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  • BDD Moderators: Keif’ Richards | negrogesic

Hydroxyzine and oxycodone metabolism/potentiation

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infraredz

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Aug 30, 2012
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As a pain patient who has started to develop a tolerance to my 10/325 percocets (every 6 hours), I have a few questions.

I am also prescribed hydroxyzine in 25mg caps. I know that hydroxyzine, like other 1st generation anti-histamines, inhibits CYP450 2d6 (among others).

It is my understanding, that oxycodone is metabolized to oxymorphone (among other metabolites) by 2d6, meaning that, if inhibited (albeit somewhat weakly) by hydroxyzine, analgesic effect will be lower as oxycodone is weaker than oxymorphone.

However, I've seen very frequently that people say to take hydroxyzine with or shortly before taking opioids (somewhere I saw an alleged 50% increase in effect).

Now, can anyone address these issues? Anyone have personal experience with hydroxyzine and oxycodone SPECIFICALLY?

Thanks.
 
Hydroxyzine is the best sedative anti histamine on the market, period (with maybe cyclizine)...

Take it 20mn before taking your oxy.

Others will chime in as to why and how metabolization interactions do occur.
 
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Woo! Finally someone proves and agrees with me that hydroxyzine sucks for opiate potentiation! High five.
 
Hydroxyzine is the best sedative anti histamine on the market, period (with maybe cyclizine)...

Take it 20mn before taking your oxy.

Others will chime in as to why and how metabolization interactions do occur.
What is the effect of this in your experience?

Oxycodone is metabolized into oxymorphone by CYP2D6/CYP3A4.

Hydoxyzine does not have any effect on 3A4, and according to some studies the inhibition of enzyme 2D6 is of not much pharmacological significance.

The potent anti-histamine effect of hydroxyzine far outweighs its inhibition of enzyme 2D6.

Related reading:

http://www.ncbi.nlm.nih.gov/pubmed/9616188
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076582/
So the incredible amount of people that recommend hydroxyzine for opioids is just due to the increased sedation? It seems strange, especially when reports of stronger subjective effects and longer duration of effects is reported.

First article information:
These data demonstrate that classic histamine H1 receptor antagonists, available in over-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the range of their expected hepatic blood concentrations, suggesting that, under specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.

Regarding 2D6:
Oxycodone is extensively metabolised in the liver, mainly via CYP3A4 to the inactive metabolite noroxycodone (47% of the dose), by 6-keto reduction to the most likely inactive metabolites, α- and β-oxycodol (8% of the dose), and via CYP2D6 to the active metabolite oxymorphone (11% of the dose), which is mainly found in a conjugated form in plasma....Serum concentrations of oxycodone (p=0.49), oxymorphone (p=0.12) and the ratio oxymorphone/oxycodone (p=0.15) did not differ between users and non-users of CYP2D6 inhibitors.
Therefore, if both studies are accurate, the CYP2D6 inhibitory aspects of hydroxyzine have little to do with increased effect of duration. This is what I was referring to regarding oxymorphone, although I had no idea it was such a small percentage of the dose. Maybe 3A4 inhibition is the main cause of increased effect and duration...?

Regarding CYP3A4:
Total daily dose and use of CYP3A4 inhibitors displayed positive association. This means that increasing the dose and inhibition of the CYP3A4 metabolic pathway favour increased oxycodone serum concentrations...Users of CYP3A4 inhibitors are predicted to have 60% higher oxycodone serum concentrations than non-users...Formation of noroxycodone [hypothesized to be inactive] by CYP3A4 is the major elimination pathway of oxycodone
It seems that 3A4 inhibition is really the way to go. Since oxycodone is NOT a prodrug (and is still quite potent agonist in its own regard), this would result in an increased analgesic effect. I couldn't find anything saying hydroxyzine inhibits CYP3A4 though....

So why do so many people recommend it? People who have tried/still use this combo PLEASE chime in.

Thanks.
 
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Personally i would always use an Antihistamine when taking Opiates, although only to counteract the itch.
 
I may have not concluded appropriately in my first post, but hydroxyzines' inhibition of 2D6 is negligible therefore does not have any or very little bearing on oxycodone-oxymorphone conversion, and its inhibition of 3A4 is non-existent.

In theory hydroxyzine should depotentiate oxycodone due to its minor inhibition at 2D6, therefore anyone experiencing increased potency from hydroxyzine is due to its powerful anti-histamine effect, and its own analgesic mechanism, but certainly not its activity at liver enzymes.

Even cimetidine which is a moderate but stronger inhibitor of 2D6 than hydroxyzine is reported to increase the potency/duration of oxycodone. This is also partially a myth. Cimetidine will increase oxycodone plasma levels and also its duration due to 2D6/3A4 inhibition, but at the huge cost of potency as it will hinder the oxycodone-oxymorphone conversion.
 
