N&PD Moderators: Skorpio
Ondansetron Inhibits the Analgesic Effects of Tramadol
http://www.anesthesia-analgesia.org/content/94/6/1553.full
http://www.anesthesia-analgesia.org/content/93/6/1626.1.full
My question is whether this would also work with Oxycodone and if not are there any other similar substances that will inhibit Oxycodone the same way Ondansetron does for Tramadol, as I wish to take the edge of my adverse reactions from Oxycodone without the use of naloxone or natlrexone ?
^ Hyperthermia, increased throbbing pressure sensation in skull, neck stiffness, nausea and vomiting induced by increased blood pressure and headches, muscle spasms, twitching, respiratory depression, agitation and a general unwell and wired typed feeling.
Not trying to fix all the symptoms as that can only be achieved by refraining from the drug, however if I can find anything to slightly take the edge off from even one of the symptoms that would be great.
psychomimetic
Bluelighter
^Why don't you just take lower doses of oxy? I'd like to know if there's an adverse effect as well, because I have both drugs talked about, but I don't want to take ondansetron if it makes me require a higher oxy dose.
I suppose its only natural for someone to assume only a higher dose of oxy would cause an adverse effect ina normal individual, however I am anything but normal. To avoid straying from the topic I failed to mention I have a medical condition namely "Autonomic Dysfunction" and a severe hypersensitivity to all substances that have a stimulating or depressing effect on the Autonomic Nervous System and sadly it only takes the minimum effective dose of any offending substance or in Oxycodone's case only 5mg to cause adverse effects.
To the best of my knowledge, ondansetron is a CYP2D6 substrate, but not an inhibitor. Theoretically, competitive inhibition of CYP2D6 by ondansetron might still interfere with the metabolism of oxycodone (specifically, the O-demethylation of oxycodone to oxymorphone), but I doubt that the interference is significant. The dosages of ondansetron are typically in the low milligram range, and enzyme inhibition through simple competitive binding mechanisms shouldn't be much of an issue.
I stumbled across this paper on co-administration of oxycodone with quinidine - a strong CYP2D6 inhibitor. Not unexpectedly, metabolism of oxycodone by the CYP2D6 pathway was inhibited by quinidine, and plasma oxymorphone levels were reduced accordingly. Interestingly, quinidine did not affect the psychomotor or subjective drug effects of oxycodone. Oxycodone is active on its own, and the contribution to analgesia and other effects by oxymorphone may not be significant.
As for tramadol, I'm not entirely convinced that CYP2D6 inhibition is the main reason why ondansetron inhibits the analgesic effects of tramadol. It may very well be a contributing factor, as CYP2D6 is the key enzyme in the conversion of tramadol to O-desmethyltramadol, which is largely responsible for tramadol's µ agonist effects. However, ladies and gentlemen, are we perhaps ignoring the obvious? Tramadol is not simply a µ agonist (a weak one at that), and its analgesic effects are partly mediated through serotonin release and/or reuptake inhibition. Ondansetron, being a serotonin antagonist with a decent selectivity for the 5-HT3 receptor subtype, should partially block the indirect serotonergic action of tramadol. Unfortunately, I don't have a reference, I'm not even sure it has ever been investigated.
fastandbulbous
Bluelight Crew
Not really as ocxycodone has an apprecxiable effect as a mu agonist anyway and is responsible for most of the analgesia obtained. It'll stop codeine working though & pronbably reduce the effect of dihydrocodeine.
I'd say it is responsible for the effect as the main analgesia is obtained from O-desmethyltramadol
To f&b, do you believe that competitive binding of CYP2D6 by a mere substrate such as ondansetron will account for a significant reduction of CYP2D6 activity and thereby cause a significant decrease in plasma levels of O-desmethyltramadol? I'd certainly agree with you if ondansetron were a CYP2D6 inhibitor, even a weak one, but the CYP2D6 pathway isn't normally saturated by competitive substrate binding except at very high substrate concentrations. It could of course be that ondansetron has an exceptionally high affinity for enzyme active sites, whilst not being an inhibitor per se. It is also quite obvious that any saturation effects would be more prominent and occur at lower substrate concentrations in CYP2D6 deficient subjects ("poor metabolisers"), but those are not likely to experience any significant contribution to analgesia by O-desmethyltramadol in any case.
I'll go with you as far as to say that O-desmethyltramadol accounts for the main µ opioid agonist effect of tramadol. However, it has been demonstrated that the total analgesic effect of tramadol is only partially attributed to µ agonism, as its analgesic effects are only partially blocked by naltrexone. Tramadol's activity as a serotonin releaser, noradrenaline reuptake inhibitor and NMDA antagonist is thought to account for the remainder of its analgesic effect. Tramadol is indeed a filthy slut of a drug which interacts frivolously with a wide range of mechanisms and receptors.
To the OP, I'd say there is a chance you're actually on to something after all. I don't know whether you have any idea about your CYP2D6 phenotype, but if you happen to be an extensive metaboliser, oxymorphone may contribute to the effects and side effects you are experiencing from oxycodone. I've done my share of oxymorphone and oxycodone, as well as other opioids. I've always felt that oxymorphone has some special qualities to it, it's somehow different from the rest, and I both loved it and hated it - that is, until my supply ran out. As to what makes it special, well I can't really put my finger on it. It has a unique empathic glow and induces a loved-up, sociable state of mind which, I can honestly say, brings back memories from the good old days of clubbing when London was rife with good MDMA. Unfortunately, so do the effects as the drug wears off, which include jitters, sleeplessness and the old familiar sense of impending doom. I don't get any of these effects with other opioids including oxycodone, just the usual opioid bliss which is not followed by any appreciable comedown. If I didn't know any better, I'd be ready to believe that oxymorphone isn't just another opioid agonist, but also a powerful empathogen acting through serotonin and/or oxytocin release. However, I'm not aware of any literature which supports this rather preposterous idea.
