From: Ryan7681 Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 26 Jul 1999 06:01:35 GMT Ultram is 10 times more addicive than hydrcodone, your doctor is wacky to prescribe that stuff to you. Although I've taken ultram and I like the effects of it when I take 2 before bedtime, it kinda numbs my body from pain ---------------------------------------------------------------------- From: fenst6798 Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 26 Jul 1999 21:42:17 GMT >I'd be curious to know where you get this information from? I have never >heard that Ultram is anywhere near as addictive as Hydrocodone, let alone 10 >times as much. Tramadol binds to the opiate receptors very poorly. Haven >taken both and presently physically dependent on Hydrocodone, I can tell you >that Ultram is no where near as strong as Hydrocodone. About all I find it >useful for is helping to ease withdrawal (though I've not fully explored >this yet) when the Hydrocodone is running low. I realize it has a dependence >liability but nowhere near as much as a full opiate agonist like >Hydrocodone. > I don't know about this "10 times as addictive" crap. However, ultram is indeed addictive. Once you are hooked on something, whether it is coffee or heroin or cigarettes or ultram, you are going to feel pretty shitty when it comes time to quit. ---------------------------------------------------------------------- From: HYDE23 Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 26 Jul 1999 22:05:14 GMT I have a completely unscientific reply. I tried Tramadol (Ultram) and found it did not even relieve my pain, let alone make me feel pretty. ---------------------------------------------------------------------- From: Brooks Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: Mon, 26 Jul 1999 21:09:12 -0700 > did not even relieve my pain, let alone make me feel pretty. Golly hyde, you don't need drugs to make you feel pretty! I'm sure you're purty all by yourself. brooks :o ---------------------------------------------------------------------- From: "Eaton T. Fores" Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: Tue, 27 Jul 1999 07:03:58 -0400 St. Ide wrote... >Hi all, > >I've been taking 30 - 80 mg's of Hydrocodone daily for the past 5 months >or so, and my doctor has given me a prescription for Ultram because he's >worried about Hydrocodone addiction. > >I took the Ultram today for the first time, and I feel like shit. I feel >sick to my stomach, shakey, chills and just generally bad. This started >about an hour after I took the Ultram. > >Could the Ultram be causing this? Does it have anything to do with my >Hydrocodone tolerance/dependence? I seem to remember someone saying >something about this in a past post. > >Any info appreciated... Ultram (tramadol) is a full opioid agonist, and its primary metabolite, desmethyltramadol, is several hundred times stronger at binding opiate receptors than tramadol itself is. Tramadol has no antagonist activity and will not precipitate withdrawal in a dependent individual. Ultram requires high doses and lots of patience to be effective. Its peak activity is not reached for about 3 hours after taking it. It is probably a good idea to take a benzo with it, to mitigate the possibility of seizure, although I'm not convinced that seizure is a real danger. Much has been made of the fact that tramadol has reuptake blocking properties as well as opioid properties. This is just marketing babble. Several other opioids (e.g., methadone) also block amine reuptake, but we don't call methadone a "centrally acting binary analgesic" because of that. We call it an opioid. In all cases where opioids block reuptake, the effect is very weak (tramadol is about 1/50th as effective as imipramine at blocking norepinepherine reuptake, if I remember correctly). A person who is in withdrawal will experience relief when given tramadol, although the relief will be slow in coming. But if you're tolerant to 80 mg hydro, you're looking at 10 or more Ultram tablets, and then you have to consider possible toxicity from so high a dose of Ultram. You're heading into uncharted territory. I've always had the weird feeling that at some level, tramadol will do something very, very bad. I have no reason to believe this, but I do. I run it up carefully, never taking more than 100mg more than a prior dose. I also always have a long-acting benzo on board, just in case I'm wrong about the seizure warnings. Do not use carbamazepine (Tegretol) as an anticonvulsant with tramadol, because it accelerates tramadol metabolism and elimination. People on Tegretol need significantly more tramadol to get the same level of pain relief. Finally, IMO this is a good drug for detoxification and withdrawal, and it should be studied for that. But for that to happen, the manufacturer would have to admit it's an opiate, and I just don't see that happening. ---------------------------------------------------------------------- From: fenst6798 Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 27 Jul 1999 16:27:17 GMT >I've always had the weird feeling that at some >level, tramadol will do something very, very bad. I have