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I may have not concluded appropriately in my first post, but hydroxyzines' inhibition of 2D6 is negligible therefore does not have any or very little bearing on oxycodone-oxymorphone conversion, and its inhibition of 3A4 is non-existent.

In theory hydroxyzine should depotentiate oxycodone due to its minor inhibition at 3A4, therefore anyone experiencing increased potency from hydroxyzine is due to its powerful anti-histamine effect, and its own analgesic mechanism, but certainly not its activity at liver enzymes.

Even cimetidine which is a moderate but stronger inhibitor of 3A4 than hydroxyzine is reported to increase the potency/duration of oxycodone. This is also partially a myth. Cimetidine will increase oxycodone plasma levels and also its duration due to 3A4 inhibition, but at the huge cost of potency as it will hinder the oxycodone-oxymorphone conversion.

Hydroxyzine inhibits 3A4? I was wondering about that but couldn't find a source.


  • What about the anti-histamine effect potentiates opiates?
  • What is the analgesic mechanism for hydroxyzine? Is this why it's prescribed with opiates for analgesic purposes (Which is my ONLY concern)?
  • The oxymorphone metabolism is fairly negligible it seems, being only 11% of the metabolites of oxycodone. Now, oxymorphone is a more potent opioid, but oxycodone is by no means a pro-drug and is significantly potent in its own regard right?
 
As a pain patient it sounds as though you've just grown a tollerance to what you are currently Rx'd. Why go through all the troubles of potentiation which is usually not all that effective once a tollerance is built. IMO you'd be much better off to just speak candidly with your doctor.
 
Dude .....oxymorphone has really nothing to do with the effects of oxycodone, really the metabolization of oxycodone into.oxymorphone is very very very minimal, and likely has nothing to do with the effects felt when taking oxycodone.

I Know this to be true because I myself, and many others I have spoken to attest to tagamet , a potent 2D6 inhibitor, to INCREASE the effects and duration of oxycodone exponentially. If oxymorphone had anything to do with the effects felt from taking oxy, than tagamet would make the effects of oxy feel weaker

There is no point in arguing whether or not hydroxyZine affects hepatic enzymes in this situation because it really doeant matter because again, the production of oxymorphone has nothing to do with the high of oxy
 
As a pain patient it sounds as though you've just grown a tollerance to what you are currently Rx'd. Why go through all the troubles of potentiation which is usually not all that effective once a tollerance is built. IMO you'd be much better off to just speak candidly with your doctor.
My issue is that I've only been taking this for 3 weeks and will not likely take it for much longer (ie before my next visit with my doctor). Also, I do not want to take anything stronger/increase dosage because of my fear of withdrawal (which is already going to happen since I have a tolerance). Therefore, I am looking for a way to make the analgesic effects of my current 10/325 percocets last longer. I was taking them every 4 hrs at first, then he brought me down to every 6 hrs and recently I am having breakthrough pain in addition to even some discomfort within 3 hrs of taking the med.

I am very interested in the relationship between hydroxyzine and oxycodone in respect to potentiation (especially of analgesic effect). Also, as to why they were/are prescribed together to pain patients.

Side note: injury was broken ribs and vertebrae in early January...

Dude .....oxymorphone has really nothing to do with the effects of oxycodone, really the metabolization of oxycodone into.oxymorphone is very very very minimal, and likely has nothing to do with the effects felt when taking oxycodone.

I Know this to be true because I myself, and many others I have spoken to attest to tagamet , a potent 2D6 inhibitor, to INCREASE the effects and duration of oxycodone exponentially. If oxymorphone had anything to do with the effects felt from taking oxy, than tagamet would make the effects of oxy feel weaker

There is no point in arguing whether or not hydroxyZine affects hepatic enzymes in this situation because it really doeant matter because again, the production of oxymorphone has nothing to do with the high of oxy
This is what I believe and why I am more interested in CYP3A4 and Grapefruit Extract.

Like the original article that Chromophobia posted (Thank you, by the way!), the amount of oxycodone converted to oxymorphone is only 11% and oxycodone is in itself still powerful as an analgesic. I could see this being more relavent in a pro-drug situation, but oxycodone has a high affinity for various opioid receptors even compared to oxymorphone (although oxymorphone is stronger, but not enough to worry abut since it's only 11%.
 
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^ Sorry I meant 2D6 in my last paragraph. Even though cimetidine is a 3A4 inhibitor also but not hydroxyzine.

Anti-histamines are naturally sedating, take them in tandem with a strong opioid and many will notice an increase in that respect.

Hydroxyzines' analgesic properties are unclear to me due to restricted journal access on select studies, but it is definitive that they exist and in some studies that they increase the analgesic benifit of opioids.

