him chilled out and able to sleep.
One other thing that may be relevant and help sort out some of this enzyme stuff is that hydrocodone does absolutely nothing for my feline unless cimetidine is taken.
Hope this post was helpful, I don't recommend anyone mix painkillers, especially ones that are less well known and strange like Tramadol with benzos. There are those out there who really know what they're doing (and unfortunately some that just wanna "get fucked up") and they are going to do it anyway, be careful, always start with low doses please
Sorry if this is off-topic and also for the overuse of parenthesis lol.
Last edited by Wayne Brady; 24-02-2012 at 04:40.
Reason: there, their, they're confusion
VERY interesting stuff. I have been interested in the significant (albeit dangerous) dual potentiation of 5-HT and tramadol with SSRI's. FYI I wouldn't throw grapefruitjuice in there just for kicks though since it may interact in ways we can't predict.
Last edited by GeographyGeography; 18-01-2013 at 04:56.
What dose is appropriate for potentiating this [Tramadol], and other opiates?
In a Swimmie's times past, he has tried adding Cemetidine for other opiates. Is there a difference in the level of potentiation, specific to Tramadol? As I recall, the Swimmer's Cimetidine doses ranged from 300mg to 750mg, or there about.
Has anyone else observed this relationship between mild muscle relaxants and Tramadol?
Tiddles has! Tiddles is my cat's third weakest alternative avatar (or MCTWAA for short ) Specifically with carisoprodol. Even a normal therapeutic dose of carisoprodol will mildly improve the tramadol experience for Tiddles.
By far the best potentiator MCTWAA has found for tramadol is gabapentin, although it would probably be more accurate to state that the tramadol potentiates the gabapentin since it works best if the gabapentin is taken around four hours after dosing the tramadol and if the two are taken in the wrong order then neither works very well and it's a royal waste of drugs. None of us know the mechanism for these effects I'm afraid. I'm sure Tiddles would love to hear anyone's ideas on the subject though
Some caveats are that:
Tiddles seems to be a hypermetaboliser of both tramadol and gabapentin (lucky imaginary cat avatar!) and gets way better results in terms of analgesia and positive mood changes than most users report. He doesn't know whether it would work for well for more ordinary avatars but speculates that it would still be better than either drug alone.
MCTWAA gets far less out of gabapentin if he doesn't follow the following rules:
Eat a smallish, medium-to-high fat, snack shortly before each dose.
Do not exceed 1g (1000mg) per dose.
Space each dose 30-60 mins apart.
If more than three of these doses are wanted during a day then separate each cluster of 3 up-to-1g doses at least four hours apart.
Swallow each dose with plenty of regular soda (cola seems best).
I could post more detail on the reasons for the gabapentin rules if anyone's interested but it's basically because absorption of gabapentin by the body is rather low compared to most drugs and if the whole day's amount were to be taken in one go on an empty stomach with water then most of it would be wasted and one's cat's avatar wouldn't!
Tiddles has never had supplies of tramadol and pregabalin at the same time and therefore has no idea if the strong similarity between pregabalin and gabapentin would mean that it work well with tramadol. He finds it just like gabapentin but better on it's own on the rare occasions he can get some though so he's prepared to bet that it would, probably even better. In the same vain he tortures himself from time to time imagining just how wonderful a combo tapentadol and pregabalin might be but that's getting in to the realms of pure speculation for MCTWAA! If you know any creature that's tried it please let me know what it reports so that I can pass it on to him
So does anyone have info on exactly what dosages are needed and the space of time to take Cimetidine and Tramadol for potentiation? I'm prescribed 400mg Tramadol a day for ADHD/Dysthymia, some recent abstracts and scientific discoveries are truly showing trams worth.
hi guys!
well, i know this thread is not new but while i was browsing on how to potentiate tramadol i "stumbled" on it..
at first,i have to admit, i was a bit frustated, for almost everyone was mentioning stuff such as"cimetidine(if im not mistaken or mispelling) and here in portugal i did never found anything of the sorts,maybe it has a different brand name but..not that"popular(i'd know if it was!!)..
but something real nice happened while i was browsing and reading this very tread ...although im by no means an opiate or benzo first timer,quite the opposite,i have a real good tolerance to both(and im not even that clean),i combined 500mg of tramadol with 40 mg of diazepam and...bam!slow but surely,it did hit me in a way i was not expecting.for sure it s not the same as a stronger opiod/opiate but still the effect is quite enjoyable...it s like it acts a s a real good anti depressive(as stated before by a lot of people)but also has some influence on my creative process as a plastic artist,even though it has some strange effect on my eyes,it s like i momemtraly loose focus or something..
i know i dont really add much info but still i wanted to sahre my tramadol/diazepam combo..quite enjoyable..
stay safe mates
r
Mr. Gradient... I have a question.