If it makes any kind of sense to the OP, ridiculous as it may seem, a proper CYP2D6 inhibitor such as terbinafine or cimetidine might be worth looking into.
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fastandbulbous
Bluelight Crew
Depends on how competetive it is for CYP 2D6 compared with tramadol. Sorry that's the best I can give you without figures such as Ki values etc
negrogesic
Bluelight Crew
Have you tried Remeron? I've seen a couple of cases where mirtazapine proved more effective than ondansetron as an anti-emetic. Its cheaper, and it won't inhibit tramadol's o-demethylation by CYP2D6, which is crucial to the analgesic properties of racemic tramadol
Plus its ultra-high affinity for the H1 receptor (as well as appreciable anti-adrenergic properties) will produce an additive effect with any opioid, including tramadol.
People get turned off by remeron because the first 2 or so weeks are pretty dysphoric and unpleasant (depending on the individual). After that, it improves mood, reduces anxiety and even improves cognition....
And while tramadol is certainly a pretty shitty opioid, the RC o-desmethyltramadol (when IV'ed at 100mg) was as strong as a big dose of fentanyl (IV). It does have some body-load that is likely a remnant of its other actions, but this was only felt because of misuse (almost two grams of o-desmethyltramadol IV'ed over the course of a evening, no tolerance other than an astronomically high natural tolerance). The next day I felt pretty beat up.
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That is exactly what I thought after many years of adverse reactions to various opiates so I finally had the the cytochrome p450 test expecting the results to corrospond with horrible reactions that I have but it came back indicating that...
CYP2D6*1/*1 = Normal function
CYP2C19*1/*1 = Normal function
CYP2C9*1/*1 = Normal function
I have tried exploring every avenue trying to work out why my body is rejecting all these substances, it seems a dose of any psychoactive substance sufficient enough to get you high, drunk, sedated, stimulated is enough to have me feeling horribly ill, all of it accounts to my past history and the reasons I developed Autonomic Dysfunction in the first place.
I have seen many specialists over the years, even shrinks and neuropsychiatrists trying to explore a psychological possibility yet they have all dismissed an anxiety factor after various tests and agreed with the Autonomic Dysfunction as the initial problem. Even when they tried various antidepressants and found that it messed up my Autonomic functions even more resulting in fevers and other distrupted vitals due to shifts in seretone, dopamins levels which is why "Remeron" as suggested by "negrogesic " in the post above is not possible.
So for the past 2 weeks I have been trying Cannabis after a 10 year break but again even with that I am experiencing complications, not with heart rate as one would expect ina panic or anxiety situation but in fact with my digestive tract, every time I consume cannabis it messes up my intestinal tract resulting in belching and regurgitating mouthfulls of stomach acid and food, waking up throughout the night with acid reflux, spams, stomach pains, nausea, vomiting, increased gut motility which is already a problem and a side effect of my Dysautonomia, these effects begin 10 minutes after smoking and last well after the effects have worn off into the next day until they settle down requiring loads of antiacids and PPI's.
So I conclude my Autonomic function is very very very messed up, a total train wreck! More specificaly accounted to damage to certain neurotransmitters causing imbalances in serotonin, noradrenaline, and dopamine which is why any drugs that acts on those terminals causes problems for me, even the shifts within my own body result in fevers and other complications. If I can just find a way to stabilise serotonin, noradrenaline, and dopamine I believe that would be the key to solving all my problems. Every class of psychoactive drugs seems to produces its own unique individualised adverse reaction varying greatly in its symptoms. Thankfully my Neurologist is beginning to think outside of the box and has agreed to administer the ofending substances under tests conditions whilst monitoring my vitals during these adverse reactions, it will all be published in a medical journal, yay freak of the year! 8)
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magicmoonbeams
Greenlighter
Autonomic dysfunction
This dysautonia that you speak of seems to be my problem as well, after an excess of ecstacy and meth use for a few months...then stopping. Are you having symptoms 10 years after stopping? As far as the illness when trying to enjoy any kind of substance that can [possibly be"fun" now, I've noticed that the mental highs and lows or euphoria with various substances I've tried before is no longer attainable..basically a reflexive body reaction which is not pleasant. I never thought I would miss a "crash-down" but if I try X or meth or cannabis I only react bodily..and badly so. The dysautonia seems to be an oversensitization of the sympathimimetic system that cannot seem to correct itself. I do not enjoy drugs anymore and bizarrely it's kinda sad because I've experienced an emptiness and meagerness of emotions and increase in apathy although I do not take any prescribed pharmas. Apathy is not at all fun to me , combined with a destroyed digestive system, I just make it thrrough the days now. Magnesium supplementing at night , along with chamomile tea has been helpful and so has eating less calcium products. This may not be appealing but you may need to try some laxatives and get a good clearing out of toxins and stress. I'm slowly improving, but it's been a long and lonely road.