no reason to >believe this, but I do. I run it up carefully, never taking more than 100mg >more than a prior dose. I agree with you. I have never heard of any toxic effects from high doses of Ultram, but something about this drug just makes me nervous. When I do take it, I always try to limit my doses as well. It is probably a good idea for anyone else experimenting with this to do the same. At least, until we get some hard information. ---------------------------------------------------------------------- From: "APW" Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: Tue, 27 Jul 1999 14:32:42 -0400 Harry wrote > APW wrote: > > > > I'd be curious to know where you get this information from? I have never > > heard that Ultram is anywhere near as addictive as Hydrocodone, let > > alone 10 times as much. > I would believe that it is much more addictive even though it doesn't > work as well. My ex-gf worked at a rheumatologists' office, and people > were constantly trying to cadge Ultram scrips because they got a habit > on them really bad, much worse than on hydro. That stuff is evil. Humm. This certainly bares watching. I can tell you from experience, that tramadol has never even relieved pain much less given me any feeling that could warrent it an abusable substance. Ultram is a very mysterious drug. Not even scheduled in the U.S.A. Yet it has a dependence liability and some people get "high" off of it? Maybe the same folks who can get off of darvocet will get a buzz off of tramadol. ---------------------------------------------------------------------- From: Samson Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 27 Jul 1999 21:34:03 GMT In article <7nk4la$2rk$1@nntp1.atl.mindspring.net>, "Eaton T. Fores" wrote: > Ultram (tramadol) is a full opioid agonist, and its primary metabolite, > desmethyltramadol, is several hundred times stronger at binding opiate > receptors than tramadol itself is. Tramadol has no antagonist activity and > will not precipitate withdrawal in a dependent individual. [...] Very long abstract of an article I couldn't read if I wanted to follows. Just to supplement some of these points. Comments in brackets (as though it won't be obvious). Drugs 1997;53 Suppl 2:18-24 Dayer P, Desmeules J, Collart L. [Pharmacology of tramadol]. [Article in French] (+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. [I haven't looked at the structure, myself, but why read any further? It is just a little bit disingenuous to advertise something as "not an opiate" when it was clearly selected with the aim of developing a novel opioid agonist.] It is a central analgesic with a low affinity for opioid receptors. [As, of course, is meperidine] Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. [Now, that's pretty low. Then again these statements are always misleading. No one stops to think that the glass of orange juice they're about to drink is 10 to 100,000 times more acidic than a glass of water. Molecules laugh at our fascination with exponents.] Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. [Uh...that leaves a certain action I won't mention to (+)-tramadol. Here's a science project for someone...] The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. [Yeah, whatever...] After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, [They're not booing, they're chanting "muuuuuuu"!] are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required. [What has been described, here, is a meperidine analogue with a high oral bioavailability.] > A person who is in withdrawal will experience relief when given tramadol, > although the relief will be slow in coming. But if you're tolerant to 80 mg > hydro, you're looking at 10 or more Ultram tablets, and then you have to > consider possible toxicity from so high a dose of Ultram. You're heading > into uncharted territory. I've always had the weird feeling that at some > level, tramadol will do something very, very bad. I have no reason to > believe this, but I do. I run it up carefully, never taking more than 100mg > more than a prior dose. I also always have a long-acting benzo on board, > just in case I'm wrong about the seizure warnings. Do not use carbamazepine > (Tegretol) as an anticonvulsant with tramadol, because it accelerates > tramadol metabolism and elimination. People on Tegretol need significantly > more tramadol to get the same level of pain relief. > > Finally, IMO this is a good drug for detoxification and withdrawal, and it > should be studied for that. But for that to happen, the manufacturer would > have to admit it's an opiate, and I just don't see that happening. It seems pretty transparent to me. Of course, loperamide is an opiate, and no one seems to care. (Though it was scheduled at one time.) ---------------------------------------------------------------------- From: "Eaton T. Fores" Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: Tue, 27 Jul 1999 18:54:16 -0400 Samson wrote in message ... > (+/-)-Tramadol is a synthetic 4-phenyl-piperidine > analogue of codeine. Anyone who is good at looking at structural formulae and visualizing the three-dimensional molecule in solution would