Bronchodilator activity, and antihistaminic and analgesic effects have been demonstrated experimentally and confirmed clinically.

http://www.pfizer.com/files/products/uspi_vistaril.pdf

Analgesia obtained when 10 mg of morphine was combined with 100 mg of hydroxyzine was significantly superior to that obtained with morphine alone.

http://www.anesthesia-analgesia.org/content/59/9/690

Oxycodone is moderately potent on its own but one can't neglect its metabolites which are not limited to but include oxymorphone, codeine, and morphine. Nonetheless oxycodone is not a prodrug because it is not fully dependant on cytochrome P-450 enzymes and metabolites for its analgesic efficacy.

Edit:

Dude .....oxymorphone has really nothing to do with the effects of oxycodone, really the metabolization of oxycodone into.oxymorphone is very very very minimal, and likely has nothing to do with the effects felt when taking oxycodone.

I Know this to be true because I myself, and many others I have spoken to attest to tagamet , a potent 2D6 inhibitor, to INCREASE the effects and duration of oxycodone exponentially. If oxymorphone had anything to do with the effects felt from taking oxy, than tagamet would make the effects of oxy feel weaker

^This = 100% subjective

Two studies on the pharmacokinetics of oxycodone:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381353/?page=1

http://www.chem.agilent.com/Library/applications/5990-3815EN.pdf

The second study shows less but definitely non-negligible serum levels of noroxymorphone.
 
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Hydroxyzine will increase sedation and analgesia through synergism of effects, NOT potentiation.

Potentiation is done by inhibiting liver enzymes to increase the duration of effects, or in the case of a prodrug like codeine, to increase the amount of the parent drug produced. Also, for drugs such as amphetamines, potentiation could mean raising stomach ph to increase the amount absorbed. Usually, potentiation doesn't increase the pain killing effects of drugs that don't rely on a metabolite for pain killing effects, but rather to increase the duration effects.

Synergism on the other hand is a result of targeting other receptors in the brain to help incrwase analgesia of opiates. An example would be hydroxyzine and opiates. Hydroxyzine acts as a serotonin receptor antagonist, and anti histamine which makes the opiates feel more effective. Another example would be adding a muscle relaxer such as klonopin or soma. These drugs target different receptors other than opiate receptors to aide in pain reduction by relaxing the muscles. anoother very good synergism is Pregabalin or gabapentin with opiates. I can personally attest to lyrica or gabapentin to be one of the best non narcotic pain killers especially when combined with opiates.

Some things to help with pain, definitely stick with hydroxyzine, it helps alot with pain. In addition try a muscle relaxer such as benzo with such. properties such as valium/klonopin or opt for another.muscle relaxer like flexeril or carisoprodol . Pregabalin and or gabapentin are also an excellent choice and really really help with pain. These are my favorite as a pain patient. Marihuana is also an excellent synergizer with opiates and help with pain.

My favorites to help with pain....
1. Pregabalin / gabapentin
2. Marijuana
3. Benzo with muscle relaxant props such as klonopin or valium
4. Hydroxyzine
5. Muscle relaxers like flexeril

You can try potentiators aswell to make the oxy last longer. Tagamet aka cimitidine is excellent and is sold OTC all across amaerica

Good luck
 
Hydroxyzine will increase sedation and analgesia through synergism of effects, NOT potentiation.

Potentiation is done by inhibiting liver enzymes to increase the duration of effects, or in the case of a prodrug like codeine, to increase the amount of the parent drug produced. Also, for drugs such as amphetamines, potentiation could mean raising stomach ph to increase the amount absorbed. Usually, potentiation doesn't increase the pain killing effects of drugs that don't rely on a metabolite for pain killing effects, but rather to increase the duration effects.

Synergism on the other hand is a result of targeting other receptors in the brain to help incrwase analgesia of opiates. An example would be hydroxyzine and opiates. Hydroxyzine acts as a serotonin receptor antagonist, and anti histamine which makes the opiates feel more effective. Another example would be adding a muscle relaxer such as klonopin or soma. These drugs target different receptors other than opiate receptors to aide in pain reduction by relaxing the muscles. anoother very good synergism is Pregabalin or gabapentin with opiates. I can personally attest to lyrica or gabapentin to be one of the best non narcotic pain killers especially when combined with opiates.

Some things to help with pain, definitely stick with hydroxyzine, it helps alot with pain. In addition try a muscle relaxer such as benzo with such. properties such as valium/klonopin or opt for another.muscle relaxer like flexeril or carisoprodol . Pregabalin and or gabapentin are also an excellent choice and really really help with pain. These are my favorite as a pain patient. Marihuana is also an excellent synergizer with opiates and help with pain.