If cimetidine works in the way your friend has described to you, how long in his approximation must one wait to re-dose tramadol?
It was said that taking cimetidine daily will further potentiate the effects of tramadol down the road. This seems contrary to the idea that cimetidine taken after tramadol potentiates and taken before, negates its effectiveness. Do any of your research animals or friends have a week or so of data to confirm said phenomena of cimetidine related reverse tolerance to tram? I'll admit I know little of the physiological purpose and mechanism of cimetidine but these facts seemed incompatible and I could not find a clear resolution within your posts, thank you.
Anyone who wants to answer please do. Also, I agree with Ruca, lets have a consensus on how long one should wait after taking tram to take cimetidine; it seems several of you could produce answers on good authority. Gradient says 30-180 min, no offense but thats a rather loose approximation, what amount of delay worked best for your friend's research animals?
something real nice happened while i was browsing and reading this very tread ...although im by no means an opiate or benzo first timer,quite the opposite,i have a real good tolerance to both(and im not even that clean),i combined 500mg of tramadol with 40 mg of diazepam and...bam!r
Anyone else haven any benzo/tramadol experience? This seems to be a nice combo. The more I read the more I think this may not be as bad as it sounds. The benzo may even make recreational Tramadol dosages safer by raising the seizure threshold. Obviously, I am speculating about something potentially dangerous so take this for what it is.
Anyone else haven any benzo/tramadol experience? This seems to be a nice combo. The more I read the more I think this may not be as bad as it sounds. The benzo may even make recreational Tramadol dosages safer by raising the seizure threshold. Obviously, I am speculating about something potentially dangerous so take this for what it is.
Yes I know someone who took it daily with benzos with weed on top sometimes. Never was in danger or found it dangerous but never went apesh!t or above 500mg a day + 40mg valium or equivalent. Works well together lasts a long time and is good on depression yeah....for a while. 2 difficult drugs to get off.
If cimetidine works in the way your friend has described to you, how long in his approximation must one wait to re-dose tramadol?
It was said that taking cimetidine daily will further potentiate the effects of tramadol down the road. This seems contrary to the idea that cimetidine taken after tramadol potentiates and taken before, negates its effectiveness.
lets have a consensus on how long one should wait after taking tram to take cimetidine; it seems several of you could produce answers on good authority. Gradient says 30-180 min, no offense but thats a rather loose approximation, what amount of delay worked best for your friend's research animals?
I see three separate, well considered questions. All of them, unfortunately, can only be confronted with speculation; metabolic enzyme expression and activity vary tremendously between individuals - due to both genetic and environmental factors - including sensitivity to enzyme substrates, baseline expression of cytochrome isotypes, and rates of upregulation (or down) of cytochrome isotypes to name a few issues. All of this to say: I am unable to tell you what will work for you with any certainty.
I assume you're referring to the statement I made concerning increased expression of cytochrome isotypes induced by regular administration of cimetidine? The issue you bring up is quite valid; this idea may only be effective if cimetidine is always ingested in the manner I've described - as tramadol will more effectively be converted to its metabolites due to upregulated expression of inhibited cytochrome enzymes in response to regular cimetidine inhibition.
Again, I'd like to re-iterate that this is mostly speculation fueled by some personal observation. I'm happy to discuss any other potential problems.
2 x 50mg Tramal SR (tramadol slow release)
-crushed and swallowed
{Then roughly 2 hours later}
2 x 50mg Tramal SR - crushed and swallowed
And
10mg temazepam
---------------------
Wish I'd payed more attention to timing sorry.
Result is though I didn't feel much to start with it definitely crept up on me.
Feeling quite pleasant, heavy body stoned feeling that makes you think moving is going to suck but doesn't when you do move or get up. Not as messed up as I'd like to be but a nice relaxed high. I'm really not sure as to what is potentiating or synergizing with what because Tramadol and Temazepam on their own do nothing for me.
Also I should add that last night was the first block of sleep I had after a 4 day sleep deprived Speed binge so I don't know if these things are enhanced from already being a little foggy and surely still a little sleep deprived.
Also I heard that taking codeine when or after tramadol peaks is the thing to do. Is it around the peak or after to get the best out of codeine?
! Since this method of potentiation is so distinct from typical methods for the majority of other opiates, I figured it warranted a thread of its own - I apologize if this was a mistake. I'd be quite interested to know if this works for any other chimps out there.
) Specifically with carisoprodol. Even a normal therapeutic dose of carisoprodol will mildly improve the tramadol experience for Tiddles.