quickly see just how close the relevant parts of tramadol are to codeine. The places to look are the oxygens and nitrogens (there's actually a rule of thumb called the "morphine rule" that outlines the basic stereochemical requirements for mu-opioid activity), and the distance between the N and the phenolic ring. Manufacturers often hide stereochemical reality when they flatten the structural formula for the printed page. This was obviously done with tramadol, whose structure in the PDR requires one to imagine the molecule folding in solution in order to see how well it fits the morphine rule. Another place I've seen this in is venlafaxine and sibutramine, the former of which has a five-membered (cyclohexane) aliphatic ring, while the latter has a four-membered aliphatic ring which is hidden in the structural formula by drawing it as a square with the carbons shown explicitly. Both molecules also contain the phenethylamine nucleus, but are rendered so as to look utterly unlike amphetamine at a casual glance. Their pictures look very different in the PDR, but they are stereochemically uncannily similar (and pharmacodynamically essentially interchangable). I've sometimes wondered if it's possible to buy O-desmethyltramadol from a chemical supplier. My guess is that, like its other demethylated cousins, its oral bioavailability would be low, but it might pack a parenteral punch. > It is just a little bit disingenuous to advertise > something as "not an opiate" when it was clearly > selected with the aim of developing a novel > opioid agonist And, just to add to the intrigue, it is really a prodrug. It can be truly said that the affinity of tramadol for the mu-receptor is negligible. The biotransformation to O-desmethyl-T for some reason is very slow, and it is certainly true that latency of onset of activity gives a drug less "abuse potential." Of course, some people are patient. > Nevertheless, this affinity for mu receptors of the CNS > remains low, being 6000 times lower than that of morphine. But mu binding is not *linearly* proportional to analgesic activity, even though it is well correlated. For example, a compound with a 300-fold increase in affinity may show two or three times the analgesic activity. > Moreover, and in contrast to other opioids, the > analgesic action of tramadol is only partially inhibited > by the opioid antagonist naloxone This one is interesting. Obviously, if the dose of antagonist is low enough, it will not completely reverse narcosis. But I recall doing work with enkephalinase inhibitors whose analgesic action (weak) was only partially reversed by naloxone. I'm not sure what to make of this. > the duration of the analgesic effect after a single oral > dose of tramadol 100mg is about 6 hours IME a high dose (> 500mg) of tramadol produces mu effects that are unmistakably apparent 24 hours after dosing. > What has been described, here, is a meperidine > analogue with a high oral bioavailability Yes, either that or perhaps a propoxyphene with less toxicity as the dose is raised. In any case, there is nothing novel about this drug, not even its marketing strategy (we saw all this with Darvon decades ago). ---------------------------------------------------------------------- From: nurscm Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 28 Jul 1999 21:35:05 GMT >Yes, either that or perhaps a propoxyphene with less toxicity as the dose is >raised. In any case, there is nothing novel about this drug, not even its >marketing strategy (we saw all this with Darvon decades ago). I've done codeine, hydro's and percs. I got some Ultram. Took one. Nothing. Next time, took 2. I felt like I'd taken some kind of antihistamine that makes my head crawl. Still had the headache. These things are worthless. ---------------------------------------------------------------------- From: fenst6798 Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 28 Jul 1999 21:56:46 GMT >I've done codeine, hydro's and percs. I got some Ultram. Took one. Nothing. >Next time, took 2. I felt like I'd taken some kind of antihistamine that >makes >my head crawl. Still had the headache. These things are worthless. > You are going to have to take more than one or two if you expect to feel any effects. ---------------------------------------------------------------------- From: "Eaton T. Fores" Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: Wed, 28 Jul 1999 18:05:54 -0400 NursCM wrote > These things are worthless. I'm pleased that you feel that way. It's my sincere hope that everyone continues to regard them as worthless. ---------------------------------------------------------------------- From: Samson Newsgroups: alt.drugs.hard Subject: Re: Ultram & Opioids Date: 29 Jul 1999 06:23:31 GMT "Eaton T. Fores" wrote: > Samson wrote in message ... > > > (+/-)-Tramadol is a synthetic 4-phenyl-piperidine > > analogue of codeine. > > Anyone who is good at looking at structural formulae and visualizing the > three-dimensional molecule in solution would quickly see just how close the > relevant parts of tramadol are to codeine. The places to look are the > oxygens and nitrogens (there's actually a