My favorites to help with pain....
1. Pregabalin / gabapentin
2. Marijuana
3. Benzo with muscle relaxant props such as klonopin or valium
4. Hydroxyzine
5. Muscle relaxers like flexeril

You can try potentiators aswell to make the oxy last longer. Tagamet aka cimitidine is excellent and is sold OTC all across amaerica

Good luck

Thank you. I actually already take 3600mg of Gabapentin a day, as well as 30mg of Clorazepate (Tranxene which is a prodrug for desmethyldiazepam), but have been taking these for a long time and have an immense tolerance to them unfortunately.

I think potentiation is ideally what I want, especially an increase in duration. Other than Tagamet, any other suggestions?
 
Hydroxyzine will increase sedation and analgesia through synergism of effects, NOT potentiation.

Potentiation is done by inhibiting liver enzymes to increase the duration of effects, or in the case of a prodrug like codeine, to increase the amount of the parent drug produced. Also, for drugs such as amphetamines, potentiation could mean raising stomach ph to increase the amount absorbed. Usually, potentiation doesn't increase the pain killing effects of drugs that don't rely on a metabolite for pain killing effects, but rather to increase the duration effects.

Synergism on the other hand is a result of targeting other receptors in the brain to help incrwase analgesia of opiates. An example would be hydroxyzine and opiates. Hydroxyzine acts as a serotonin receptor antagonist, and anti histamine which makes the opiates feel more effective. Another example would be adding a muscle relaxer such as klonopin or soma. These drugs target different receptors other than opiate receptors to aide in pain reduction by relaxing the muscles. anoother very good synergism is Pregabalin or gabapentin with opiates. I can personally attest to lyrica or gabapentin to be one of the best non narcotic pain killers especially when combined with opiates.

Some things to help with pain, definitely stick with hydroxyzine, it helps alot with pain. In addition try a muscle relaxer such as benzo with such. properties such as valium/klonopin or opt for another.muscle relaxer like flexeril or carisoprodol . Pregabalin and or gabapentin are also an excellent choice and really really help with pain. These are my favorite as a pain patient. Marihuana is also an excellent synergizer with opiates and help with pain.

My favorites to help with pain....
1. Pregabalin / gabapentin
2. Marijuana
3. Benzo with muscle relaxant props such as klonopin or valium
4. Hydroxyzine
5. Muscle relaxers like flexeril

You can try potentiators aswell to make the oxy last longer. Tagamet aka cimitidine is excellent and is sold OTC all across amaerica

Good luck

^ Pharmacologically you're wrong. Both cimetidine and hydroxyzine depotentiate oxycodone. Hydroxyzine is a mild 2D6 inhibitor and cimetidine is a moderate inhibitor of 3A4 and 2D6.

As I explained and as you repeated hydroxyzine will increase the sedation of opioids therefore spiking perceived potentiation, and cimetidine will increase duration of oxycodone* by inhibition of enzymes also spiking perceived potentiation.


Thank you. I actually already take 3600mg of Gabapentin a day, as well as 30mg of Clorazepate (Tranxene which is a prodrug for desmethyldiazepam), but have been taking these for a long time and have an immense tolerance to them unfortunately.

I think potentiation is ideally what I want, especially an increase in duration. Other than Tagamet, any other suggestions?

^Your only options are GABA agonists and cannabis. With GABA agonists being highly addictive.
 
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^ Pharmacologically you're wrong. Both cimetidine and hydroxyzine depotentiate oxycodone. Hydroxyzine is a mild 2D6 inhibitor and cimetidine is a moderate inhibitor of 3A4 and 2D6.

As I explained and as you repeated hydroxyzine will increase the sedation of opioids therefore spiking perceived potentiation, and cimetidine will increase duration by inhibition of enzymes also spiking perceived potentiation.




^Your only options are GABA agonists and cannabis. With GABA agonists being highly addictive.

Well what about Cimetidine or Grapefruit juice extract? All I want is to be able to take less opioid, less often with the same pain relief... and it sounds like thats what Cimetidine and (I think) grapefruit juice do.
 
Um ok, tagmet isn't a strong inhibitor, but mind saying why I am wrong?
How the fuck do they potentiate oxy, you sir are quite wrong. You obviously don't know what your are talking about because oxycodone is highly.metabolized through cytochrome 450 and tagmet definitely increases the duration of oxy. Your post also contradicts yourself. First you say tagamet and hydroxyzine and tagamet depotentiates oxy, then you say ir potebtiates it and increase duration? Which one is it? Finally, "spiking perceived potentistion" doesn't make sense at all dude. What? First there is no spike in levels I'd you take an inhibitor, and the potentiation is not simply perceived, it is not placebo whatsoever which is why on many medical websites there are interactions that say tagamet and gfj increase the duration Nd effects.


Infrared, disregard what chromaphobe said, tagmet will definitely increase Increase the duration of oxycodone, it is not placebo.
Go with cimitidne, it is more reliable and easier to dose

Chrome, this forum is not about telling people they are wrong, so next time when you want to think only about yourself, remember this isn't your thread
 
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