rule of thumb called the "morphine > rule" that outlines the basic stereochemical requirements for mu-opioid > activity), and the distance between the N and the phenolic ring. Actually, the 'morphine rule' is harder to visualize in morphine than in any of the synthetic opiates. The four tenets of the rule -- (1.) A tertiary nitrogen - (2.) a two-carbon 'spacer' - (3.) A quarternary carbon - (4.) A benzene ring (not necessarily phenolic) -- These are much easier to picture in two dimensions, i.e., (1) (2) (3) (4) R R \ | N---C---C---C---Phe ('R' = just anything other than hydrogen) / | R R 'Morphine rule' is sort of a misnomer. It's really the 'meperidine' rule. It was invoked to explain how something bearing so little resemblance to morphine could have such similar pharmacological activity. It's much easier to 'see' in meperidine and methadone than in morphine. (You can't see it in fentanyl, of course. It's not there. So much for the 'rule'...) > Manufacturers often hide stereochemical reality when they flatten the > structural formula for the printed page. This was obviously done with > tramadol, whose structure in the PDR requires one to imagine the molecule > folding in solution in order to see how well it fits the morphine rule. I don't think so. I stopped by the library to take a look at it today. As it happens, you can fit it right against the picture of oxycodone on the opposite page and get a nice view of how the 'rule' applies to oxycodone. Here, based on my memory of a few hours ago, I put tramadol next to meperidine, for the benefit of those who don't know what we're talking about. On the left margin, the number of each 'tenet' (see above) is put on the line where it shows up in the structure. For those using browsers with different spacing than mine, this will just be a jumble of slashes and pipes. Deal with it... Meperidine ---------- CH3 | 1 N / \ / \ / \ 2 | | | | 2 | | \ / \ / \ / O 3 |\ / \ | \ / \ | C=O C2H5 /\\ / \\ / \\ 4 || | || | || | \ // \ // \// Tramadol -------- CH3 CH3 \ / 1 N \ \ \ (Something may be missing, here) 2 | | 2 |___ / \ OH / \ \ / \ 3 |\ / | \ / | \____/ /\\ / \\ / \\ 4 || | || | || | \ //\ \ // OCH3 \// For those who can see, tramadol is sort of like meperidine with the piperidine ring opened, and a big cyclohexyl goiter on its side. It's interesting to note how that cyclohexyl group corresponds with the 'C' ring in a 7-8 saturated morphine derivative (e.g., hydrocodone). Add in the -OH (analogous to the 6-OH group in morphine), and it would probably be better described as the 'methadone analogue of dihydrocodeine'. [[Ed. Note: Ed. is pretty sure that some of these structural analogies were off by a letter of the alphabet or two, but Ed. isn't presently inclined to figure it out, right now. Ed. is also quite certain that you are not interested, and even more certain that Ed. isn't either. -- Ed.]] (There's no piperidine: it's not a 'phenyl-piperidine' analogue of anything.) Now, if anyone would like to attempt an ASCII rendering of dihydrocodeine, take a shot... > > Nevertheless, this affinity for mu receptors of the CNS > > remains low, being 6000 times lower than that of morphine. > > But mu binding is not *linearly* proportional to analgesic activity, even > though it is well correlated. For example, a compound with a 300-fold > increase in affinity may show two or three times the analgesic activity. Thus my analogy to the difference in the 'acidity' of a glass of citrus juice vs. water. If I understand correctly, 'binding affinity' like 'acidity', is a dissociation constant. A glass of lemonade at pH 2 is 100,000 times as 'acidic' as a glass of water at pH 7, described in terms of the dissociation of H+ in each solution. If binding affinity is analogous, then a 6000- fold difference would be somewhere around a 4-fold difference in analgesic activity. (Which must be right, since the log(10) of 300=~2.5, and log(10)6000=~3.8.) > > Moreover, and in contrast to other opioids, the > > analgesic action of tramadol is only partially inhibited > > by the opioid antagonist naloxone > > This one is interesting. Obviously, if the dose of antagonist is low > enough, it will not completely reverse narcosis. But I recall doing work > with enkephalinase inhibitors whose analgesic action (weak) was only > partially reversed by naloxone. I'm not sure what to make of this. In any case, some investigators at the FDA symposium someone recently gave a link for claim, in no uncertain terms, that the actions of tramadol *are* reversed by naloxone. Also, if some non-opioid mediated action of the parent drug is partially responsible for the analgesic effect,then, naturally, naloxone would only partially reverse it. I understand that in general, 'endogenous' analgesia (e.g., stress-induced analgesia) though typically associated with opioid activity, is minimally inhibited by naloxone due to the coactivation of adrenergic systems, which also seem to have a role in pain modulation. (Now, opioid activity, whether it is induced by endogenous or exogenous ligands, is certainly *correlated* with analgesia, but has the precise cause-effect relationship been determined?)